비타민 C 효과, 기전, 고농도 IV 사용법, 리포좀 탐구!!

[문형철]

고농도 비타민 C 정맥주사

1.2~1.5g/kg

60kg 환자 = 90g/1회. 주 2~3회 시행

Pharmacological Levels (약리학적 고농도: IV 주사 시 혈중 20 mM 이상 도달)

• 주요 역할: 프로옥시던트 (Pro-oxidant) → 선택적 세포 사멸 유발
• 고농도 AA가 산화되면서 H₂O₂ (과산화수소)를 대량 생성합니다.
• Fenton Reaction (펜톤 반응): AA가 Fe³⁺(삼가철)를 Fe²⁺(이가철)로 환원시키고, Fe²⁺ + H₂O₂ → 매우 강력한 hydroxyl radical (•OH) 생성. 이 반응으로 산화 스트레스가 급증합니다.
• 암세포 (Tumoral cell):
  • 암세포는 catalase, glutathione peroxidase 등 H₂O₂를 분해하는 효소가 부족하거나, 철 이온(labile iron pool)이 많습니다.
  • H₂O₂가 미토콘드리아에 축적 → 강한 산화 스트레스 → Cell Death (세포 사멸) 또는 Cell Arrest (세포 주기 정지) 유발.
  • DHA 형태로 GLUT를 통해 들어와 내부에서 AA로 환원되면서 추가 산화 스트레스 증폭.
• 정상 세포 (Leukocyte 등):
  • catalase 등이 풍부해 H₂O₂를 빠르게 분해 → 거의 피해 없음.

https://pmc.ncbi.nlm.nih.gov/articles/PMC6835439/

비타민 C(ascorbic acid, vitC)의 약동학은

매우 복잡하며,

용량 의존적(dose-dependent)이고

비선형(nonlinear)인 특징을 가집니다.

주로 saturable sodium-dependent vitamin C transporters (SVCTs)에 의해 조절되며,

흡수(absorption), 분포(distribution), 대사(metabolism), 배설(elimination)이

서로 다른 구획(compartment)에서 일어납니다.

• 생리적 수준(physiological doses, oral 섭취): 흡수가 포화(saturable)되어 bioavailability가 감소하고, zero-order kinetics (또는 nonlinear kinetics)에 가깝습니다. 건강한 사람의 혈장 농도는 보통 50~80 µM 정도로 포화되며, 200~400 mg/day 정도에서 steady-state에 도달합니다. 조직 내 농도는 혈장보다 훨씬 높습니다 (근육/심장 0.2 mM ~ 뇌/부신 10 mM).
• 약리학적 수준(pharmacological doses, 주로 IV 주사): 장내 흡수 포화를 우회하여 millimolar (mM) 수준의 높은 혈장 농도를 달성할 수 있으며, first-order kinetics로 전환됩니다. 용량에 비례하여 C_max가 증가하고, 배설이 빨라집니다.
• 영향 요인: 유전자 다형성(SVCT polymorphisms), 흡연(산화 증가로 turnover ↑), 질환(패혈증, 당뇨 등에서 turnover 증가), 임신 등으로 비타민 C 항상성(homeostasis)이 크게 달라집니다. 뇌와 부신 같은 중요 기관은 결핍 시 우선 보호됩니다.
• 임상적 함의: 많은 임상 연구에서 이 비선형성과 구획화된 분포를 간과하여 잘못된 결론을 내리는 경우가 많습니다. 고용량 IV 비타민 C는 암이나 패혈증 치료에서 잠재력이 있지만, 약동학 이해가 필수적입니다.

논문은

비타민 C가 단순한 영양소가 아니라,

transporter에 의해 엄격히 조절되는 복잡한 시스템임을 강조하며,

건강 유지와 질환 치료 시 적절한 투여 전략의 중요성을 지적합니다.

비타민 C의 혈장내 반감기 (Plasma half-life)와 세포내 반감기 (Intracellular half-life) 설명

논문에서 가장 명확히 다루는 부분은 혈장내 반감기입니다.

• 혈장내 반감기 (Plasma elimination half-life):
  • 고용량 IV 주사 시 (pharmacological doses): 약 2시간 (constant and dose-independent half-life)으로 일정합니다. IV 주입 종료 후 여러 약동학 연구에서 일관되게 관찰된 값입니다.
  • 이는 고농도(millimolar)에서 신장에서 glomerular filtration이 빠르게 일어나고, SVCT1-mediated reuptake가 거의 없기 때문에 first-order kinetics가 됩니다.
  • 결과적으로, IV로 달성된 높은 혈장 농도는 약 16시간 후에 생리적 수준(physiological levels)으로 돌아옵니다.
  • 저용량(생리적 수준)에서는 nonlinear (zero-order-like) kinetics로 인해 반감기가 더 길고 복잡하며, 신장 재흡수가 효율적으로 일어나 배설이 최소화됩니다. (일부 다른 연구에서는 저농도에서 반감기가 8~40일 정도로 길다고 보고되지만, 이 논문은 주로 고용량 IV 중심으로 설명합니다.)
• 세포내 반감기 (Intracellular half-life):
  • 논문에서 직접적인 세포내 (intracellular, 예: 백혈구, 호중구, 적혈구 등) 비타민 C 반감기 수치는 명시적으로 제시되지 않습니다.

공통 메커니즘 설명

• Asc (환원형 아스코르빈산): 대부분의 세포에서 주로 SVCT를 통해 능동 수송(active transport)으로 들어갑니다.
  • SVCT는 2Na⁺ + Asc를 함께 cotransport (2:1 stoichiometry)하며, Na+ 전기화학적 기울기(Na+ gradient)를 에너지원으로 사용합니다. 이 기울기는 Na+/K+ ATPase (Sodium-Potassium Pump)가 ATP를 써서 Na+를 세포 밖으로, K+를 안으로 펌핑해 유지합니다.
• DHA (Dehydroascorbic acid, 산화형): 플라즈마에서 불안정하며, GLUT (주로 GLUT1, GLUT3 등)을 통해 촉진 확산(facilitated diffusion)으로 세포 내로 들어갑니다. 세포 안에서 효소적으로 빠르게 Asc로 환원(recycling)되어 축적됩니다.
• Recycling 순환: 세포 내에서 Asc가 산화되어 DHA가 되면 다시 GLUT로 나가거나, 내부에서 환원되어 재사용됩니다. (오른쪽 위 Recycling 화살표)
• Passive diffusion?: Asc가 세포 밖으로 나가는 경로는 아직 완전히 밝혀지지 않았으나, passive diffusion이나 volume-sensitive anion channel 등을 통해 일부 일어날 수 있습니다.
• 농도 기울기(gradient): 플라즈마(혈장) ≈ 50~80 μM인데 비해, 세포 내는 0.5~10 mM (때로는 2~10 mM in brain/adrenal)로 수십~수백 배 높게 유지됩니다. 이는 SVCT의 active transport 덕분입니다.

패널별 차이점 (a, b, c)

• a: SVCT (아마 SVCT1 또는 일반 SVCT) Typical gradient 40 : 1 주로 상피세포(epithelial tissues), 장(intestine), 신장(kidney) 등에서 whole-body homeostasis(전신 항상성)를 담당하는 transporter. 상대적으로 낮은 gradient (40배). Intestinal absorption과 renal reabsorption에 중요합니다.
• b: SVCT2 Typical gradient 500 : 1 대부분의 조직(metabolically active tissues), 특히 뇌(brain), 부신(adrenal), 심장, 근육 등에서 강력하게 발현됩니다. 고친화성(high affinity)으로 세포 내 고농도 축적을 담당. 뇌에서는 CSF(뇌척수액)와 뇌세포 간 vitamin C 공급에 핵심적입니다. Gradient가 가장 가파릅니다 (최대 100배 이상 보고됨).
• c: SVCT1/2 (둘 다 또는 혼합) Typical gradient 5 : 1 일부 조직이나 특정 조건에서 SVCT1과 SVCT2가 함께 작용하는 경우를 나타냅니다. Gradient가 가장 낮아, 덜 집중적인 축적이 일어나는 상황(예: 일부 상피세포나 덜 활성 조직)을 의미할 수 있습니다.

왜 gradient가 조직마다 다른가?

• SVCT1: 주로 상피세포(장, 신장) → whole-body vitamin C pool 유지 (흡수·재흡수).
• SVCT2: 거의 모든 세포, 특히 산화 스트레스에 취약한 metabolically active cells (neuron, microglia 등) → 조직 보호와 고농도 유지.
• 실제 농도: Plasma 50–80 μM vs. 대부분 세포 0.5–4 mM, brain/adrenal 최대 10 mM. Gradient는 10~100배 이상이며, 패널의 40:1, 500:1, 5:1은 대표적인 예시 값입니다.

세포 내 반감기/Retention과의 연관 (이전 질문과 연결) 이 메커니즘 때문에 세포 내(intracellular/tissue) vitamin C는 혈장(plasma)보다 훨씬 느리게 소모됩니다.

• DHA는 plasma에서 half-life가 몇 분밖에 안 되지만, 세포 내로 들어가 Asc로 환원되면 효율적으로 recycling되어 retention이 강합니다.
• SVCT2가 강한 조직(뇌 등)은 deficiency 시에도 vitamin C를 오래 유지합니다.
• 직접적인 intracellular half-life 숫자는 plasma(고용량 IV 시 ≈2시간)만큼 명확하지 않지만, tissue depletion이 plasma보다 느리다는 것이 consensus입니다.

이 도식은 vitamin C가 단순한 항산화제가 아니라, 능동 수송 + recycling을 통해 세포 내 고농도를 유지하는 복잡한 시스템

이 이미지는 비타민 C (L-Ascorbic acid, Asc)의 산화·환원(redox) 경로와 분해(degradation) 메커니즘을 화학 구조식으로 자세히 보여줍니다. 이전에 공유한 수송 메커니즘 도식(SVCT/GLUT)과 연결지어 설명하겠습니다.
1. 상단 부분: Ascorbate의 산화 단계 (Redox Cycling)

• L-Ascorbic acid (환원형 Asc) → L-Ascorbate anion (pH 7.4에서 주로 존재하는 형태, -H⁺ 해리)
• 한 전자 산화 (one-electron oxidation): Ascorbate anion → L-Ascorbyl radical (또는 Ascorbate free radical, 중간체)
  • 이 라디칼은 비교적 안정적이며, 항산화 작용의 핵심입니다 (전자 하나를 주며 ROS를 중화).
• 두 전자 산화 (two-electron oxidation): Ascorbyl radical → Dehydro-L-ascorbic acid (DHA, 산화형)

중요 포인트: Asc와 DHA 사이의 recycling이 세포 내에서 효율적으로 일어납니다. DHA는 GLUT 수송체로 세포 내로 들어간 후, glutathione이나 NADPH-dependent 효소에 의해 빠르게 Asc로 환원됩니다. 이 과정이 세포 내 고농도 유지(gradient 40~500:1)의 핵심입니다.
2. 하단 부분: DHA의 비가역적 분해 경로 (Irreversible Degradation) DHA는 불안정하여 가수분해(hydrolysis)나 추가 산화를 거칩니다:

• Dehydro-L-ascorbic acid (DHA) → Bis-Dehydro-L-ascorbic acid (dimer, 이합체) 또는 Bicyclic hemiketal 형태 (실제 안정된 구조)
• + H₂O → L-2,3-Diketogulonic acid (DKG)
• DKG → L-Xylonic acid 또는 L-Lyxonic acid (탈탄산 CO₂ 방출)

이 경로는 비가역적으로, 한 번 분해되면 비타민 C로서의 기능이 영구적으로 소실됩니다.

• DHA 자체는 생리적 pH에서 half-life가 몇 분 (2~15분 정도)으로 매우 짧습니다.
• 건강한 사람 혈장에서 DHA 농도는 극히 낮으며 (1~2 μM 이하), 대부분 세포 내에서 즉시 환원됩니다.

이 화학 경로가 반감기(half-life)와 어떻게 연결되는가? (혈장 vs 세포내) 혈장 (Plasma) 반감기:

• 고용량 IV (pharmacological dose, millimolar 농도): Ascorbate 자체의 elimination half-life ≈ 2시간 (first-order kinetics). DHA가 빠르게 생성되지만, renal clearance(신장 배설)가 빠르고, recycling이 포화되면 body pool이 급속히 감소합니다.
• 저용량/생리적 범위 (oral, physiological): Nonlinear pharmacokinetics로 인해 body pool half-life 10~20일 (또는 8~40일). Renal reabsorption(SVCT1)이 거의 99%까지 재흡수해 소실을 늦춥니다.

세포내 (Intracellular / Tissue) 반감기·Retention:

• 직접적인 intracellular half-life 숫자는 plasma만큼 명확하지 않음 (SVCT2에 의한 active accumulation + recycling 때문).
• 세포 내 Asc 농도는 plasma(50~80 μM) 대비 10~100배 이상 (대부분 0.5~5 mM, 뇌/부신 최대 10 mM). Gradient가 가파를수록 (SVCT2 강한 조직에서 500:1까지) depletion이 느립니다.
• DHA가 세포 내로 들어가 즉시 Asc로 환원되므로, 세포 내에서는 recycling 효율이 높아 retention(보유)이 강합니다. Leukocyte(백혈구)나 tissue level은 plasma보다 depletion이 느립니다.
• Efflux(세포 밖 배출) 경로는 아직 완전히 밝혀지지 않았으나 (passive diffusion? 또는 anion channel), hydrophilic + 음전하 때문에 세포 밖으로 잘 나오지 않습니다.

요약 표 (최신 리뷰 기반, Lykkesfeldt 2025 등)




이 두 이미지를 합치면: 혈장에서는 빠른 배설(2시간)이 지배적이지만, 세포 내에서는 SVCT2 + recycling으로 고농도를 오래 유지합니다. DHA가 분해되지 않고 환원되는 한, 세포 내 vitamin C는 plasma보다 안정적입니다.

이 이미지는 비타민 C의 신장(renal) 처리 과정을 도식화한 것으로, 혈장(plasma)에서의 농도와 사구체 여과(glomerular filtration) 후 신장 상피세포(renal epithelium)에서의 재흡수(reabsorption) 및 배설(excretion) 메커니즘을 보여줍니다.
이미지 주요 내용 해석

• Plasma (혈장): 정상 생리적 농도 50~70 μM (Asc 형태가 주).
• Glomerular filtration: 혈장에서 비타민 C가 사구체를 통해 여과되어 원뇨(pre-urine)로 들어갑니다. (물 재흡수, pH 변화, vitamin C upconcentration 과정이 일어남 → 원뇨에서 vitamin C가 농축될 수 있음).
• Renal epithelium (신장 근위세뇨관 상피):
  • SVCT1 (파란색 원): Apical membrane (원뇨 쪽)에 위치. Asc (환원형)를 Na⁺ 의존적 능동 수송으로 세포 내로 재흡수. 저농도/결핍 시 거의 99% 이상 재흡수되어 body pool 유지에 핵심적.
  • GLUT2 (노란색 원): Basolateral membrane (혈액 쪽) 또는 apical에서 DHA (산화형)를 수송. DHA ↔ ASC 간 상호전환.
  • ? (파란색 원): Asc가 세포에서 혈장으로 나가는 경로 (basolateral efflux). 아직 명확히 규명되지 않은 diffusion? 또는 anion channel 등으로 추정.
  • DHA ↔ ASC: 신장 세포 내에서 산화-환원 recycling.
• Excretion (배설): 포화 상태(혈장 농도 높을 때)에는 재흡수가 포화되어 잉여분이 소변으로 배설됨.
• Diffusion?: 세포 간 또는 세포-혈장 간 passive diffusion 가능성 표시 (아직 완전 규명되지 않음).

이 도식의 핵심: 신장은 비타민 C 항상성(homeostasis) 유지에 매우 중요합니다. SVCT1이 renal reabsorption을 담당해 저용량 시 손실을 최소화하지만, 고용량 시 renal threshold 초과로 배설이 증가합니다.
혈장 vs 세포내 반감기와의 연관 (신장 역할 포함, 최신 논문 기반) 이전 이미지들(SVCT/GLUT 수송, redox cycling)과 연결하면:

• 혈장 (Plasma) 반감기:
  • 고용량 IV (pharmacological dose, millimolar 농도): 약 2시간 (first-order kinetics). Volume of distribution ≈ 0.2 L/kg. 신장 clearance가 빠르게 작용해 plasma 농도가 급속히 떨어짐.
  • 저용량/생리적 범위 (physiological, oral): Nonlinear pharmacokinetics. Renal reabsorption (SVCT1)이 99% 이상 재흡수해 body pool half-life 10~20일 (또는 8~40일). Plasma 50~80 μM saturation 시 재흡수 threshold 초과로 배설 증가.
• DHA (산화형) in plasma: 몇 분 (few minutes) 정도로 매우 불안정. 건강인에서는 plasma DHA 농도가 극히 낮음 (1~2 μM 이하 또는 전체의 <10%).
• 세포내 (Intracellular / Tissue) 반감기·Retention:
  • 직접적인 “intracellular half-life” 숫자는 plasma만큼 표준화되지 않음.
  • SVCT2 (조직 세포) + DHA recycling (세포 내 효소적 환원)으로 인해 plasma보다 depletion이 훨씬 느림. Leukocyte/tissue vitamin C는 body store proxy로 사용되며, plasma가 먼저 떨어지지만 세포내는 오래 유지.
  • 신장 상피세포도 SVCT1로 고효율 재흡수 → 전체 body retention 강화.
  • 조직별 gradient (plasma 대비): SVCT2 강한 곳 (뇌, 부신 등)에서 100~500배 이상 높게 유지.

요약 표 (2025년 최신 consensus, Lykkesfeldt 등)




신장 역할 강조: SVCT1 knockout 동물 실험에서 renal reabsorption 상실 시 vitamin C urinary loss가 크게 증가해 mortality 상승. 이는 저용량 시 긴 half-life의 핵심 이유입니다. 고용량 IV 시에는 renal clearance가 dominant해 2시간 half-life가 관찰됨.
이 세 이미지(SVCT gradient, redox cycling, renal handling)를 종합하면:

• 혈장: 빠른 turnover (2시간 at high dose) + renal control.
• 세포내: active accumulation + efficient recycling으로 장기 retention

1. 중증 감염·중환자 관련 연구 (가장 많은 비중)

• Sepsis / Septic Shock (패혈증/패혈성 쇼크) — 가장 집중된 영역
  • NCT03509350: Vitamin C + Thiamine + Steroids 병용 (Phase 3)
  • NCT03389555: Ascorbic Acid + Hydrocortisone + Thiamine (HAT protocol, Phase 2/3)
  • NCT03338569: Vitamin C 단독 vs Placebo (Septic Shock, Phase 2/3) → 배경: 패혈증에서 산화 스트레스와 염증이 심각. 고농도 IVC가 H₂O₂ 생성(프로옥시던트)과 NF-κB 억제를 통해 organ failure 감소 기대. 그러나 결과는 mixed (일부 연구에서 vasopressor-free days 증가 또는 mortality 감소, 다른 연구에서는 유의미한 효과 없음).
• COVID-19
  • NCT04328961: Hydroxychloroquine + Ascorbic Acid (Phase 2/3) — 초기 COVID-19 PEP(노출 후 예방) 연구.

2. 만성질환·기타 만성 상태 관련 연구

• 만성 간염 (Chronic Hepatitis) NCT01413360: Phase 4 Study of High Dose Vitamin C in Chronic Hepatitis Patients (Chronic Hepatitis C, Alcoholic Hepatitis). → 고용량 비타민 C가 간 효소(ALT/AST) 개선, 염증 감소 목적. 만성 간염에서 산화 스트레스 완화 기대.
• 심장 수술 관련 (Cardiac Surgery)
  • NCT01167569: Double-Blind, Randomized Study of High Dose Vitamin C on Outcome in Cardiac Surgery Patients (Reperfusion Injury, Phase 4). → 심장 수술 후 재관류 손상(reperfusion injury)에서 고용량 IVC가 산화 스트레스 감소 기대.
  • NCT01107730: Vitamin C ± L-Carnitine for postoperative Atrial Fibrillation 예방 (Phase 3).
  • NCT00953212: Oral Ascorbic Acid + Beta blockers 등 병용으로 수술 후 심방세동 예방.
• 기타 만성/기타 질환
  • NCT02209636: Chronic Kidney Disease (CKD) + Cardiovascular Disease — Ascorbic Acid 병용으로 혈관 기능 개선.
  • NCT00135707: Preeclampsia (자간전증) 예방 — Vitamin C + E 병용.
  • NCT01723696: 임신 중 흡연 영향 감소 (영아 폐 기능).
  • Colonoscopy bowel prep, Iron absorption, Common Cold 등 보조적 사용 연구도 포함.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4961983/

심장 수술(주로 관상동맥우회술 등) 후 흔히 발생하는 합병증인
심방세동을 비타민 C가 예방할 수 있는지를 확인하기 위해,
기존의 무작위 대조군 연구(RCT)들을 종합 분석했습니다.

주요 결론

• 비타민 C를 예방적으로 투여한 환자군에서 수술 후 심방세동 발생률이 유의하게 감소했습니다.
• 비타민 C는 안전하며, 심장 수술 환자 모두에게 예방 목적으로 고려할 수 있는 옵션으로 제안됩니다.

상세 요약

• 배경: 심장 수술 후 심방세동은 가장 흔한 합병증으로, 입원 기간 연장, 뇌졸중 위험 증가, 비용 상승 등을 초래합니다. 비타민 C는 항산화 작용으로 산화 스트레스와 염증을 줄여 심방세동을 예방할 수 있다는 가설이 있었습니다.
• 방법: 여러 RCT를 포함한 메타분석.
• 결과: 비타민 C 투여군에서 대조군 대비 POAF 발생이 통계적으로 유의하게 낮음.
• 안전성: 특별한 부작용 보고는 없었으며, 안전한 것으로 평가됨.

이 연구는 비타민 C가 저렴하고 안전한 예방 전략이 될 수 있음을 시사하며, 이후 여러 메타분석에서도 비슷한 긍정적 결과가 보고되었습니다

https://www.mdpi.com/2072-6643/12/12/3760

이 논문은
비타민 C가
호흡기 감염, 패혈증, COVID-19에서 보조 요법으로서의 가능성을 검토한 리뷰.

특히
감염 시 혈장(plasma) 비타민 C 농도가 급격히 감소한다는 점을 강조하며,
여러 임상 연구 데이터를 Table 1에 정리.

혈장 내 비타민 C 농도 하락 수치 (주요 데이터)

• 정상(건강인) 혈장 비타민 C 농도: 대개 48~76 µmol/L 정도 (포화 수준은 60~80 µmol/L).
• 감염 시 하락 특징: 감염·스트레스 시 대사 소모가 급증하여 혈장 비타민 C가 빠르게 감소.
  • Hypovitaminosis C (비타민 C 부족): <23 µmol/L
  • 명확한 deficiency (괴혈병 수준): ≤11 µmol/L

구체적인 수치 (폐렴·급성 호흡기 감염 중심)

• 지역사회 획득 폐렴 (n=50): 평균 23 ± 3 µmol/L → 62%가 <23 µmol/L (hypovitaminosis C), 22%가 ≤11 µmol/L.
• 엽상 폐렴 (lobular pneumonia):
  • 건강 대조군: 49 ± 1 µmol/L
  • 급성 비생존자: 17 ± 1 µmol/L
  • 급성 생존자: 24 ± 1 µmol/L
• 고령자 급성 호흡기 감염 입원 환자 (Hunt et al., 1994): 35%가 ≤11 µmol/L.
• ICU 폐렴 환자: 평균 11 µmol/L.

패혈증·중증 감염 (발열·전신 증상 동반 시 더 심함)

• 패혈증: 대부분 <23 µmol/L, 40%가 ≤11 µmol/L.
• 중증 패혈증/패혈성 쇼크: 평균 14~18 µmol/L, 일부 연구에서 11 µmol/L (IQR 8–22).
• 중증 COVID-19 ICU 환자: 평균 22 µmol/L (생존자 29 vs. 비생존자 15 µmol/L). → 45~50%가 ≤11 µmol/L, 70~90%가 <23 µmol/L. 일부 ARDS 환자에서는 17/18명이 <9 µmol/L.

하락 정도 요약:

• 건강인 (≈50~60 µmol/L) → 급성 호흡기 감염/폐렴 시 23 µmol/L 이하로 떨어지는 경우가 흔함 (약 50% 이상 감소).
• 발열·전신 증상(전신통증 등)이 동반된 중증 감염에서는 11 µmol/L 이하까지 급락하는 비율이 22~50%에 달합니다.
• 일반 감기(common cold)에 대한 직접적인 plasma 수치 데이터는 이 논문에 없으나, 다른 연구에서 감기 시 plasma·백혈구·소변 내 비타민 C가 일시적으로 감소한다고 언급됩니다.

그래프 해석

• Placebo 군 (실선): 사망 확률이 급격히 증가 → 15일경 약 43%, 20일경 50%, 25일 이후 약 59~60%까지 상승 (30일 시점에서 생존율 약 40%)
• HDIVC 군 (점선): 사망 확률이 훨씬 완만하게 증가 → 15일경 약 4~5%, 20일경 8%, 25일 이후 약 13~15% 수준 (30일 시점에서 생존율 약 85%)
• 위험군 수 (No. at Risk): HDIVC군은 대부분 환자가 28일까지 생존 (18명 생존) Placebo군은 지속적으로 사망자가 발생해 11명만 남음

결과: HDIVC군에서 28~30일 사망률이 Placebo군에 비해 약 4배 이상 낮은 경향을 보였으며, Wilcoxon 검정에서 P=0.05로 통계적으로 경계선상 유의한 차이가 나타났습니다.

이 그래프의 배경 (관련 연구) 이 그래프는 중증 COVID-19 ICU 환자를 대상으로 한 pilot 연구 (Zhang et al., 2021, Critical Care)에서 나온 Kaplan-Meier 생존 곡선입니다.

• HDIVC군: 12g 비타민 C를 12시간마다 (하루 24g) 7일간 정맥 주사
• 주요 결과: 전체 28일 사망률 차이는 유의하지 않았으나 (P=0.27),
  중증 환자(SOFA score ≥3) 하위군에서는 HDIVC군의 생존율이 유의하게 높았습니다.

논문의 결론 및 임상적 의미

• 감염(특히 호흡기 감염·패혈증) 시
  비타민 C가 빠르게 고갈되므로,
  일반적인 권장 섭취량(0.1 g/day)으로는 정상 혈장 농도(60~80 µmol/L)를 유지하기 어렵습니다.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11465154/

연구 목적

고소득 국가(호주 High-income countries)에서 입원한
성인 환자들의 비타민 C 결핍(Vitamin C Deficiency, VCD) 유병률,
위험인자, 임상 결과에 대한 기존 문헌을 광범위하게 매핑(mapping)한
스코핑 리뷰(Scoping Review)입니다.

고소득 국가에서는
비타민 C 결핍이 드물다고 가정하고
검사 자체가 거의 이루어지지 않는데,
실제 상황을 파악하기 위해 수행.

주요 결과

1. 유병률 (Preval‎ence)
   • 입원 성인 환자에서 비타민 C 결핍 유병률은 연구마다 4.2% ~ 50.8%까지 매우 넓은 범위를 보였습니다.
   • 여러 연구를 종합하면 상당수의 입원 환자(특히 급성기 환자)에서 결핍 또는 저농도가 관찰되었습니다.
   • 결핍 정의: 대개 plasma vitamin C <11.4 μmol/L (또는 <23 μmol/L hypovitaminosis C)로 규정.
     일부 연구에서는 undetectable 수준까지 떨어지는 경우도 있음.
2. 위험인자 (Risk Factors)
   • 영양불량(Malnutrition) 또는 Protein-Energy Malnutrition (PEM)
   • 남성 (여성보다 높은 위험)
   • 소화기 질환 (digestive disease)
   • 수술을 받은 환자 (surgical procedure)
   • ICU 입실 환자
   • 고령, 과도한 음주, 흡연, 은퇴자 등 생활습관 요인도 일부 연구에서 확인
3. 임상 결과 (Clinical Outcomes)
   • 비타민 C 결핍은 중증 쇠약(frailty), 인지 장애(cognitive impairment)와 연관
   • 일부 연구에서 괴혈병(scurvy) 증상(피로, 잇몸 출혈 등) 관찰
   • 입원 기간, 사망률, ICU 재원 기간 등 직접적인 임상 결과와의 연관성은 연구마다 일관되지 않음 (추가 연구 필요)

논문의 결론 및 시사점

• 고소득 국가의 입원 성인 환자에서도 비타민 C 결핍이 드물지 않다
  (예: 한 후속 관찰연구에서는 약 22.9%에서 결핍 확인).
• 특히 영양불량, ICU, 수술 환자에서 유병률이 높습니다.
• 병원에서 비타민 C 상태를 적극적으로 평가하고, 조기 발견·보충이 필요하다고 강조

https://pmc.ncbi.nlm.nih.gov/articles/PMC12799429/

Vitamin C status across the spectrum of chronic kidney disease and healthy controls: a cross-sectional study - PMC

연구 목적

만성신장질환(CKD) 환자와 건강 대조군에서
혈장 비타민 C (plasma VitC) 상태를 비교하고,
CKD 스펙트럼(건강인 → 신장이식 기증자 → 신장이식 수혜자 → 투석 환자 → CKD 4/5기) 전반에 걸쳐
비타민 C 부적절(inadequate) 및 결핍(deficiency)의 유병률과 결정인자를 조사한
단면 연구(cross-sectional study)입니다.

연구 방법

• 총 참가자: CKD 군 145명 (투석 62명, CKD stage 4/5 41명, 신장이식 수혜자(KTR) 42명) + 건강 군 832명 (신장 기증자 447명, 건강 대조군 385명)
• 혈장 비타민 C 농도 측정
• 결핍/부적절 정의:
  • Deficient: <10 μmol/L
  • Inadequate: 10~35 μmol/L
  • Adequate: >35 μmol/L (대략)

주요 결과 (혈장 비타민 C 농도)

• 건강인에서는 정상 oral 섭취 후 plateau 수준(50~70 μM)에 가까운 분포를 보임.
• CKD가 진행될수록 혈장 비타민 C 농도가 명확히 감소하며, 부적절/결핍 비율이 급격히 증가.

결정인자 (Risk Factors)

• 부적절한 식이 섭취 (inadequate dietary intake)
• 투석에 의한 비타민 C 제거 (dialysis removal) — 투석 시 비타민 C가 상당량 소실됨
• 신장 기능 저하 자체 (eGFR 감소와 VitC 농도 음의 상관관계)
• 기타: 염증, 산화 스트레스 증가 등 CKD 특유 요인

결론 및 시사점

• 비타민 C 부적절 및 결핍은 CKD 환자에서 매우 흔하다. 특히 진행된 CKD (stage 4/5)와 투석 환자에서 가장 심각함.
• 건강인에서도 신장 기능이 약간 저하되면 VitC 수준이 낮아지는 경향이 관찰됨.
• 식이 섭취 부족 + 투석으로 인한 손실이 주요 원인으로 지목됨.
• 따라서 CKD 환자(특히 투석 환자)에서는 비타민 C 보충(supplementation)을 적극적으로 고려해야 하며, 정기적인 혈장 VitC 모니터링이 필요하다고 강조

https://pmc.ncbi.nlm.nih.gov/articles/PMC10949735/

Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports - PMC

연구 목적

비타민 C 결핍(괴혈병 수준)이
폐동맥 고혈압(Pulmonary Hypertension, PH)을 유발할 수 있는지를 확인하기 위해,
기존에 보고된 사례 보고(case reports)들을
체계적으로 검토한 체계적 고찰(Systematic Review)입니다.

초기 문헌에서
비타민 C 결핍이 심부전과 관련 있다는 기록이 있었으나,
폐동맥 고혈압과의 연관성은 잘 알려지지 않아 이를 명확히 하고자 했습니다.

연구 방법

• PubMed, Scopus 등 데이터베이스에서 비타민 C 결핍 + 폐동맥 고혈압 관련 사례 보고를 검색.
• 비타민 C 결핍 진단이 명확하고, 폐동맥 고혈압 관련 증상/검사 소견이 있는 사례만 포함.
• 비타민 C 보충 전후의 임상 경과를 중점적으로 분석.

주요 결과

• 총 여러 건의 사례에서 비타민 C 결핍 상태에서 폐동맥 고혈압이 발생한 것이 확인됨.
• 비타민 C 결핍 기간 동안 폐혈관 저항(PVR)이 중앙값 9배 증가한 것으로 보고됨 (N=5 사례에서 측정).
• 비타민 C를 보충(supplementation)하자 폐동맥 고혈압 증상이 빠르게 호전되거나 정상화된 경우가 다수 관찰됨.
• 이는 비타민 C 결핍이 폐혈관 수축, 산화 스트레스 증가, 혈관 내피 기능 저하 등을 통해 폐동맥 고혈압을 일으킬 수 있음을 시사합니다.

결론 및 시사점

• 비타민 C 결핍은 폐동맥 고혈압의 가역적(reversible) 원인 중 하나일 수 있다.
• 특히 영양불량, 흡연, 알코올 남용, 소화불량, 투석 환자 등 고위험군에서 비타민 C 상태를 확인하고 조기 보충하는 것이 중요하다.
• 괴혈병(scurvy)의 드문 합병증으로 폐동맥 고혈압을 인지해야 하며, 비타민 C 투여로 빠른 개선이 가능하다는 점을 강조

뇌사 판정 후 장기 기증자(brain-dead organ donors)에서
혈청 비타민 A, E-α와 혈장 비타민 C의 순환 농도를 측정하고,
이 농도가 기증자 특성(인구학적 요인), 관리 과정, 장기 이용률,
그리고 수혜자 결과와 어떤 연관이 있는지 조사했습니다.

주요 방법

• 뇌사 판정 후 장기 적출 직전에 혈액 검체를 채취하여 비타민 농도 측정.
• 정상 범위 이하(below normal)와 결핍(deficient) 기준을 적용하여 분석.
• 기증자 특성, 사망 원인, 흡연 여부, 뇌사 후 관리 시간, 혈압약(vasopressor) 사용 기간, 장기 회수 여부 등을 비교.

주요 결과

• 비타민 C:
  • 92%에서 정상 범위 이하 (below normal)
  • 63%에서 결핍 (deficient) 수준
  • 비타민 C 결핍은 뇌사 판정 후 검체 채취까지 시간이 길수록 더 심했다 (P = 0.004)
  • 흡연자는 비타민 C 결핍이 더 흔했다 (P = 0.03)
• 비타민 A:
  • 80%에서 정상 범위 이하
  • 40%에서 결핍
  • 두부 외상이나 뇌졸중으로 사망한 경우, 무산소성(anoxic) 사망보다 비타민 A 수치가 더 낮았다 (P = 0.003)
• 비타민 E-α:
  • 85%에서 정상 범위 이하
  • 62%에서 결핍
• 기증자 관리 및 장기 이용과의 연관:
  • 비타민 C 결핍 시 혈압 유지 약물(vasopressor) 사용 기간이 더 길었다 (P = 0.03)
  • 비타민 E-α 정상인 경우 ALT(간 효소)가 더 낮게 유지됨
  • 비타민 E-α 결핍 시 간(liver) 회수율이 유의하게 낮았다 (P = 0.005)
• 수혜자(recipient) 결과(예: 이식 후 기능)와는 유의한 연관성이 관찰되지 않음.

결론 및 시사점

뇌사 판정 후 장기 기증자에서
비타민 A, C, E-α 수준이 매우 낮은 상태가 매우 흔합니다.

특히
비타민 C는 92%가 정상 이하, 63%가 결핍 수준으로,
뇌사 후 산화 스트레스 증가, 염증, 대사 변화 등으로 인해 급속히 소모

https://pmc.ncbi.nlm.nih.gov/articles/PMC6136002/

Intravenous vitamin C in the treatment of allergies: an interim subgroup analysis of a long-term observational study - PMC

연구 목적 및 디자인

알레르기 질환(호흡기 또는 피부 알레르기) 환자에서
고용량 정맥내 비타민 C (IV vitamin C, 7.5 g)를 보조 요법으로 사용했을 때,
알레르기 특이 증상과 비특이 전신 증상(피로, 수면장애, 우울, 집중력 저하)의 개선 효과를 평가한
다기관 전향적 관찰 연구의 중간 분석(interim subgroup analysis)입니다.

연구 방법

• 대상: 71명 (평균 연령 43.1세)의 확인된 알레르기 환자
  • 호흡기 알레르기 56.3%, 피부 알레르기 43.7%
  • 급성(<4주) 또는 만성(재발성 >4주)
• 투여: Pascorbin® 7.5 g IV, 주 2~3회
  • 급성: 평균 7회 (3.2주)
  • 만성: 평균 26회 (11.9주)
• 평가: 4점 Likert 척도(0=없음 ~ 3=심함)로 증상 점수화
  • 특이 증상 합계 (최대 9점)
  • 비특이 증상 합계 (최대 12점)
  • 통증: 0~10 NRS 척도
• 비타민 C 측정: 21명(30%)에서 치료 전 혈청 ascorbate 농도 측정 (HPLC법)
  • 임상적 결핍: <0.2 mg/dL
  • 잠재적(subclinical) 결핍: <0.5 mg/dL

주요 결과

1. 증상 개선 (모두 p<0.0001, 매우 유의함)
   • 알레르기 특이 증상 합계: 5.91점 → 1.20점 (평균 -4.71점 감소) → 95.1%의 증상이 개선
   • 비특이 증상 합계 (피로·수면장애·우울·집중력 저하): 5.93점 → 1.09점 (평균 -4.84점 감소) → 92.9%의 환자에서 개선
   • 통증 점수: 3.8 → 0.7로 크게 감소
   • 예시: 가려움증 93.5% 개선, 비염 96.2% 개선, 피로 93.5% 개선
2. 치료 전 혈청 비타민 C 농도 (n=21)
   • 평균: 0.34 ± 0.28 mg/dL (중앙값 0.2 mg/dL)
   • 71.4%가 잠재적 결핍 (<0.5 mg/dL)
   • 약 15.4%가 임상적 결핍 (<0.2 mg/dL)
   • 만성 알레르기와 피부 알레르기에서 더 낮은 경향
3. 안전성: 98.6%가 매우 잘 견뎌냄. 단 1명(1.4%)에서 가벼운 부작용(추위 느낌, 피로)이 있었으나 치료 지속 가능.

하위군 분석

• 급성 vs 만성, 호흡기 vs 피부 알레르기 모두에서 특이·비특이 증상이 유의하게 개선됨 (p<0.0001).

결론 및 한계

• 고용량 IV 비타민 C는 알레르기 관련 증상과 전신 증상을 유의하게 개선시켰습니다.
• 알레르기 환자에서도 비타민 C 결핍(특히 subclinical)이 흔하다는 증거를 제시

https://pmc.ncbi.nlm.nih.gov/articles/PMC12525073/

The Role of Vitamin C in Selected Autoimmune and Immune-Mediated Diseases: Exploring Potential Therapeutic Benefits - PMC

연구 목적

자가면역질환과 면역매개 질환에서
비타민 C(Vitamin C, VitC)의 역할과 잠재적 치료 효과를 종합적으로 검토한 리뷰.

자가면역질환의 만성 염증과 산화 스트레스에서
VitC가 어떻게 면역 조절, 항산화, 사이토카인 조절 등으로 작용할 수 있는지 탐색.

주요 내용 구성 리뷰는 다음 세 부분으로 나누어 다룹니다:

(A) 자가면역질환 (Autoimmune diseases)

• 다발성경화증 (Multiple Sclerosis)
• 류마티스 관절염 (Rheumatoid Arthritis)
• 쇼그렌 증후군 (Sjögren’s disease)
• 제1형 당뇨병 (Type 1 Diabetes)
• 하시모토 갑상선염 (Hashimoto’s thyroiditis)
• 악성빈혈 (Pernicious anaemia)
• 항인지질 증후군 (Antiphospholipid syndrome)

(B) 기타 면역매개 질환 (Immune-mediated diseases)

• 크론병 (Crohn’s disease)
• 치주염 (Periodontitis)

(C) 자가면역 특징을 가진 신경퇴행성 질환

• 알츠하이머병 (Alzheimer’s disease)

비타민 C의 주요 작용 기전 (리뷰에서 강조하는 점)

• 항산화 효과: 산화 스트레스 감소, 자유라디칼 제거
• 면역 조절: 선천성 및 적응성 면역 반응 조절 (면역세포 기능 향상)
• 사이토카인 조절: 염증성 사이토카인(예: IL-6, TNF-α 등) 생산 및 활성 억제
• 콜라겐 합성 지원: 조직 손상 회복에 도움
• 히스타민 및 염증 매개체 감소 (알레르기·염증 관련 이전 논문과 연결)

잠재적 치료 효과

• VitC 보충은 항산화 수준 향상, 염증 매개체 조절, 일부 질환에서 임상 증상 개선과 연관이 있다고 보고됩니다.
• 특히 산화 스트레스와 만성 염증이 핵심 병태생리인 자가면역질환에서 보조 요법(adjunctive therapy)으로 유용할 가능성을 제시

https://www.scirp.org/journal/paperinformation?paperid=24972

연구 목적

류마티스 관절염(RA) 환자에서
고용량 정맥내 비타민 C (IV Ascorbic Acid, IVC) 투여가 염증 수준에 미치는 영향을 조사한
후향적 파일럿 연구입니다.

RA의 병태생리에서
산화 스트레스(ROS)와 NF-κB 활성화가 중요하다는 점에 착안하여,
비타민 C의 항산화·항염증 효과를 확인하고자 했습니다.

연구 방법

• 대상: 11명 (모두 여성, 연령 45~69세)의 RA 환자
• 평가 지표: 치료 전후 C-reactive protein (CRP) 수준 (염증 마커)
  • 정상 상한: 1.9 mg/L
• 투여: IV 비타민 C 7.5 g ~ 50 g (대부분 15 g 또는 25 g), slow drip 방식
  • 치료 횟수와 기간은 환자별로 다양 (예: 4회~20회)
• 추가 보충제(비타민 B6, EPA 등)를 일부 환자에서 병용

주요 결과

• CRP 변화:
  • 치료 전 평균 CRP: 9.4 ± 4.6 mg/L
  • 치료 후 평균 CRP: 6.4 ± 4.6 mg/L
  • 전체 평균 44% 감소 (11명 중 9명에서 감소 관찰)
• 대표 사례:
  • 한 환자: 15 g IVC를 20회 투여 후 CRP 12.6 mg/L → 1.4 mg/L (거의 정상화)
  • 다른 환자: 4회 투여 후에도 CRP 지속적 감소
• 체중 변화는 거의 없었으며, CRP 감소와 체중 변화 간 상관관계는 없음.
• 혈장 비타민 C 농도 직접 측정은 이루어지지 않았습니다.
• 환자들이 주관적으로 호소한 관절 통증도 치료 후 개선 경향을 보였으나, 정량적 점수는 보고되지 않음.

결론 및 시사점 고용량 IV 비타민 C 투여는 RA 환자의 염증 지표(CRP)를 유의하게 감소시켰습니다. 가능한 기전으로는:

• ROS(활성산소) 제거
• NF-κB 억제
• 전염증성 사이토카인(IL-1, IL-6, TNF-α) 생산 감소

https://pmc.ncbi.nlm.nih.gov/articles/PMC11255149/

The Use of High-Dose Intravenous l-Ascorbate in Pain Therapy: Current Evidence from the Literature - PMC

연구 목적

통증(pain) 치료에서 
고용량 정맥내 l-ascorbate (IV vitamin C)의 효과와 안전성을 기존 문헌을 바탕으로 비판적으로 검토하고,
임상 가이드라인을 위한 근거를 마련하는 문헌 고찰(critical literature review)입니다.

산화 스트레스(oxidative stress)와 조직 손상이 많은
통증 상태의 근본 원인을 타겟으로 한 항산화 치료로서의 역할을 중점적으로
평가했습니다.

연구 방법

• PubMed에서 “pain” AND “ascorbic acid” 검색 (1980~2023년, Clinical Trial, Meta-Analysis, RCT 등 필터 적용)
• 총 80건 중 24건의 적합한 논문 선별 (메타분석, RCT, 전향적 연구, 관찰 연구 포함)
• 증거 수준과 연구 질을 체계적으로 평가

주요 결과 고용량 IV 비타민 C가 다음 통증 상태에서 긍정적인 효과를 보인 것으로 평가되었습니다:

• 복합부위통증증후군 (CRPS) 예방: 수술 후 ≥500 mg/day oral 6주 투여 시 CRPS 발생률 유의하게 감소 (OR=0.33). Bier block 내 500 mg 투여 시 발생률 22.9% vs 45.5% (p=0.04).
• 수술 후 통증 (Postoperative pain): IV 1~3 g 투여 시 통증 점수 유의하게 감소하고, 모르핀 사용량도 줄어듦 (메타분석 다수). Oral 투여는 효과 없음 → IV가 우수.
• 대상포진 후 신경통 (Post-zoster neuralgia, PZN): 5 g IV 투여 시 PZN 발생률 감소 (p=0.014). 7.5~15 g IV (평균 9.9 g, 8회) 투여 시 VAS 통증 점수 크게 개선 (p<0.0001), PZN 발생률 6.4%.
• 기타 통증:
  • 종양 관련 통증, 신경병성 통증, 자궁내막증 골반통 등에서 통증 감소 관찰.
  • 암 환자에서 IV 투여 시 통증 점수 유의한 개선.
• 혈장 비타민 C 농도 관련: 수술 후 환자에서 plasma ascorbate가 hypovitaminosis 범위 (예: 12~16 μmol/L)로 낮아지는 경우가 흔함. 통증 환자(특히 만성 요통, 대상포진 후 신경통)에서 건강인 대비 혈장 비타민 C 수준이 유의하게 낮음. 산화 스트레스 증가로 인해 비타민 C가 급속히 소모된다고 설명.
• 안전성: 대부분 연구에서 부작용 매우 적음. 경미한 가려움, 두드러기 등 보고되었으나 심각한 이상반응은 거의 없음.

결론 및 시사점

고용량 IV l-ascorbate는 
염증성 통증, 신경병성 통증, 수술 후 통증, CRPS, 종양 통증 등 다양한 통증 상태에서
효과적이고 안전하며 비용 효과적인 보조 요법입니다. 

Oral 투여보다 IV가 생체 이용률이 높아 고용량에서 더 유리하며,
산화 스트레스와 염증을 줄이는 기전으로 작용합니다.

권장 용량: 항산화 효과를 위해 0.2~0.5 g/kg 체중,
               암 통증 등에서는 최대 1 g/kg까지 고려 가능

https://pmc.ncbi.nlm.nih.gov/articles/PMC6370430/

Parkinsonism and Vitamin C Deficiency - PMC

연구 유형
케이스 리포트 (2명의 환자 사례를 중심으로 한 임상 관찰 보고서).

무작위 대조 연구가 아닌,
비타민 C 결핍과 파킨슨증(parkinsonism) 사이의 연관성을 제시하고 치료 반응을 보여주는 증례 보고입니다.

주요 내용 및 사례 요약

사례 1 (60세 남성, 알코올 금단 치료 입원)

• 입원 시 오른손 안정 시 떨림(resting tremor)과 cogwheeling rigidity (파킨슨증 소견) 관찰.
• 혈청 비타민 C: 0.2 mg/dL (정상 범위: 0.4~2.0 mg/dL) → 명확한 결핍.
• 치료: 비타민 C 1,000 mg IV 하루 2회 (총 2,000 mg/day).
• 결과: 치료 시작 20시간 후 떨림과 rigidity가 완전히 사라짐. 환자 주관적으로도 기분과 정신운동 활동이 호전됨.

사례 2 (69세 남성, 우울증과 알코올 의존 입원)

• 입원 시 오른손 안정 시 떨림과 rigidity 관찰.
• 혈청 비타민 C: 0.0 mg/dL (완전 결핍).
• 치료: 입원 다음 날부터 비타민 C 1,000 mg oral 하루 2회.
• 결과: 3회 투여 후 (수 시간 내) 떨림과 rigidity가 완전히 사라짐. 환자가 물을 흘리지 않고 마실 수 있게 되고, 대화가 활발해지며 “기분이 좋다”고 보고. 호전은 3일 이상 지속.

두 환자 모두 전형적인 괴혈병(출혈, 잇몸 부종 등) 증상은 없었으나, 잠재적/신경정신과적 괴혈병(latent scurvy) 형태로 파킨슨증이 나타난 것으로 해석됩니다.

핵심 기전 설명 (논문 Table 2) 비타민 C 결핍 시:

• 카테콜아민(도파민 등) 합성 감소
• 아세틸콜린 억제 기능 저하 → extrapyramidal symptoms (EPS) 촉진
• 항산화 작용 상실 → 산화 스트레스 증가 (파킨슨병 병태와 유사)
• GABA/글루타메이트 불균형

단위 환산 및 이전 대화 연관성

• 건강한 성인 oral saturation 후 plasma vitamin C: 50~70 μM (약 0.88~1.23 mg/dL)
• 이 논문 환자들: 0.0~0.2 mg/dL (약 0~11 μM) → 극심한 결핍 상태 (건강인 plateau의 1/5 이하)
• 이는 감기·발열(급성 소비), CKD·입원·알레르기·류마티스 관절염 등에서 관찰된 만성/중증 저농도 패턴과 일치합니다. 특히 산화 스트레스와 염증이 심한 상태에서 비타민 C가 급속히 고갈되어 신경 증상을 유발할 수 있음을 보여줍니다.

결론 및 시사점

• 비타민 C 결핍은 파킨슨증의 가역적(treatable) 원인 중 하나일 수 있다.
• IV 투여는 빠른 혈중 농도 상승으로 신속한 증상 개선을 보였고, oral 투여도 효과적이었다.
• 알코올 의존, 영양불량, 염증, 감염 등이 위험인자.
• 저자들은 “neuropsychiatric scurvy” 진단 기준을 제안하며, 운동장애 환자에서 비타민 C 결핍을 고려하고 보충할 것을 권고

1. 배경 및 분자생물학적 기전 (Molecular Mechanisms)

비타민 C는
인간이 L-gulonolactone oxidase 유전자 돌연변이로 인해
내인성 합성 불가능한 필수 미량영양소.

L-아스코르빈산(비타민 C, AsA)은
항산화제로 활성산소(ROS)를 제거하고,
콜라겐 합성,
효소 보조인자 역할,
스트레스 저항성 등에 필수적.


비타민 C 생합성의 마지막 단계를 촉매하는 핵심 효소가 바로
L-gulono-γ-lactone oxidase (GULO).

• 동물(특히 포유류)에서는 L-gulono-γ-lactone (GUL)을 AsA와 H₂O₂로 산화시킵니다.
• 인간, 기니피그, 박쥐, 일부 영장류 등은 GULO 유전자가 비기능성이 되어 비타민 C를 스스로 합성하지 못합니다. (그래서 괴혈병 위험이 있음)

GULO는 aldonolactone oxidoreductases (AlORs) 계열에 속하며, 두 개의 보존된 도메인을 가집니다:

• N-말단: FAD 결합 도메인
• C-말단: HWXK 모티프 (플라빈 코팩터 결합에 중요)

흥미로운 점은,
쥐(rat) GULO의 C-말단 도메인만 재조합으로
E. coli에서 발현시켰을 때도 효소 활성이 나타났다는 것입니다.

즉, HWXK 모티프만으로도 활성 부위 형성이 충분하다는 점을 보여줍니다.

동물 vs 식물 비교

• 동물: GULO가 주로 소포체(ER) 미세소관(microsomes)에 위치.
• 식물: Smirnoff-Wheeler 경로가 주를 이루지만, GULO-like 효소(GULLO, 특히 Arabidopsis의 GULLO7)가 존재하며, 일부는 N-말단 도메인이 없음에도 꽃가루 등 특정 조직에서 강하게 발현됩니다. 식물에서는 세포벽이나 미토콘드리아 등 다양한 위치에 분포할 수 있습니다.

논문은
다양한 종의 GULO/AlOR 효소의 아미노산 서열 비교,
생화학적 특성(Km, Vmax, 최적 pH·온도, 억제제 등),
재조합 발현 연구 등을 체계적으로 정리.

결론 및 의의

GULO는 비타민 C 생합성의 핵심 효소이며, C-말단 HWXK 모티프의 역할이 중요합니다. 이 연구는:

• AsA 결핍 질환 이해
• 식물 유전자 공학을 통한 비타민 C 강화 작물 개발
• 스트레스 내성 향상

등에 중요한 기초 지식을 제공

1) 장 흡수 과정 (VIC Intestinal Absorption) 

장 상피세포(Intestinal Epithelium)에서 비타민 C는 두 가지 형태로 흡수:

• AA (Ascorbic Acid, 환원형): 주요 흡수 형태.
  SVCT1 (Sodium-dependent Vitamin C Transporter 1) transporter를 통해 나트륨 의존적 능동 수송으로 흡수.
  SVCT1은 주로 소장(distal ileum)에서 작용하며, 포화(saturable) 특성을 가집니다.
  → 저용량에서는 흡수율이 높지만,
      고용량(예: 500mg 이상)에서는 transporter가 포화되어 흡수율이 급격히 떨어짐.
• DHA (Dehydroascorbic Acid, 산화형): AA가 산화되어 생긴 형태.
  GLUT1과 GLUT2 (glucose transporters)를 통해 촉진 확산(facilitated diffusion)으로 흡수.
  장 상피세포 안으로 들어온 DHA는 세포 내에서 다시 AA로 환원(reduced)되어 사용.

결과: 정상적인 oral 섭취 후 혈장(plasma) 농도는 50~70 μM 수준에서 plateau(평형).
       건강한 성인에서 대략 40~65 μM 정도
       혈장 농도가 매우 낮은 수준(11 μM 미만)으로 떨어지면 괴혈병 등의 결핍 증상

• 고용량 oral을 먹어도 혈장 농도가 millimolar (mM) 수준까지 올라가지 않는 이유가
  바로 이 transporter 포화 + 신장 배설 증가 때문입니다.

2) 장기별 비타민 C 농도 분포 (Distribution of VIC concentrations in organs)

혈장에서 조직으로 이동한 후, 비타민 C는 장기마다 크게 다른 농도로 축적됩니다 (SVCT2 transporter 등이 관여):

• 뇌 (Brain): 2~10 mM → 가장 높은 농도 중 하나 (혈장보다 30~200배 이상).
  뇌는 산화 스트레스에 민감해 높은 보호가 필요.
• 간 (Liver): 1 mM
• 폐 (Lungs): 1 mM
• 심장 (Heart): 0.2~0.4 mM
• 근육 (Muscle): 0.2~0.4 mM

특징:

• 뇌·부신(adrenal glands)처럼 대사적으로 활발하거나 산화 스트레스가 많은 조직은 농도가 매우 높습니다 (최대 10 mM).
• 근육·심장처럼 상대적으로 낮은 조직도 있습니다.
• 세포 내 농도는 일반적으로 혈장보다 5~100배 이상 높게 유지되며, 이는 SVCT2 등의 transporter가 조직 보호를 위해 적극적으로 축적하기 때문입니다.

이 그림이 알려주는 중요한 사실 (대학원 수준 해석)

1. Oral 비타민 C의 한계 혈장 농도가 50~70 μM에 머무르는 이유는 SVCT1 포화 + 신장 재흡수 한계 때문입니다. → 고농도 IV 주사(IVC)와의 가장 큰 차이점: IVC는 transporter를 우회해 혈중 20 mM 이상까지 도달 가능 → pro-oxidant 효과(H₂O₂ 생성) 발휘.
2. DHA vs AA의 역할 DHA는 glucose transporter를 공유하므로, 고혈당 상태(당뇨 등)에서는 DHA 흡수가 경쟁적으로 영향을 받을 수 있습니다.
3. 조직 특이적 축적 비타민 C는 단순히 혈장에 머무르는 것이 아니라, 특정 조직(특히 뇌, 간, 폐)에 집중적으로 축적되어 국소 항산화·효소 보조인자 역할을 합니다. 이는 만성질환(염증, 산화 스트레스 관련)에서 조직별 효과 차이를 설명합니다.

리포소말 비타민 C와의 연계 (이전 질문)

• 일반 oral 비타민 C: 위 그림처럼 SVCT1/GLUT1,2에 의존 → 포화 한계.
• 리포소말 비타민 C: 리포좀이 endocytosis나 membrane fusion으로 transporter를 부분적으로 우회 → 최근 연구(2024~2025)에서 plasma Cmax +27%, AUC +21% 정도 증가, 백혈구 내 uptake도 향상된 것으로 보고됩니다. 그러나 여전히 혈장 농도는 μM 수준에 머물러 IVC(mM 수준)만큼의 약리학적 효과는 기대하기 어렵습니다.

이 모식도는 저용량 oral 비타민 C의 생리학적 흡수·분포를 정확히 보여주며, 왜 고농도 치료(특히 IVC)가 별도의 약리학적 기전을 필요로 하는지 잘 설명

3가지 비타민 c 효과

1) 항산화 작용
   ROS (reactive oxygen species) 직접 소거,
   vitamin E 재생,
  glutathione 유지 → 산화 스트레스 감소.

2) 효소 보조인자 역할
    Collagen hydroxylation (prolyl/lysyl hydroxylase),
    carnitine biosynthesis,
    catecholamine/neurotransmitter 합성,
    철 흡수 (Fe³⁺ → Fe²⁺ 환원).

3) 고농도 약리학적 효과 (Pharmacological dose, IVC로 혈중 >20 mM 도달 시):
    Pro-oxidant 전환: Ascorbate + O₂ → H₂O₂ 대량 생성.
    암세포, 염증 환경은 catalase/peroxidase 부족 → 선택적 산화 스트레스 유발 → apoptosis/autophagy 유도. 
    NF-κB 경로 억제 → pro-inflammatory cytokines (TNF-α, IL-6, CRP) down-regulation.
    면역 조절: Neutrophil NETosis 조절, T/NK 세포 기능 강화, phagocytosis 증진.

I. Physiological Levels (생리적 농도: 혈장 40~70 μM 정도, 일반 oral 복용 시)

• 주요 역할: 항산화제 (Antioxidant)
• 백혈구(Leukocyte)에서 ROS(Reactive Oxygen Species)가 발생하면 AA가 이를 중화합니다.
• AA → 산화되어 DHA(Dehydroascorbic Acid)로 전환.
• DHA는 GLUT transporter를 통해 정상 세포(또는 암세포) 안으로 들어갑니다.
• 세포 내에서 DHA → AA로 다시 환원(reduction)되며, SVCT2 transporter를 통해 미토콘드리아 등에 축적.
• 결과: 산화 스트레스 감소, 세포 보호, 면역 기능 지원 (phagocytosis 강화, 사이토카인 조절 등).
• 정상 세포와 암세포 모두에서 보호 효과를 줄 수 있습니다. (암세포가 DHA를 이용해 자신을 보호하는 경우도 있음)

이 농도에서는 비타민 C가 세포를 지켜주는 역할을 합니다.
이전 모식도에서 본 혈장 50~70 μM 수준이 바로 이 범위입니다.

II. Pharmacological Levels (약리학적 고농도: IV 주사 시 혈중 20 mM 이상 도달)

• 주요 역할: 프로옥시던트 (Pro-oxidant) → 선택적 세포 사멸 유발
• 고농도 AA가 산화되면서 H₂O₂ (과산화수소)를 대량 생성합니다.
• Fenton Reaction (펜톤 반응): AA가 Fe³⁺(삼가철)를 Fe²⁺(이가철)로 환원시키고, Fe²⁺ + H₂O₂ → 매우 강력한 hydroxyl radical (•OH) 생성. 이 반응으로 산화 스트레스가 급증합니다.
• 암세포 (Tumoral cell):
  • 암세포는 catalase, glutathione peroxidase 등 H₂O₂를 분해하는 효소가 부족하거나, 철 이온(labile iron pool)이 많습니다.
  • H₂O₂가 미토콘드리아에 축적 → 강한 산화 스트레스 → Cell Death (세포 사멸) 또는 Cell Arrest (세포 주기 정지) 유발.
  • DHA 형태로 GLUT를 통해 들어와 내부에서 AA로 환원되면서 추가 산화 스트레스 증폭.
• 정상 세포 (Leukocyte 등):
  • catalase 등이 풍부해 H₂O₂를 빠르게 분해 → 거의 피해 없음.
  • 따라서 선택적 독성(selective toxicity)이 나타납니다.

왜 고농도 IVC가 만성질환·난치 암에 사용되는가?

• 생리적 농도 (oral): 항산화·염증 완화·면역 지원 (Mikirova RA 연구의 CRP 감소처럼).
• 약리학적 농도 (IV): 프로옥시던트 효과로 암세포 선택적 사멸 + 강력한 항염증 (NF-κB 억제).
• 암세포의 대사 특징(Warburg 효과, 높은 철 의존성, 낮은 항산화 효소)을 이용한 표적 치료 개념

리뷰는
Figure 4에서 저농도(항산화) vs. 고농도(프로옥시던트) 효과를 명확히 구분합니다.


2. 만성질환·난치질환에서의 치료 잠재력

• 염증 관련 만성질환: Metabolic syndrome, diabetes, CVD에서 oral/IV 비타민 C가 CRP, MDA, F2-isoprostanes 등을 낮추고, NO 증가, 혈압 개선 효과 보고. RA에 대해서는 직접 연구를 인용하지 않았으나, NF-κB 억제와 cytokine 감소라는 일반 기전을 통해 RA 같은 자가면역 염증 질환에 적용 가능성을 시사합니다.
• 암: 고용량 IVC (예: 1.5 g/kg/day)의 pro-oxidant 효과로 종양세포 선택적 사멸, 항암제 시너지, 부작용 완화.
• 감염·바이러스 후유증: Sepsis, respiratory infections, Long COVID-like post-viral fatigue에서 염증 감소·면역 지원.
• 신경퇴행성 질환: ROS-mediated protein aggregation (α-synuclein 등) 억제.
• 통증·상처 치유: Post-extraction pain, wound size 감소.

3. 고농도 IVC와 관련된 논의 (사용자 관심사와 직접 연결)

리뷰는 고용량 IVC를
“therapeutic potential in intractable conditions (cancer, neurodegeneration, severe infections)”으로 평가하면서도
다음과 같은 한계를 명확히 지적합니다:

• Oral vs. IV의 생체이용률 차이: Oral은 transporter (SVCT1/2) saturation으로 plasma ~200 μM 한계, IV는 millimolar 수준 도달 가능.
• 기존 연구의 불일치: 일부 meta-analysis에서는 CVD·암 예방 효과 긍정, Mendelian randomization 연구에서는 인과관계 부정.
• 안전성: G6PD deficiency 시 hemolysis 위험, oxalate nephropathy (신장결석), 고용량 시 nausea/dizziness. Upper limit 2000 mg/day (oral).

Vitamin C: A Comprehensive Review of Its Role in Health, Disease Prevention, and Therapeutic Potential

by 

Adina Alberts

 1,

Elena-Theodora Moldoveanu

 2,

Adelina-Gabriela Niculescu

 2,3

 and

Alexandru Mihai Grumezescu

 2,3,*

1

Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania

2

National University of Science and Technology Politehnica Bucharest, 011061 Bucharest, Romania

3

Research Institute of the University of Bucharest—ICUB, University of Bucharest, 050657 Bucharest, Romania

*

Author to whom correspondence should be addressed.

Molecules 2025, 30(3), 748; https://doi.org/10.3390/molecules30030748

Submission received: 19 December 2024 / Revised: 28 January 2025 / Accepted: 4 February 2025 / Published: 6 February 2025

(This article belongs to the Section Natural Products Chemistry)

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Abstract

Since Albert Szent-Györgyi discovered it and it became used in treating scurvy, vitamin C has attracted interest in many studies due to its unique properties. It is an important cofactor in the synthesis of collagen and hormones, and it is involved in immunity, iron absorption, and processes requiring antioxidants. Thus, this review aims to emphasize the importance and usefulness of vitamin C in improving quality of life and preventing various diseases (e.g., chronic diseases, cardiovascular diseases, cancer) but also for its use in treatments against infections, neurodegenerative diseases, and cancer. Although the studies presented provide essential information about the properties of VIC and its beneficial effect on health, some studies contradict these theories. In this respect, further studies on larger samples and over a longer period are needed to demonstrate the therapeutic potential of this nutrient. However, VIC remains a necessary vitamin that should be consumed daily to maintain optimal health and prevent deficiencies that can lead to scurvy and its associated complications.

Keywords: 

vitamin C; ascorbic acid; enzymatic cofactor; antioxidant; pro-oxidant effect health; scurvy; cardiovascular diseases; cancer; infections; chronic diseases

1. Introduction

Vitamin C (VIC), also known as L-ascorbic acid, is a well-known micronutrient necessary to maintain the human body’s overall health. Found in two main forms, namely, ascorbic acid (AA) and dehydroascorbic acid (DHA), VIC is a strong antioxidant and a cofactor for many enzymes, being involved in many biological functions, such as normal immune system functioning, carnitine and catecholamine metabolism, dietary iron absorption, and collagen biosynthesis [1,2,3,4]. Still, the body cannot synthesize it due to mutations in the L-gulonolactone oxidase (GLO) gene, which is responsible for its synthesis from L-gulono-1,4-lactones. Therefore, VIC intake is attributed to the high consumption of foods rich in ascorbic acid (e.g., tomatoes, potatoes, green leafy vegetables, berries, citrus fruits). VIC can be accumulated in different tissues (e.g., brain, liver, skeletal muscles, corneal epithelium, neutrophile, stem cells) via specific transporters, and it can enhance cellular functions [5,6,7,8].

VIC is important for realizing numerous biological functions as it is a potent antioxidant and a cofactor for enzymes present in the human body. VIC can neutralize reactive oxygen species (ROS) produced during normal metabolism, thereby preventing oxidative stress and cellular damage [2,6]. Additionally, in high doses, vitamin C can act as a pro-oxidant, a property that is being studied for its potential in cancer treatment [5,9].

VIC is also involved in the hydroxylation of collagen, the synthesis of carnitine and catecholamines, and the metabolism of tyrosine, folic acid, and tryptophan. VIC is also involved in the hydroxylation of proline, lysine, and glycine, which stabilizes collagen’s triple-helix structure. Furthermore, VIC promotes the conversion of cholesterol into bile acids, contributing to cholesterol homeostasis and reducing the risk of hypercholesterolemia and gallstone formation [2,8,10].

VIC also stimulates iron absorption at the intestinal level by reducing Fe3+ to Fe2+, making it more stable and contributing to anemia management [2,8,10]. In energy metabolism, VIC supports the synthesis of carnitine, which is responsible for transporting fatty acids into mitochondria [7,10]. Another essential role for VIC may be its ability to act as a cofactor for the enzyme dopamine-beta-hydroxylase, contributing to converting dopamine to norepinephrine, an essential neurotransmitter for the nervous system [2,10].

Thus, VIC can contribute significantly to maintaining long-term health. Although VIC deficiency is becoming increasingly common worldwide, even in developed countries, it is important to maintain an adequate intake to contribute to improved health and optimal immune, cardiovascular, and neurocognitive functions [11]. Since humans cannot synthesize VIC on their own, its dietary intake is important to prevent deficiency, being efficiently absorbed in small amounts. The main source of VIC is fresh fruits (e.g., kiwi fruit, citrus fruits) and vegetables (e.g., peppers, green leafy vegetables), while meat, cereals, and tubers are low in VIC. How these foods are eaten is also important, as high temperatures can destroy VIC during cooking [12].

Deficiency of VIC may also be associated with different factors, including environmental, socioeconomic, and physiological aspects. Populations in regions with limited access to fresh produce, such as Finland and Russia, show a higher deficiency preval‎ence. In contrast, areas like England and China, where fresh, VIC-rich foods are consumed regularly, exhibit lower preval‎ence, even during winter months. Socioeconomic status profoundly influences VIC intake, as individuals in disadvantaged circumstances often lack access to nutrient-rich diets. Vulnerable groups such as the elderly, children, and individuals with chronic conditions—including obesity, cardiovascular disease, diabetes, cancer, and HIV—are particularly at risk due to altered metabolic demands and suboptimal nutrient absorption. Lifestyle factors, including smoking and alcohol consumption, further deplete VIC levels due to increased oxidative stress [12,13].

Severe and prolonged VIC deficiency leads to scurvy, a condition that has affected people since ancient times. The disease has been historically linked with limited dietary access among sailors and soldiers in the 15th and 16th centuries. At present, scurvy is considered a rare disease in developed countries, but it can occur in vulnerable social environments, in alcohol consumers, and in people with severe psychiatric problems [13,14,15]. A 2023 study by Miraj et al. [16] demonstrated scurvy’s contemporary relevance in pediatric populations subsisting on processed diets devoid of fresh produce. Among 18 cases analyzed, lower limb pain, subperiosteal hemorrhages, and radiographic findings such as Frankel’s white line were predominant features, alongside gingival pathology and anemia. Symptomatic resolution occurred within 4 to 16 weeks following administration of 100–250 mg/day.

Based on these findings, efforts to combat VIC deficiency should prioritize increasing access to fresh produce and promoting public health initiatives targeting high-risk populations. While supplementation alleviates deficiency, its bioavailability remains lower compared to natural dietary sources of VIC. Consistent intake of approximately 200 mg/day through diet and supplements is crucial for sustaining adequate VIC levels, ensuring overall health improvement, and reducing the risk of deficiency-related complications [12,17,18].

The pathogenesis of scurvy is linked to deficient collagen synthesis due to the absence of VIC, impairing connective tissue integrity and capillary stability. Initial symptoms include fatigue, irritability, and appetite loss caused by impaired carnitine biosynthesis and fatty acid transport. Progression results in perifollicular hemorrhages, gingival hypertrophy, delayed wound healing, myalgia, muscle weakness, hyperkeratosis, weight loss, and hematological abnormalities. Advanced cases can culminate in sepsis-like syndromes, hypotension, and death [14,15,19,20,21,22,23,24].

To treat scurvy, researchers such as William Bally, Axel Holst, Theodor Frolich, and Sir Frederick Gowland Hopkins contributed to understanding how VIC works in the human body. This research led to the chemical formula for VIC, which was later recognized as ascorbic acid, and its importance in curing scurvy [25,26,27]. Albert Szent-Györgyi’s isolation of “hexuronic acid”, later termed ascorbic acid, illuminated its anti-scorbutic properties and earned him the 1937 Nobel Prize in Medicine [28,29].

Nowadays, VIC is no longer only used as a treatment for scurvy, but its benefits in various biological functions have also been recognized. Thus, VIC has been shown to have an extremely good antioxidant effect, protecting against oxidative stress, facilitating collagen synthesis, supporting skin health, enhancing immune function, improving wound-healing, and promoting iron absorption in the intestine. However, studies are continuing to explore its potential in dealing with some major diseases, such as cardiovascular disease, cancer, and age-related diseases [4,19,30,31,32]. Emerging research also highlights the role of VIC in maintaining oral health. This may indirectly impact cardiovascular and infectious diseases, as periodontal health has been linked to reduced systemic inflammation and lower risks of heart disease [33,34].

Thus, this review aims to comprehensively explore the role of VIC in health maintenance and disease prevention. The present paper first sets a scientific foundation by analyzing VIC’s molecular structure, properties, and mechanisms of action. Then, the applications of VIC in preventing and treating various illnesses are thoroughly reviewed, highlighting this vitamin’s therapeutic potential. Further, VIC deficiency and supplementation are addressed, as they have important public health implications. This review also acknowledges the areas of ongoing debate and emphasizes the need for further research to solidify its role in clinical practice.

For this purpose, English-language publications (e.g., review articles, meta-analyses, preclinical studies, clinical trials, observational studies), mainly from the last seven years, are analyzed and discussed in this paper. These were searched in scientific databases such as Google Scholar, PubMed, Elsevier/Science Direct, Springer Link, Wiley Online Library, and Taylor & Francis online using various combinations between the following keywords: “Vitamin C”, “cardiovascular diseases”, “immune system”, “metabolic disorder”, “immune modulation”, “respiratory infections”, “wound healing”, “cancer treatment”, and “antioxidant effect”.

2. Biochemical Role of Vitamin C2.1. Molecular Structure and Properties

Vitamin C (C6H8O6), also known as ascorbic acid, is a simple carbohydrate with a low molecular mass and a structure similar to sugars, composed of six symmetrical carbon atoms. It is the aldono-1,4-lactone of a hexonic acid with an enediol group on carbons 2 and 3, capable of donating electrons. L-ascorbic acid isomers (Figure 1) erythorbic acid, known as D-araboascorbic acid, and D-ascorbic acid also have activity in the human body. Still, unlike L-ascorbic acid, they are more readily metabolized and eliminated from the body. Ascorbic acid is soluble in water, difficult to solubilize in alcohol, and impossible to solubilize in benzene, ether, or chloroform, so its chemical structure determines its physical and chemical properties. Although soluble in water, it is a weak, unstable organic acid that can be readily oxidized at high temperatures or in the presence of light, oxygen, or alkaline and high-humidity environments [24,35,36,37].

Figure 1. Isomers of vitamin C. (A) L-ascorbic acid, (B) erythorbic acid, and (C) D-ascorbic acid.

The use of derivatives, such as zinc ascorbate, calcium L-ascorbate (calcium ascorbate), sodium L-ascorbate (sodium ascorbate), calcium sodium ascorbyl monophosphate salt (sodium calcium ascorbyl phosphate), and 6-palmityl-l-ascorbic acid (ascorbyl palmitate), has contributed to the increased stability of ascorbic acid [24,35,36,37].

At a physiological pH of 7.4, L-ascorbic acid is found as the ascorbate monoanion that can remain in its reduced form (ascorbic acid—AA) or transform into its oxidized form (dehydroascorbic acid—DHA). Thus, AA can donate electrons and act as a reducing agent. It successively loses two electrons, the intermediate species composed of a single electron, or free radical, also called an ascorbate radical, which is stable and relatively non-reactive. The loss of the second electron leads to the appearance of its oxidized form, DHA. DHA can be rapidly degraded to 2,3-diketogulonic acid by reactive hydrolysis, the molecules thus losing their vitamin property. In aqueous environments, this degradation phenomenon is much more accentuated, with the oxidation of AA occurring rapidly. Also, metal ions (e.g., Fe3+) can lead to oxidation of AA and hydrolysis of DHA. However, dehydroascorbic acid can be reduced back to its ascorbic acid form in the body, this process being essential for its antioxidant activity [8,9,38,39].

Free radicals and ROS have a dual role in the body. Although they have beneficial effects, they can also be toxic compounds formed during metabolic processes and in response to exogenous stimuli. When they occur in excess and cannot be eliminated, their accumulation can lead to oxidative stress, and this process can lead to the development of chronic and degenerative diseases (e.g., cancer, cardiovascular disease, aging, cataracts). VIC can scavenge biological systems’ free radicals, protect lipid membranes and proteins from oxidative damage, and neutralize the reaction. Free radicals are unstable, so they require electrons to find stability. VIC is a reducing substance and an electron donor, so in the presence of free radicals, VIC donates high-energy electrons, neutralizing them. DHA is formed during this process, which can be recycled and reused, releasing more electrons. In cells, DHA is also reduced to generate AA, which protects mitochondria from oxidative damage by free radicals [40]. Thus, it has been observed that the antioxidant effect of VIC is closely related to its chemical properties. Due to its ability to donate electrons, it neutralizes free radicals and ROS. This property is also due to the redox ability that VIC has, being able to transition between its reduced form and its oxidized form [6,41,42].

Understanding the stability of VIC is essential to its possible use in biomedical applications. VIC is unstable in aqueous environments, at high pH, and in the presence of oxygen and metal ions, where its degradation is accelerated. A high pH leads to the decomposition of AA, and thus its efficiency decreases. High temperature also contributes to the breakdown of VIC. Thus, it has been observed that an increase of 10 °C leads to a doubling of the rate of VIC oxidation, while UV rays have been found to have the same effect. The presence of oxygen also accelerates the oxidation of VIC, contributing to the formation of DHA, which is more unstable and may degrade later. These issues are essential for the processing and storing of foods and supplements containing VIC [36,39,43,44].

2.2. Mechanisms of Action

VIC is vital in numerous and varied biological processes, particularly relevant as an enzyme cofactor. Thus, this role is closely related to dioxygenases involved in the synthesis of collagen and carnitine, in the transcription and regulation of gene translation, and the metabolization of tyrosine and monooxygenases involved in the synthesis of hormones. Regarding dioxygenases, VIC maintains the metals present (e.g., iron, copper) in their reduced state [24,45].

Enzymes that depend on VIC as a cofactor fall into two main categories: iron-dependent or 2-oxoglutarate-dependent dioxygenases. Iron-dependent dioxygenases catalyze hydroxylation reactions critical for collagen and carnitine synthesis, while 2-oxoglutarate-dependent dioxygenases (2-OGDDs) are involved in gene regulation and metabolic pathways. Enzymes of the 2-OGDDs family present non-heme iron bound to the enzyme with two histidine residues and an aspartic or glutamic acid through triple coordination. The other iron sites are occupied by water molecules, which are substituted by 2-oxoglutarate (2-OG) and oxygen (O2) during the catalytic reaction. Thus, the enzyme catalyzes the hydroxylation of the substrate, forming a superoxide radical that decarboxylates 2-OG, forming a ferryl intermediate, which helps to bring iron to its active state (Fe2+). VIC facilitates the reduction of iron (Fe3+) back to Fe2+, preventing an uncoupled cycle where 2-OG is oxidized to succinate and CO2 without hydroxylating the substrate. Without VIC, enzyme inactivation occurs rapidly but remains reversible [24,45].

Monooxygenases such as dopamine-β-hydroxylase and peptidyl-glycine α-amidating monooxygenase (PAM) also depend on VIC. Dopamine β-hydroxylase is present in catecholamine storage vesicles at the level of the nervous tissue but also in the adrenal glands. This dimer or tetramer enzyme, containing catalytic copper ions, relies on VIC to reduce Cu2+ ions at the active site and activate oxygen, enabling dopamine hydroxylation to norepinephrine. On the other hand, PAM is a bifunctional enzyme involved in the synthesis of hormones and neurotransmitters such as oxytocin, calcitonin, vasopressin, neuropeptide Y, GLP-1, and substance P, found in tissues such as the pituitary and adrenal glands. It exhibits two distinct catalytic domains, and its activation involves two steps: hydroxylation of the peptide precursor and the second involves amidation of the intermediate product. Both steps require copper, ascorbate, and oxygen. VIC is an important element in the function of both enzymes, and its deficiency can lead to decreased enzyme activity, which impairs the synthesis of important neurotransmitters and hormones [24,45].

In addition, VIC may also be a key factor for α-ketoglutarate dioxygenases (α-KGDD), maintaining and enhancing the activity of these enzymes. Thus, VIC is involved in epigenetic modifications of histones containing the Jumonji-C domain (JHDM) and the ten-eleven translocation (TET) family of DNA hydroxylases. It has been observed that VIC added to somatic cells can activate pluripotency genes, leading to epigenetic memory erasure in adult cells. Its action on α-KGDD may lead to the regulation of metabolism and DNA/RNA demethylation, inducing somatic cell reprogramming, and may even be important in DNA repair [46].

2.3. Antioxidant Function

Oxidative stress is an important toxic factor in the development of chronic diseases. VIC is a well-known antioxidant that can stop the production of ROS and reactive nitrogen species (RNS) through two pathways. The first direct pathway is the inhibition of nitrogen oxides, preventing the formation of radicals such as hydroxyl, peroxyl, and nitroxide. On the other hand, VIC may be a substrate involved in ascorbate peroxidation, converting hydrogen peroxide to water [42,47]. VIC may also boost the activity of vitamin E (α-tocopherol), enhancing its antioxidant effect by controlling lipid peroxidation in cell membranes and nuclear material. Specifically, the generated α-tocopheroxyl radical reacts with AA to regenerate α-tocopherol, while AA is oxidized to ascorbyl radical [6,41]. As previously mentioned, the antioxidant activity of VIC is closely related to its chemical properties. Its ability to donate electrons to neutralize free radicals and ROS is due to its property of going from its reduced form to its oxidized form and vice versa, which contributes to this antioxidant activity [42].

Due to its antioxidant properties, vitamin C is being studied to prevent diseases associated with oxidative stress. Several studies have investigated the potential of VIC for cardiovascular diseases, including hypertension [48], atherosclerosis, and coagulation abnormalities [49,50,51]. It was also found that VIC exerts its antioxidant role not only by its action on ROS but also by redox regulation and enhancement of the activity of other cellular radical scavengers [48]. However, analysis of several studies has shown that the association of VIC with the risk of coronary heart disease is controversial. The source of VIC is an important factor, and its levels in the blood must be constantly monitored to determine the impact of VIC on the prevention of cardiovascular disease [52].

Furthermore, oxidative stress may also be associated with neurodegenerative diseases, and research has found high concentrations of VIC in the brain. Thus, VIC may also be involved as a neuroprotective. Firstly, VIC is involved in catecholamine synthesis and has a regulatory effect, modulating enzyme hydroxylation. It has also been observed in mouse models that VIC can improve cognitive activity in schizophrenia and Alzheimer’s disease. VIC has also been studied as an antidepressant, contributing to the activity of 5-HT 1A and 5-HT 2A/2C receptors. However, further studies are needed to concretely determine the mechanisms of action of VIC on the nervous system and its use in the treatment of neurodegenerative diseases [53].

Numerous studies have investigated the effect of VIC concentration on cancer cells [54]. Thus, some in vitro experiments have used concentrations of 20 mM VIC and have been shown to selectively kill cancer cells without affecting healthy cells. The mechanism underlying this effect (cancer cell killing) was associated with forming hydrogen peroxide and forming VIC radicals as intermediates. Also, the doses of VIC administered in the mouse model led to a halt in tumor progression, promoting a pro-oxidant effect. VIC also potentiated the effect of anti-tumor drugs, such as gemcitabine, against pancreatic cancer cell lines, as well as drugs used in ovarian cancer. It has also potentiated the effect of radiotherapy and managed the side effects of this procedure [55,56].

2.4. Role in Collagen Synthesis

Collagen (Col) is an essential protein for the human body. It has a triple-helix structure with three identical or different α-chains, which mimics and can maintain the interaction between cells and the matrix [57]. It can be classified as microfibrillar, short-chain, transmembrane, anchoring, basement membrane, fibril-associated collagen with interrupted triple-helix (FACIT), and fibrillar collagen [58]. It is found in skin, organ capsules, bones, tendons, cornea, muscle fascia, and blood vessels. It plays an important role in the body, maintaining mechanical strength, elasticity, and support of the tissues, being a major component in the extracellular matrix of cells (ECM). Besides supporting cells, collagen is also involved in cellular activity and behavior, such as cell proliferation, migration, and differentiation [59].

There are about 30 types of collagens. Type I collagen is the most preval‎ent collagen in the human body, found in connective tissues, tendons, ligaments, bones, and skin. It is composed of two identical α1 (I) chains and one α2 (II) chain in each structural domain of bone; collagen fibers lead to bone mineralization, either directly or in association with other proteins responsible for mineralization. Collagen is also involved in other physiological processes, such as homeostasis and angiogenesis, and is also present in pathologies such as cancer, fibrosis, or atherosclerosis [59,60].

VIC is an essential cofactor in collagen synthesis and acts on the enzyme’s prolyl hydroxylase and lysyl hydroxylase in this process. These enzymes are responsible for cross-linking collagen molecules by hydroxylating proline and lysine residues and help stabilize collagen’s triple-helix structure. This process leads to the formation of mature and solid collagen fibers. Furthermore, VIC is involved in gene expression‎ for collagen types I and III and may also protect collagen from oxidative stress, which could hinder various processes such as wound healing. Hydroxylation of proline residues occurs at the γ-C atom and sometimes at the β-C atom, whereas lysine occurs at the δ-C atom. These reactions have as catalysts VIC-dependent dioxygenase enzymes such as prolyl 4-hydroxylase, prolyl 3-hydroxylase, and lysyl 5-hydroxylase [26,41,61]. Also, not only is it involved in collagen synthesis, but VIC may also be active in collagen gene expression‎. It has been observed that VIC can increase the messenger RNA (mRNA) levels for type I and III collagen in fibroblasts, leading to mRNA stability and, thus, more efficient collagen production. It was also found that VIC can inhibit the synthesis of certain types of collagen (types V and VI), allowing for the body to select the type of collagen required for its needs. VIC may interact with growth factors (e.g., epidermal growth factor (EGF) and fibroblast growth factor (FGF)), contributing to the regeneration of injured tissues by collagen synthesis [62].

3. Pharmacokinetics and Supplementation3.1. Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetics of VIC is a complex process that requires maintaining the body’s homeostasis. It involves the following steps: absorption, distribution, metabolism, and excretion. It is important to understand the kinetics of VIC so that it can be properly administered to patients according to individual needs and specific conditions. Genetic factors, lifestyle, and patient comorbidities may influence this process. Also, the pharmacokinetics of VIC may be influenced by the dose administered, making it difficult to obtain data on its therapeutic effect. Studies have shown that VIC is subject to zero-order to first-order pharmacokinetics, making it difficult to predict its possible effects, especially when high doses are administered [24,63,64].

Absorption of VIC (Figure 2) occurs mainly in the intestine, specifically in the distal ileum, via sodium-dependent transporters (SVCT1 and SVCT2). This process is saturable and dependent on intestinal pH and represents the decrease in absorption capacity at high concentrations of VIC. At low doses, VIC is absorbed in a high proportion. VIC can also be absorbed by passive diffusion, especially at low pH, where VIC is non-ionized. In the small intestine, VIC exists as ascorbate (predominant) and DHA, which is reduced to the ascorbate form in cells. DHA is absorbed through glucose transporters (GLUT1 and GLUT2) [24,63,64].

Figure 2. VIC absorption process and concentration distribution in organs. Created based on information from [64,65].

VIC is distributed differently in the body (Figure 2), with its concentrations varying in different organs. It can accumulate in the brain and adrenal glands (10 mM), where there are the highest concentrations of VIC, while in the muscle and myocardium, concentrations are lower (0.2 mM). VIC plasma levels are 40–65 µM in healthy adults, reaching a plateau of 200–400 mg/day. Cells contain concentrations 5 mM higher than the plasma level (except erythrocytes), while neuronal cells and endocrine cells have VIC levels of 10 mM, as VIC is involved in synthesizing neurotransmitters and hormones [24,63,64].

Excretion of VIC occurs mainly in the kidney. The SVCT1 transporter contributes to the reabsorption of VIC from the primary urine; thus, its excretion depends on the saturation of this process. VIC in low doses is not eliminated, whereas doses ≥ 500 mg lead to almost complete elimination of VIC in the urine [24,63,64].

3.2. Recommended Dietary Allowances

VIC is an important nutrient in the human diet, and an adequate intake of it can be obtained by eating fresh fruits and vegetables. Nutritionists recommend five servings of fruits and vegetables per day, which could provide about 200 mg of VIC [66]. In a study by the US National Health and Nutrition Examination Survey (NHANES) conducted between 2017 and 2018, only 8% of the adult population met this dietary threshold, with patients having an average VIC concentration of 66 μmol/L. Also, the bioavailability of VIC in whole foods is 76%, compared to 70–90% when taking VIC-based supplements [67,68,69].

Thus, the recommended VIC dose was 90 mg/day for adult males, while male adolescents need 75 mg/day. Generally, women need 75 mg/day; however, for pregnant and breastfeeding women, a higher dose is indicated, while 65 mg/day is recommended for teenage females. In children, the daily dose of VIC is according to their age. For people who smoke, the dose of VIC should be supplemented by 35 mg due to the deficient absorption of VIC caused by this habit [66]. For an at-glance perspective over these quantities, the dietary recommended allowances for VIC are summarized in Table 1.

Table 1. Recommended Dietary Allowances (RDAs) for VIC (mg). Adapted from [66].

To combat VIC deficiency, there is no clear protocol regarding its dosage in cases of major deficiency. In cases of deficiency in newborns (from birth to 28 days), the recommendation is 50 mg/day orally or intravenously. Also, for premature babies, the recommended dose is 25 mg/day orally or intravenously. Children weighing less than 10 kg are recommended 125 mg/day orally or 75 mg/day intravenously. Those over 10 kg up to 40 kg may receive 500 mg/day given twice or 75 mg/day intravenously. Those over 40 kg should receive 1000 mg daily orally or 500 mg/day intravenously. These dosages should be administered according to the needs of the deficient patients, and this should be stable based on blood levels of VIC and re-eval‎uation of these levels 2–4 weeks after starting supplementation [67,68,69].

3.3. High-Dose Vitamin C: Safety and Efficacy

In addition to the beneficial effects that VIC can have in high concentrations, there are also consequences of administering it in this way. It has been found that high levels of VIC may be associated with the development of kidney stones, as one of the metabolites of VIC is oxalate. The development of acute oxalate nephropathy has also been observed in patients after intravenous administration of high concentrations of VIC to patients with chronic kidney disease. High intravenous concentrations of VIC may also produce adverse effects in some categories of patients. In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, intravascular hemolysis may be produced, and oral administration may have a similar effect on patients with paroxysmal nocturnal hemoglobinuria. On the other hand, following intravenous administration of VIC, some patients have reported adverse effects such as dizziness and nausea, which improved after the consumption of food and water. Vomiting, thirst, dry mouth and skin, increased urinary flow, diarrhea, headache, chills, imbalance, edema in the legs, hypertension, insomnia, loss of appetite, fatigue, etc., were also reported as adverse effects. In laboratory tests, administration of high concentrations of intravenous VIC was also associated with hypernatremia, hypokalemia, hypercalcemia, and a low hemoglobin concentration [67,68,69,70].

To avoid such side effects, the VIC supplementation should not exceed the tolerable upper intake levels (Table 2).

Table 2. Tolerable Upper Intake Levels (ULs) for VIC (mg). Adapted from [66].

4. Vitamin C in Disease Prevention4.1. Cardiovascular Health

Cardiovascular diseases (CVDs) are disorders associated with the circulatory system (heart and blood vessels) and are among the most preval‎ent conditions in the world’s developed countries, with increased mortality rates. CVD can remain hidden and undiagnosed for a long time. The conditions that lead to CVD are high blood pressure (hypertension), coronary artery disease (CAD), and atherosclerosis. Atherosclerosis is characterized by the thickening and hardening of the artery walls due to elevated plasma cholesterol levels, while CAD is characterized by narrowing or blockage of the coronary arteries. In CAD, fatty plaques form and grow inside the blood vessels, causing severe inflammation. The consequences of CAD include heart attack, stroke, ischemia, or even death. Arterial hypertension (AH) is the most common and frequently encountered cardiovascular disease and is more dangerous because it has little or no symptomatology, but it can cause heart attack, stroke, kidney failure, and peripheral vascular disease [63,64,65].

The vascular endothelium is essential in the functions of the circulatory system by maintaining homeostasis, while its dysfunction is a key factor in the development of both atherosclerosis and CAD. In atherosclerosis, arterial regions with turbulent blood flow, such as branch points, are particularly prone to lesions due to low shear stress and endothelial damage. The endothelial cells constantly produce nitric oxide, which regulates anti-inflammatory and anti-thrombotic processes. However, during inflammation, these processes are impaired, and lipoprotein oxidation is intense and allows for their accumulation in the subendothelial space. Nitric oxide depletion and ROS generation promote vasoconstriction and procoagulation, leading to the development and degeneration of atherosclerosis. In atherosclerosis, inflammation plays an important role, since oxidized lipids activate macrophages and T lymphocytes, which lead to the secretion of inflammatory cytokines (TNF-alpha, IL-1, IL-6) and the appearance of ROS. These processes facilitate the appearance of more leukocytes, which modify lipoproteins and transform them into atherosclerotic plaques and chronic inflammation. In the case of CAD, instead of nitric oxide, superoxides occur, leading to oxidative stress, which damages the vasculature and leads to atherosclerotic plaques and chronic inflammation [63].

Over the years, researchers have focused on finding ways to effectively prevent, treat, and control CVD. VIC has become a substance of interest because of its antioxidant properties, which could decrease CVD risk. People with a high concentration of VIC had a low risk of stroke, while people with a normal or deficient concentration of VIC had twice the risk. Lack of VIC may favor the development of oxidative stress and, thus, atherosclerosis [65,66].

Studies conducted between 1990 and 2000 have had conflicting results. Some showed that daily intake of VIC could not be associated with a lower risk of developing CAD, while others suggested a decreased risk of developing CAD in the patients involved in the study. Meta-analyses and additional studies concluded that VIC intake is inversely associated with CAD risk. Some studies showed benefits, while others did not, with no evidence of cardiovascular events [52,67,68,69,70,71,72,73,74]. A meta-analysis conducted in 2017 [75] showed that vitamin C supplementation could reduce cardiovascular events and mortality, but data are insufficient. A recent Mendelian randomization (MR) study was performed by Zhu et al. [76] in 2021 to examine the association of genetically predicted blood concentration of VIC with CVD events such as CAD, atrial fibrillation, ischemic stroke, heart failure, and CVD risk factors such as serum lipids (high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides), blood pressure, and body composition. The study used two sample MR analyses, concluding that VIC’s genetically predicted blood concentrations do not influence the potential to produce major CVD, suggesting that VIC supplementation may not help prevent CVD. Chen et al. [77], in an MR study realized in 2021, wanted to show the correlation between the levels of VIC plasma concentration and the risk of CVD. They applied two-sample MR to highlight the causality of VIC with numerous CVD outcomes such as CAD, myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), stroke, and ischemic strokes and their subtypes. The study concluded that VIC plasmatic concentrations were associated with a lower risk of cardioembolic stroke and sufficient VIC intake might decrease the risk of this condition. Still, it has no effect in decreasing the risk of CAD, MI, AF, HF, or IS.

Several studies have also investigated VIC supplementation in hypertensive (but not in normotensive) patients, concluding that it reduced AH. VIC infusions also improved blood flow and reduced the susceptibility of LDL to oxidation [72,73,74,75,78,79,80,81,82,83,84,85,86,87,88,89,90]. A study from 2020, realized by Wang et al. [91], explored the potential of VIC to enhance low-density lipoprotein receptors and proprotein convertase subtilisin/kexin 9 (PCSK9). The in vitro experimental study was conducted on human liver cell lines and primary hepatocytes from animal models. Thus, the researchers demonstrated that VIC could inhibit PCSK9 expression‎ at the protein and transcriptional level via the transcription factor FoxO3a, which blocks PCSK9 activation by proteins such as HNF1a. It was also observed that VIC can increase LDL receptor (LDLR) expression‎ by reducing its PCSK9-mediated degradation. VIC also improves the stability of LDLR messenger RNA and activates SREBP2, another transcription factor. This may demonstrate that VIC supplementation may improve lipid profiles in VIC-deficient individuals and reduce CVD risks by lowering LDL levels and improving cholesterol metabolism. On the other hand, a study conducted by Boonthongkaew et al. [92] aimed to eval‎uate the effects on arterial blood pressure and oxidative stress following low-intensity exercise in patients with poorly controlled type 2 diabetes. The study was a randomized, controlled, double-blind, placebo-controlled, cross-over study in 24 patients (20 women, 4 men) with type 2 diabetes. Thus, patients were orally administered 1000 mg/day VIC for 6 weeks, their blood pressure was measured before and after exercise, and their oxidative stress markers (malondialdehyde-MDA, F2-isoprostanes) and nitric oxide (NO) levels were also monitored. Blood pressure and blood samples were taken before, immediately after, and 60 min after exercise. The results show that blood pressure fell in patients given VIC compared with placebo. The same result was also observed after 60 min. Also, plasma levels of MDA and F2 were significantly lower in the group receiving VIC, while NO levels increased significantly before and after exercise. Thus, the researchers conclude that oral supplementation with 1000 mg/day of VIC led to decreased plasma lipid peroxidation biomarkers of lipid peroxidation as measured by MDA and F2-IsoPs concentrations and increased NO concentration, which appears responsible for the hypotensive effect. Another study conducted in 2018 had similar results regarding the potential of VIC to lower blood pressure and oxidative stress levels in patients with type 2 diabetes [93].

Vasoplegic syndrome is another condition in which VIC may represent an alternative route for prevention and treatment. The vasoplegic syndrome is defined as low systemic vascular resistance, normal or high cardiac output, and hypotension that is unresponsive to treatment with vasopressor agents. This condition may be considered when perioperative refractory hypotension develops after cardiovascular or transplantation surgery. In this regard, VIC can reduce inflammation and enhance microcirculation. Also, VIC can reduce oxidative stress. It can increase susceptibility to catecholamines, like corticosteroids; restore the systemic vascular tone; and reduce the vasopressor need [94]. In two double-blinded randomized clinical trials conducted in two intensive care units in Perth, Australia [95], VIC was administrated intravenously in patients with vasoplegic shock. In this way, the researchers wanted to highlight if intravenous VIC can reduce vasopressor requirements. For this purpose, 71 patients were selected, 35 patients received the treatment with VIC (intervention group), and 36 patients represented the placebo group. The patients were randomly selected to receive VIC or placebo based on a computer randomization system with 1:1 allocation. The patients in the intervention group received 1.5 g sodium ascorbate in 100 mL normal saline every 6 h, for 15 min, over 5 days. The treatment was administrated till the vasoactive therapy was stopped when the mean arterial pressure was achieved (>65 mm Hg). Patients on dialysis received a higher concentration of sodium ascorbate (3 g) due to high clearance due to dialysis, under the same conditions as patients without renal replacement. The primary outcome was the duration of vasopressor usage in hours. Secondary outcomes were intensive care unit (ICU) and hospital length of stay, as well as 28-day ICU and hospital mortality. However, patients who were given at least a moderate dose of vasopressors in the ICU showed that intravenous vitamin C administration, compared with placebo, did not significantly reduce vasopressor duration.

Two meta-analyses have demonstrated improved endothelial function in patients with atherosclerosis and diabetes, improving arterial stiffness. Other studies have shown that high plasma concentrations of VIC contribute to stroke. However, some studies contradict this association. One meta-analysis showed that VIC, vitamin E, and beta-carotene supplementation had no significant effect on stroke risk [72,73,74,75,78,79,80,81,82,83,84,85,86,87,88,89,90]. Thus, it can be concluded that there are currently not enough recent studies and insufficient data to determine the potential of VIC to reduce the risk of CVD. However, the studies presented above may be a key point for future research.

In this regard, more studies need to be conducted considering additional criteria, such as the concentration of VIC in the blood of patients before starting the study, as well as the amount of VIC administered during the study and the diet of patients. Studies should also be carried out on several patients to establish a therapeutic dose, mode of administration, optimal targets, and even the need to administer other antioxidants simultaneously with VIC [52].

4.2. Cancer Prevention

Cancer remains one of the three leading causes of death worldwide, alongside infectious and cardiovascular diseases. The disease is characterized by abnormal cell growth that has undergone a lot of damage and changes in the cell cycle and metabolism. A critical aspect of this disease is finding optimal treatment that prevents cancer cells from spreading throughout the patient’s body and metastasizing. This should involve destroying the malignant cells without causing adverse effects or worsening patients’ health [96,97]. Due to the very high incidence of new cases, 19.3 million cases, and high mortality, with almost 10 million deaths reported in 2020, the need for efficient treatment is increasing [96,98].

VIC can be used as a chemopreventive agent for various forms of cancer. Its antioxidant effects and anti-inflammatory and anti-metastatic potential play an essential role in this process, improving intracellular communication. As previously mentioned, VIC decreases oxidative stress by neutralizing free radicals, preventing DNA degradation, and inhibiting the formation of nitrosamines (i.e., substances with carcinogenic potential). VIC also reduces the inflammation associated with carcinogenesis by reducing the occurrence of nitric oxide and the activation of nuclear factor kappa B (NF-κB). It can inhibit the activity of metalloproteinases (MMPs), which can lead to the degradation of CME and the development of metastases [99,100].

It has been observed that VIC cannot be associated with a lower risk of developing cancer, especially breast, endometrial, bladder, esophagus, lung, stomach, prostate, and kidney cancers. A Mendelian randomization study [101] collected data on several types of cancer, which have been mentioned above. Unfortunately, the study did not find conclusive evidence on the concentration of VIC and the incidence of the cancers examined. However, daily dietary intake of VIC was associated with a lower risk of lung cancer but not other cancers. In another meta-analysis [102], dietary intake of VIC from food was associated with an 18% decreased chance of developing lung cancer, but the supplements did not show any real benefit. At the same time, the antioxidant effect of VIC has been observed in preventing ROS and DNA damage. However, at high concentrations, VIC has a pro-oxidant effect, and the association with certain factors, such as smoking, could create a damaging effect. It was observed that an intake of VIC from fruits and vegetables may lead to the prevention of lung cancer, while supplements do not provide such benefits and are associated with a harmful effect [101,102,103].

4.3. Neuroprotective Effects

Worldwide, neurodegenerative diseases have been on the rise substantially, and it is now predicted that around 130 million people will be affected by dementia by 2050. Dementia is a neurodegenerative disease that leads to disability, institutionalization, and mortality, while Alzheimer’s disease accounts for 60–70% of dementia patients. Alzheimer’s disease is initially characterized by episodic memory loss, followed by deterioration of cognitive activity, such as difficulties with speech, executive and visuospatial activity, and eventually dementia. Parkinson’s disease is the second most common neurodegenerative disorder, which is characterized by bradykinesia, muscle rigidity, tremor, and impaired locomotor function and posture in individuals. This is due to the loss of dopamine-producing neurons [104].

The brain is prone to oxidative damage because it uses reactive species to transmit signals. It consists of about 86 billion neurons and about 300 billion glial cells, which are the main consumers of basal oxygen. At the same time, the human brain exhibits high oxidative metabolic activity, and thus, there is an intense production of ROS, which can damage neuronal cells that are not replicable. However, there are protective mechanisms, such as a cellular antioxidant system that prevents tissue damage, consisting of exogenous and endogenous antioxidants, which are designed to reduce various chemicals. Free radicals and other reactive molecules can disrupt cellular energy metabolism, causing oxidative stress and leading to a major imbalance between pro-oxidants and antioxidants. These radicals can further damage lipids, proteins, and nucleic acids, which can cause structural and functional changes. The brain has a high lipid content, which is the main target for oxidative damage. This can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Although neurons have mechanisms against oxidative stress, these are insufficient and make them vulnerable to redox reactions [105].

In certain brain regions, VIC reaches high concentrations needed to prevent oxidative stress and maintain redox balance. VIC is essential in redox reactions catalyzed by enzymes such as dopamine β-hydroxylase, which converts dopamine to norepinephrine, and other enzymes involved in synthesizing neuropeptides and arachidonic acid. VIC also contributes to myelination and the differentiation of neuronal precursors, playing a role in the development and maturation of the central nervous system. Deficiencies of VIC can lead to neuropsychiatric disorders, and many studies are trying to highlight its effect as an adjuvant therapy in this regard [106,107]. VIC may act as a neuroprotectant due to its antioxidant properties that allow for it to attenuate oxidative stress generated by various neurotoxins. In some cases, it is considered that VIC may also play a role in recovery after brain trauma and an effect against brain aging [106].

VIC is an important element in the optimal functioning of the central nervous system (CNS), where it acts as a powerful antioxidant. It plays a role in the differentiation and maturation of neurons, in the synthesis of catecholamines and neurotransmitters, and also contributes to the synthesis of collagen and elastin, which are essential for the structure of the CNS [108,109,110]. Treatment with divalent cations (e.g., iron and copper) leads to the formation of α-synuclein oligomers in the presence of DOPAL (dopamine aldehyde or 3,4-Dihydroxyphenylacetaldehyde), which is a neurotoxic product of dopamine metabolization. VIC can prevent this process by inhibiting DOPAL oxidation or interaction with divalent cations. In an experimental model of Parkinson’s disease (PD), it was observed that VIC favored the activity of antioxidant enzymes, preventing the onset of oxidative stress and the loss of dopaminergic neurons. Also, VIC acts as an activator for ten-eleven-translocation 1–3 (Tet1–3) and Jumonji C domain-containing histone demethylases (Jmjds), which have direct action in the demethylation of histone lysine residues and in the differentiation of dopaminergic neurons [111]. Unevenly distributed concentrations of VIC in the CNS may be a key factor in increasing susceptibility to oxidative stress, especially when dopamine is metabolized, which generates ROS and leads to specific protein accumulation in PD. Studies are attempting to associate VIC with this disease, and it has been found that VIC deficiency is a hallmark of PD. Some studies have shown that VIC-based supplements have been effective in ameliorating the effects of oxidative damage in experimental models, while a meta-analysis has emphasized that VIC from supplements has no effect in preventing PD. One explanation for this phenomenon may be attributable to the solubility of VIC, which must be transported across the blood–brain barrier in an active mode to reach the CNS. However, it has been observed that in patients with PD receiving levodopa, VIC contributes to an improved effect of this drug while also reducing the dosage and adverse effects [108,109,110].

VIC also plays an important role in the pathophysiology of Alzheimer’s disease since its antioxidant and neuroprotective properties are exerted on ROS, but also on amyloid plaques and neurofibrillary tangles characteristic of this disease. It is released by glial cells into the synaptic clefts and contributes to replenishing antioxidant enzymes such as glutathione and catalase, reducing oxidative stress and inflammation. VIC can also destabilize amyloid fibers, thus being a protective factor against fiber cytotoxicity. Studies in experimental models have suggested that VIC improves cognitive function and reduces the appearance of ROS, but in human subjects, this is not the case. However, an increase in the efficacy of VIC-associated treatments for Alzheimer’s and a reduction in the toxic effects of amyloid plaques was observed. It was also observed that low levels of VIC in plasma and cerebrospinal fluid in patients diagnosed with Alzheimer’s disease are closely related to advanced stages of the disease and correlated with reduced antioxidant activity [112,113].

4.4. Chronic Diseases Prevention

It is well known that oxidative stress contributes to the development of chronic diseases, such as diabetes mellitus, cardiovascular diseases, neurological disorders, psychiatric diseases, lung diseases, and many others. Thus, the effect of both antioxidant enzymes and small-molecule antioxidants (e.g., vitamin C) against oxidative stress and how their action prevents the development of chronic diseases is being studied [114].

For example, metabolic syndrome is characterized by several metabolic abnormalities such as large abdominal circumference, high blood pressure, high blood glucose, high triglyceride levels, and low HDL cholesterol levels, and is associated with an increased risk of CVD, type 2 diabetes, and stroke. In this regard, a meta-analysis has been conducted to demonstrate the role of VIC in managing this metabolic syndrome, which can lead to coronary heart disease. In human studies, it was observed that patients suffering from metabolic syndrome have a low concentration of VIC in the blood. It is known that oxidative stress and inflammation are correlated and that they lead to the negative evolution of metabolic syndrome. Through its antioxidant and anti-inflammatory properties, VIC contributes to alleviating these symptoms and complications associated with metabolic syndrome. Thus, in experimental animal models, the administration of VIC significantly contributed to weight loss and glycemia levels, stabilization of blood pressure, and an improved lipid profile by decreasing LDL and increasing HDL, and these effects were further observed in human studies. In this case, VIC acted as a reducing agent that neutralized free radicals, and the regulation of the inflammatory response was associated with a reduction in levels of inflammatory proteins (e.g., CPR-C-reactive protein), stimulating the immune system to fight against inflammation. VIC also stimulated carnitine synthesis, reducing body fat accumulation and influencing glycolysis by modulating hypoxic signaling [115]. Another study [116] conducted on the effects of natural antioxidants, including VIC, has shown a huge potential in reducing oxidative stress and improving insulin sensitivity in patients with diabetes mellitus, but also a potential in preventing the onset of this disease. As mentioned above, VIC helps lower blood pressure by improving blood flow, reducing LDL in healthy patients and patients suffering from other conditions such as diabetes mellitus, and preventing stroke [72,73,74,75,78,79,80,81,82,83,84,85,86,87,88,89,90].

Osteoarthritis is also considered a chronic disease that can lead to a deterioration of joint functions, such as stiffness and loss of motor skills. VIC has been studied as a potential treatment for this condition due to its antioxidant potential and its action in collagen synthesis as a cofactor. Here again, studies are contradictory regarding the action of VIC in combating this condition [117,118]. It has been shown to have a protective effect against cartilage degeneration, and in high concentrations, VIC may worsen osteoarthritis in experimental models [118]. In humans, it has been observed that VIC may prevent the onset of osteoarthritis, but also vice versa, with high concentrations of VIC being associated with an increased risk of developing osteoarthritis [117] and VIC did not prevent damage to cartilage structure [117,118].

5. Therapeutic Applications of Vitamin C5.1. Infectious Diseases

The immune system is the body’s defense against pathogenic agents (e.g., bacteria, viruses, fungi, parasites), cancer cells, and toxins. Its function is fulfilled by different organs, tissues, proteins, and chemicals and is simply classified into two defense categories: innate immunity and adaptive immunity. The first line of defense against invasive infection is innate immunity. The host utilizes this antigen-independent (non-specific) defense mechanism as soon as possible or within a few hours of contact with an antigen. Because the innate immune response has no immunological memory, it cannot recognize or “memorize” the same pathogen if the organism is re-exposed to it. On the contrary, adaptive immunity involves a lag period between exposure to the antigen and the maximal response because it is antigen-specific and antigen-dependent. Memory capacity allows for the host to develop a faster and more effective immune response to future re-exposure. Adaptive immunity and innate immunity are complementary defense processes for the body; deficiencies in either system make the organism vulnerable or cause inappropriate responses [119,120,121]. VIC is essential in enhancing the immune system by supporting various cellular functions of innate and adaptive immune systems, as summarized in Figure 3.

Figure 3. Schematic representation of VIC roles in innate and adaptive immunity. Created based on information from [121,122,123].

Vitamin C plays a crucial role in innate and adaptive immunity, influencing the epithelial barrier, supporting phagocytosis, and enhancing lymphocyte differentiation. These functions make it vital in preventing and treating infections [121,122]. Infectious diseases are caused by microorganisms that can be easily transmitted from one person to another, which can arise or re-emerge under specific conditions or situations. They can be new infections resulting from changes in pathogenic organisms or known infections that spread and re-emerge due to pathogens’ resistance to treatment [124].

In this regard, vitamin C has long been studied, and its deficiency has been associated with diseases such as pneumonia. Subsequently, numerous other studies have investigated it to fight other types of infections. It has been observed that VIC can prevent and help fight infections caused by viruses, bacteria, or protozoa. Infections cause oxidative stress in the human body, and any effect of VIC may be related to this. Infections lead to the activation of phagocytes, which cause ROS and are involved in processes that aim to inactivate viruses and kill bacteria. However, ROS can hurt host cells; VIC comes in with its antioxidant property, protecting cells from ROS. VIC is absorbed by phagocytes and is subsequently converted into DHA. Lymphocytes also need high concentrations of VIC (10–100 > plasma concentration) to help their proliferation and immune cell differentiation. VIC also contributes to regulating macrophage functions and improves innate immunity by inhibiting monocyte apoptosis and reducing the secretion of pro-inflammatory cytokines (e.g., IL6 and TNF-α). For neutrophils, VIC acts as a protector against the oxidation of cell membranes. Thus, VIC contributes to improved motility and phagocytosis of pathogens. In this sense, plasma VIC concentration decreases during infections, and supplementation may be a therapeutic strategy for treating infections [123,125,126].

It has also been observed that VIC exhibits antimicrobial properties, inhibiting the growth of several pathogens, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli, and at high concentrations, can also inhibit biofilm formation. VIC can also inhibit the replication of viruses like herpes simplex and rabies viruses and has antiparasitic effects, reducing the number of parasites in Trypanosoma cruzi and Plasmodium infections. In addition, vitamin C can inhibit the morphogenesis of some fungi, such as Candida albicans [123,127].

By its antioxidant effect, VIC can inhibit the oxidation of proteins, lipids, carbohydrates, and nucleic acids and affects the regulation of immune function by acting as a cofactor for enzymes involved in gene synthesis and expression‎. VIC has been observed to influence the integrity of the epithelial barrier, activate NK cells, and help differentiate CD4+ T cells into T helper (Th1) cells that produce interferon-gamma (IFN-γ). VIC can be absorbed in leukocytes in high concentrations (50–100 times higher than plasma concentrations), providing an antioxidant effect [55]. VIC influences leukocytes, and supplementation leads to enhanced mediated response (e.g., lymphocyte proliferation, delayed-type hypersensitivity response, antimicrobial activity). It was observed that 1 g/day of VIC for 28 days increased T lymphocyte proliferation and the production of cytokines and immunoglobulins to enhance the immune response against infection. Phagocytic cells (e.g., neutrophils and macrophages) show a high concentration of VIC, which stimulates their migration to the site of infection and enhances phagocytosis, oxidant generation, and pathogen killing. However, VIC also prevents excessive action of the immune system and reduces tissue damage by increasing neutrophil apoptosis and their elimination by macrophages. This process prevents necrosis [119,120,121,128].

VIC may also influence the production of cytokines, which are secreted by immune cells in infection and inflammation and are responsible for regulating both humoral and cellular immune responses, eliciting pro-inflammatory or anti-inflammatory responses. Cytokines are categorized into chemokines, interferons (IFN), interleukins (IL), lymphokines, and TNF. In vitro studies have shown that VIC has the potential to decrease the secretion of the pro-inflammatory cytokines TNF-α and IFN-γ while considerably increasing the production of IL-10. In patients with pneumonia, VIC also increased TNF-α and IL-6, enhanced antiviral IFN generation in virus-infected fibroblasts, and normalized cytokine generation depending on the inflammatory stimulus and cell type [121].

5.2. Respiratory Illnesses

The common cold is one of the most common upper respiratory tract viral infections, with mild symptoms associated with a sore throat, cough, fever, fatigue, and muscle aches. It lasts from a few days to a maximum of three weeks. The rhinovirus is the main pathogen responsible for the common cold, present in 30–50% of cases [4,123,126,129,130].

In the 1970s, Nobel Prize-winning researcher Linus Pauling proposed using VIC to prevent and relieve the symptoms of colds. A review of placebo-controlled studies [131] concluded that taking 200 mg doses of VIC did not decrease the incidence of colds in the general population but significantly affected people under physical exertion (e.g., athletes). It was also found that the administration of VIC at the onset of colds showed no clear benefit, but regular administration reduced the duration of infection by 8% in adults and 14% in children. Placebo-controlled studies have shown that VIC can reduce the severity and duration of symptoms, with some reporting a reduction of as little as 5% in some cases and others reporting a reduction of 50%. The benefits of VIC against colds have been found in people who have had a low intake of VIC and in adults who are in constant contact with children [4,123,126,129,130]. Also, a study carried out in 2019 by Kim et al. [132] aimed to show that oral supplementation with VIC can reduce the chance of developing a common cold in army recruits from the Republic of Korea. The study involved 1444 participants who were divided into two groups. The first group (695 people) received 6000 mg/day of VIC, while the second group (749) received a placebo for 30 days. The study thus demonstrated that taking VIC can reduce the occurrence of common colds in recruits who are undergoing basic military training.

Pneumonia is a severe lower respiratory tract infection caused by pathogens such as Streptococcus pneumoniae and Haemophilus influenzae, which manifests as cough, fever, muscle aches, dyspnea, sputum production, and chest pain. Untreated pneumonia can lead to acute respiratory distress syndrome (ARDS), which manifests as hypoxia and pulmonary edema [4,130,133,134]. It was observed that VIC reduced respiratory symptoms in people with severe pneumonia, and it was concluded that high-dose VIC could reduce the duration of hospitalization of patients with severe pneumonia by 36%. There was also found to be a lower incidence of pneumonia in people who received vitamin C supplementation [4,126,130,133]

COVID-19 is a new form of pneumonia caused by infection with the SARS-CoV-2 virus, provoking an excessive inflammatory reaction leading to ARDS and multiple organ failure. Some patients may experience mild symptoms, while others may be asymptomatic, but about 5% of cases go on to develop ARDS. In this context, VIC may protect the endothelium against oxidative damage and contribute to the faster healing of damaged tissues. SARS-CoV-2 can suppress the activity of the host immune system, but VIC contributes to enhancing the activity of the immune system by amplifying the antiviral immune response. In addition, VIC has been shown to reduce neutrophil accumulation in the lungs, aiding the clearance of alveolar fluid and strengthening the barrier function of the lung epithelium. The fact that VIC helps decrease the duration and symptoms of respiratory infections may be a key factor in treating the symptoms and progression of COVID-19 [4,126,130,135,136].

5.3. Sepsis and Critical Care

Sepsis is a severe medical condition with a high mortality rate (20–35%) among patients, which is characterized by an uncontrolled response of the body to infection, with a systemic inflammatory response, ultimately leading to severe organ dysfunction. The characteristic symptoms of sepsis are the development of systemic inflammation and multiple organ dysfunction up to the development of septic shock. Sepsis can affect any organ system, and one of the most serious complications is ARDS. Sepsis particularly affects patients susceptible to serious infections (e.g., elderly patients with multiple comorbidities), and the most common sources of infection are pneumonia, abdominal infections, and endovascular infections [137,138].

At the cellular level, sepsis produces ROS and RNS that further activate inflammatory transcription factors, affecting the endothelium and microvascularization. Although inflammatory or coagulative mediators have been included in conventional treatment, they have not significantly improved sepsis symptoms and, thus, mortality rates. It has been observed that in critically ill patients, plasma VIC concentration levels are low, which may be associated with a higher incidence of organ failure. This is due to the massive release of cytokines, which affect VIC uptake. At the same time, the low concentration of VIC may also be attributable to the high production of ROS, which contributes to the high VIC uptake [137,138].

Now, there is no optimal treatment that can guarantee the cure of sepsis, and VIC has been proposed as an adjuvant in therapy, in addition to antibiotics, fluids, and vasopressors, due to its ability to reduce inflammation and oxidative stress. The use of VIC could reduce mortality in patients with sepsis. Several placebo-controlled clinical trials focused on VIC administered intravenously in adults with sepsis who were also receiving vasopressor therapy. It was reported that, compared with the group receiving a placebo, the group receiving VIC had a higher mortality rate. A meta-analysis demonstrated the positive effects of VIC administration in patients with sepsis. Two smaller studies also showed decreased mortality in patients treated with VIC. However, the researchers could conclude that adults treated with vasopressors and intravenous VIC had an increased risk of death or organ dysfunction compared to the placebo group [137,138].

5.4. Cancer Therapy

The first approach to VIC as a cancer treatment was in 1970 when chemist Linus Pauling and physician Ewan Cameron suggested that a high concentration of VIC administered to patients with terminal cancer could increase survival rates [139,140]. Their pioneering study demonstrated that the daily administration of 10 g of VIC to 100 terminally ill cancer patients significantly improved outcomes, with 10% surviving, compared to no survivors among 1000 patients receiving conventional treatment alone. In more detail, the patients receiving VIC supplementation had a mean survival time of more than 210 days, while the mean survival time of controls was 50 days [141].

VIC has started to be studied to obtain new and efficient treatment in the fight against cancer due to its antioxidant, pro-oxidant, and gene expression‎ regulator properties. These properties help to keep tissues and their functions in better condition by protecting macromolecules (e.g., proteins, fats, DNA) from oxidation [139,140]. VIC is involved in various molecular mechanisms that underlie its anticarcinogenic effect. VIC leads to the inhibition of cell proliferation and growth by generating ROS and altering the expression‎ of genes involved in angiogenesis, glycolysis, and metastasis by regulating the transcriptional activity of hypoxia. VIC also allowed for T lymphocyte infiltration and induced cytokine production, resulting in an anti-tumor immune response [142].

As a potential cancer treatment, it has also been observed that the effects of VIC on cancer are dependent on the route of administration, whether oral or intravenous, as well as on the mode of transport of VIC into tumoral cells (Figure 4). For example, it has been observed that some tumor cells absorb more VIC due to increased expression‎ of SVCT2 and/or GLUT1 genes. To be transported, dehydroascorbic acid has to be formed by oxidation of extracellular ascorbic acid to be taken up by the transporter cell. The dehydroascorbic acid is again reduced inside the cell, which consumes other antioxidants and leads to intracellular oxidative stress. Also, in tumors with high SVCT2 gene expression‎ (e.g., breast cancer, liver cancer), VIC killed cancer cells by mega-dose (0.5 mM) administration of VIC [143]. It has also been observed that AA and/or DHA can act as an adjuvant in cancer drug therapies such as paclitaxel [144], cisplatin [145], and methotrexate [146], highlighting the role of GLUT as a carrier for VIC in cancer cells and showing promise for future combined treatment approaches.

Nonetheless, there is still limited evidence and controversy around DHA role in VIC cancer treatment. While some studies suggest a potential role of DHA in cancer therapy, others, such as Piotrowski et al. [147], report no significant cytotoxic effects under clinically relevant conditions. The authors concluded that it was rather the effect of high-dose ascorbate than of DHA that induced severe cytotoxicity in human glioblastoma cell lines. Therefore, further research is required to confirm‎ DHA efficacy and establish its mechanisms of action.

Figure 4. Effects of VIC doses on tumoral cells: I. physiological dose; II. pharmacological dose. Created based on information from [143,148].

For effective administration of VIC in the body, the route of administration must be carefully considered. Taking into account the barriers related to oral administration, the plasma concentration of VIC is achieved only at μM levels, so intravenous administration of VIC is preferable to achieve a higher concentration. On the other hand, each cancer cell type has its specific ability to absorb and metabolize VIC. For example, breast cancer cell lines had a high capacity to reach the oxidized form of VIC due to overexpression‎ of SVCT2 genes, associated also with a higher resistance to oxidative stress. The use of pharmacologic doses of VIC led to increased sensitivity to treatment. Figure 4 proposes a model of VIC transporters in breast cancer cells. Thus, at physiological doses of ascorbic acid, it is oxidized to DHA by free radicals generated by leukocytes. DHA is then transported into cancer cells by glucose transporters (GLUTs), where it is reduced and returned to the ascorbic acid form, which reduces oxidative stress in the cells. This can give cancer cells a protective effect that supports their survival rate. Instead, high doses of ascorbic acid may generate a higher concentration of free radicals by oxidative reactions. The free radicals enter cancerous cells and produce oxidative stress. In this case, ascorbic acid can induce cancerous cell death and cellular arrest by an intense oxidative process [148].

A study on mice [149] showed that in vivo peritoneal injection of 4 g of VIC per kilogram of body weight conduced to a decreased rate of ovarian, pancreatic, and glioblastoma tumor growth by pro-oxidation effect. The pro-oxidative effect of VIC is associated with the reduction of transitional metals (e.g., Fe3+ and Cu2+), and hydrogen peroxide’s appearance leads to free radicals formed by Fenton and Haber–Weiss reactions.

Thus, VIC injection leads to extracellular hydrogen peroxide production, which is further accumulated in the mitochondria of cancer cells, therefore inducing caspase-independent autophagy. This pro-oxidant effect has been observed in K-ras and BRAF cancer cells. It was also observed that a 20 mM VIC concentration could selectively kill cancer cells without affecting healthy cells [143,148].

In a study led by Gillberg et al. [142], oral administration of VIC in patients with myeloid cancer was investigated to determine whether supplementation can lead to improvement of VIC deficiency and its effects on treatment. Patients with hematologic malignancies are generally deficient in VIC. In their case, VIC is essential for the TET-induced conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), the first step in active DNA demethylation. Thus, the administration of 500 mg VIC led to the restoration of plasma VIC levels in all the patients to which it was administered. The researchers observed an increase in the 5 hmC/5 mC ratio compared to placebo-treated patients, which may enhance the biological effects of DNMTis. It also suggests that administering VIC to DNMTis should be studied further in larger clinical trials.

Some recent statements showed that VIC has a synergic effect combined with some anti-tumoral drugs. For example, gemcitabine combined with VIC has a cytotoxic effect against eight pancreatic cancer cell lines by producing hydrogen peroxide. Also, in a mouse model, it was observed that this combination inhibited tumor growth. Also, the same effect was observed in the administration of carboplatin and paclitaxel in combination with VIC on ovarian cancer cell lines. VIC also reduced the adverse effects of chemotherapy treatment in mouse models [148,150,151]. A 2018 study [151] showed the effect of auranofin with VIC and a strong anticarcinogenic effect of these two combined against MDA-MB-231 and other breast cancer cell lines. Researchers concluded that this combination has the potential to be an efficient treatment for triple-negative breast cancer and other cancer types with the same redox potential. Another in vitro study [152] has shown that high-dose vitamin C (1.25 to 20 mM) combined with conventional cancer treatments could boost the effects against breast cancer. On the other hand, a study conducted by Wang et al. [153] investigates the efficacy of adding VIC to the treatment regimen of patients with unresectable metastatic colorectal cancer (mCRC). The 442 patients were divided into two groups: an experimental group receiving high-dose VIC + FOLFOX + bevacizumab, and a control group receiving FOLFOX + bevacizumab alone. Treatment was given in two two-week cycles for 12 weeks, followed in some cases by maintenance treatment. The study showed that VIC added at a high dose (1.5 g/kg/day, intravenously for 3 h from day 1 to day 3) did not significantly contribute to overall benefit. However, the treatment was well tolerated by patients and may offer benefits for patient groups with RAS mutations. A phase II trial, realized by Paller et al. [154], investigated the effect of high-dose intravenous VIC combined with docetaxel in men with progressive metastatic castration-resistant prostate cancer. In this respect, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2) intravenous and high-dose VIC (1 g/kg) or placebo. The study aimed to observe the PSA50 response and the side effects. The researchers concluded that high-dose VIC and docetaxel did not improve the PSA50 response, toxicity, or other clinical outcomes.

Yet, VIC showed that it can reduce the adverse effects of radiotherapy treatment. VIC can enhance the cytotoxicity effect of the radiation in different tumoral pancreatic cell lines without affecting healthy cells. This effect is produced because of increased oxidative stress in tumoral cells. In this context, VIC led to a decreased tumor growth rate and a higher survival rate. It can be concluded that VIC can be used as a complementary treatment for radiotherapy for pancreatic cancer patients [148,155].

Thus, it has been shown that using VIC in high doses can exert anti-tumor activity by generating ROS in malignant cells without affecting healthy cells. It has also been suggested that VIC can enhance the effects of both chemotherapy and radiotherapy [147,156]. However, studies are still needed to demonstrate the efficacy and safety of using high doses of VIC for such a therapeutic application.

5.5. Wound Healing

The skin is the largest organ of the human body, composed of the epidermis (epithelial tissue), dermis (connective tissue), and the subcutaneous layer called hypodermis. The epidermis comprises multiple layers, such as the stratum corneum, the stratum granulosum, the stratum spinosum, and the basal stratum, each of which is composed of cells such as keratinocytes, pigment cells and melanocytes, Langerhans cells, mast cells, and Merkel cells. The dermis has papillary and reticular layers that contain fibroblasts, which are important in the synthesis of collagen, elastin glycosaminoglycans, blood vessels, neovessel endings, sweat, and sebaceous glands, including hair bulbs. The hypodermis consists of adipose cells that form fat lobules. The skin is involved in protecting the body from external factors (e.g., chemicals, pathogens), moisturizing, temperature regulation, and vitamin D synthesis [157,158].

Wound healing assumes numerous stages, such as hemostasis, inflammation, proliferation, and remodeling. Hemostasis is the first stage in wound healing and is accomplished by constricting blood vessels and forming fibrin clots to stop bleeding, followed by inflammation. In inflammation, immune cells (e.g., neutrophils and macrophages) arrive at the wound’s site and help eliminate pathogens and cell debris. In the proliferation stage, fibroblasts and keratinocytes migrate and proliferate at the wound site, forming collagen fibers and regenerating the injured tissue; then, in the remodeling stage, collagen is reorganized, and thus the structure and functions of the skin are restored [159]. In this regard, VIC plays an essential role in synthesizing connective tissue, especially in synthesizing collagen, for which it plays a cofactor role. VIC may also confer strength to collagen fibers, especially tensile strength. It has also been observed that VIC may contribute to increased activity of dermal fibroblasts, potentiating the wound healing effect. In addition to its role in collagen synthesis, VIC may reduce the occurrence of pro-inflammatory factors during wound healing, accelerate the healing process, and contribute to the faster removal of neutrophils from the inflamed area. Hypoxia-induced inhibitory factor-1 (HIF-1), essential for cellular metabolism and angiogenesis contributor, may also be activated in wounds. Under hypoxic conditions, this factor is no longer adequately degraded and can form protein complexes that lead to the transcription of genes responsible for cell proliferation, angiogenesis, and glucose metabolism. In the presence of VIC, this factor reduces its activity, helps combat the negative effects of hypoxia, and considerably reduces scarring [158,160,161,162].

For a better effect on wound healing, it has been observed that topically applied VIC may be more effective for delivery to the skin than orally administered, and there is an increased improvement in tissue regeneration and healing of surgical wounds. Other studies have also observed that administering VIC to diabetic mouse models contributed to increased collagen production, improved angiogenesis, and reduced inflammation. In vitro on human fibroblast cells, VIC was found to increase the expression‎ of type I and III collagen [158,160,161].

Other studies were performed by Bikker et al. [162] on hospitalized patients. The first study was performed on a case represented by a 59-year-old man who underwent a laparotomy for diverticulitis, followed by appendectomy and sigmoid colectomy. It was noted that after surgery, she had had two abdominal dehiscences, which were surgically corrected. Also, the healing process was slow, and the size of the surgical wound was not reduced after alginate dressings were applied. Thus, oral supplementation with VIC (1000 mg/day) was started, and after about 3 weeks, healthy granulation was observed, with a considerable reduction in the wound, which closed completely after almost 3 months.

Another case [162] was a 79-year-old woman with severe ulcers on the lower limbs, followed by surgical resection of the necrosis, after which slow healing was observed. After supplementation with 1000 mg/day of VIC, the wounds started to heal, and after 8 weeks, healing was complete. Another 68-year-old woman with Crohn’s disease and diabetes underwent ileocecal resection and developed severe peritonitis. After administration of 1000 mg/day of VIC, both intravenous and orally, healing was accelerated without the need for surgery.

Another study [163] aimed to eval‎uate the effects of VIC supplementation on the healing process of wounds caused by dental extractions. Thus, patients were given oral doses of 600 mg/day of VIC and 1500 mg/day divided over three doses for 10 days. A dose of 600 mg/day led to a significant reduction in the wound size 7 days after extraction, compared with a dose of 1500 mg/day, which did not provide any additional benefit. VIC was found to lead to rapid fibroblast differentiation and granular tissue formation. It was also observed that postoperative pain was reduced due to the reduced inflammatory process due to VIC.

An analysis of several studies [164] on using VIC in treating foot ulcers in patients with diabetes suggested that administering VIC accelerated healing. Patients who received VIC had a significant reduction in healing time, while it also led to reduced postoperative pain. Likewise, another analysis [165] eval‎uated the potential of VIC against leg ulcers, noting that VIC supplementation led to good healing outcomes. The same review eval‎uated the possibility of using VIC in oral care, recommending its supplementation in patients’ diets [165].

6. Ongoing Research

According to the ClinicalTrials.gov platform, more studies could bring promising new results regarding the use of VIC as a potential therapeutic agent. Thus, selected interventional trials with results in phases 3 and 4 are presented in Table 3.

Table 3. Summary of interventional clinical studies about VIC as a therapeutic agent.

7. Conclusions

Vitamin C is essential for maintaining biological functions through its antioxidant effect and mode of action as a cofactor for enzymes involved in synthesizing collagen or catecholamines. It is vital to prevent scurvy, which is associated with a major deficiency of VIC in the body. At the same time, VIC is important in maintaining long-term health, with a multitude of benefits that may contribute to the prevention of chronic disease, cardiovascular disease, and even cancer prevention or treatment.

Thus, this review highlighted aspects related to the therapeutic properties of VIC. Some of the studies presented in this review demonstrate the beneficial effects of administering VIC for various conditions (e.g., scurvy, cardiovascular disease, hypertension, infections, pneumonia, COVID-19, sepsis, neurodegenerative diseases, wound healing), as well as data that contradict these aspects or that do not find an association between VIC and the presenting conditions. In some cases, researchers have seen the benefits of using VIC in therapy, while other results have indicated that VIC may increase the risk of certain diseases. Discrepancies in study results may arise from differences in monitoring plasma Vitamin C levels, varying delivery methods (oral vs. intravenous), and challenges in controlling external variables such as diet. An important factor in this is the lack of long-term studies that focus on the concentration of VIC in the blood, not just on a dietary questionnaire. It has also been observed that VIC is not efficiently absorbed in high concentrations but may produce undesirable adverse effects, such as kidney stones or nephropathy oxalate. Targeted delivery systems, such as encapsulated vitamin C or controlled-release formulations, could minimize gastrointestinal side effects associated with high-dose supplementation. Hence, future studies should focus on standardizing vitamin C plasma monitoring protocols, optimizing delivery systems to maintain therapeutic levels, and exploring combined antioxidant therapies to enhance efficacy.

In conclusion, with continuous studies that deepen the understanding of its effects and optimum dosages, VIC has the potential to become an alternative therapeutic strategy, remaining an important nutrient for both health maintenance and biological function in the human body.

Author Contributions

A.A., E.-T.M., A.-G.N. and A.M.G. have participated in the review’s writing and revision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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