Re: 타우린 인체 대부분 질환 치료 '울혈성 심부전' 치료제 일본 승인...

[문형철]

차아염소산염을 중화시켜 타우린 클로라민을 생성하여 항염증(Kim and Cha, 2014; Marcinkiewicz and Kontny, 2014)

미토콘드리아에서 tRNALeu(UUR)의 우리딘과 결합하여 슈퍼옥사이드 감소 (Jong et al., 2012; Schaffer et al., 2014a)

미토콘드리아 ND6 단백질을 암호화하여 ATP를 생성합니다 (Jong et al., 2012; Schaffer et al., 2016; Shetewy et al., 2016) 미토콘드리아 막 투과성 및 세포 사멸을 방지합니다 (Ricci et al., 2008, Shetewy et al., 2016).

타우린 접합을 위한 기질을 제공하여 미토콘드리아 질환인 MELAS에 도움이 됩니다(Rikimaru 외, 2012; Schaffer 외, 2014b).

해당 과정 중 NADH/NAD+ 비율을 감소시켜 복합체 I 및 NADH 민감성 효소를 활성화합니다 (Schaffer et al., 2016).

PPAR알파 수치를 증가시켜 지방산 산화를 회복시킵니다(Schaffer et al., 2016).

담즙산과 결합하여 장에서 지질 흡수를 촉진합니다 (Schaffer et al., 2016).

신진대사 관련 유전자의 전사 프로파일을 변화시킨다 (Park et al., 2006).

장수를 유도하는 유전자를 조절합니다 (Ito et al., 2014a).

전사인자 변화 (Schaffer et al., 2016)

단백질 인산화 및 세포 신호 전달을 조절합니다(Lombardini, 1996; Ramila 외, 2015).

단백질 폴딩을 개선하여 ER 스트레스를 완화합니다(Ito et al., 2015a).

ER 스트레스를 억제하여 뇌졸중 뇌 손상을 개선합니다(Gharibani 외., 2015).

뇌졸중 및 알츠하이머병의 신경세포 보호 (Prentice et al., 2015)

GABAA, 글리신 및 NMDA 수용체에 작용하여 CNS를 보호합니다(El Idrissi and L'Amoreaux, 2008; Chan et al., 2013).

GABAA 수용체와 결합하여 발작을 감소시킵니다 (L'Amoreaux et al., 2010).

글루탐산 탈카르복실 효소를 증가시켜 발작을 예방합니다 (El Idrissi and L'Amoreaux, 2008).

유비퀴틴-프로테아좀 시스템과 오토파지를 활성화하여 심근세포를 보호합니다(Jong et al., 2015).

독소 매개 오토파지를 약화시킵니다(Li et al., 2012; Bai et al., 2016).

Ca2+ 과부하를 감소시켜 심근경색 및 뇌졸중 시 심장과 뇌를 보호합니다(Li et al., 2012; Bai et al., 2016).

허혈-재관류 중 타우린 손실은 저산소증으로 인한 Ca2+ 과부하를 감소시켜 심장을 보호합니다 (Schaffer et al., 2002).

타우린 고갈은 SR Ca2+ ATPase의 활성 감소로 인해 심근 병증을 유발합니다 (Ramila et al., 2015).

Ca2+ 결합 단백질을 유도하여 간질 중 뇌 신경세포를 보호합니다 (Junyent et al., 2010).

글루타메이트에 의한 [Ca2+]i의 상승을 감소시켜 글루타메이트 흥분 독성으로부터 뉴런을 보호합니다 (Wu et al., 2005).

Biomol Ther (Seoul)

. 2018 Apr 10;26(3):225–241. doi: 10.4062/biomolther.2017.251

Effects and Mechanisms of Taurine as a Therapeutic Agent

Stephen Schaffer 1, Ha Won Kim 2,*

• Author information
• Article notes
• Copyright and License information

PMCID: PMC5933890  PMID: 29631391

Abstract

Taurine is an abundant, β-amino acid with diverse cytoprotective activity. In some species, taurine is an essential nutrient but in man it is considered a semi-essential nutrient, although cells lacking taurine show major pathology. These findings have spurred interest in the potential use of taurine as a therapeutic agent. The discovery that taurine is an effective therapy against congestive heart failure led to the study of taurine as a therapeutic agent against other disease conditions. Today, taurine has been approved for the treatment of congestive heart failure in Japan and shows promise in the treatment of several other diseases. The present review summarizes studies supporting a role of taurine in the treatment of diseases of muscle, the central nervous system, and the cardiovascular system. In addition, taurine is extremely effective in the treatment of the mitochondrial disease, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and offers a new approach for the treatment of metabolic diseases, such as diabetes, and inflammatory diseases, such as arthritis. The review also addresses the functions of taurine (regulation of antioxidation, energy metabolism, gene expression‎, ER stress, neuromodulation, quality control and calcium homeostasis) underlying these therapeutic actions.

초록
타우린은 

다양한 세포 보호 활성을 가진 풍부한 β-아미노산입니다. 

일부 종에서는 타우린이 필수 영양소이지만 

사람에게는 준필수 영양소로 간주되지만 

타우린이 부족한 세포는 주요 병리를 보입니다. 

이러한 발견은 

타우린의 치료제로서의 잠재적 사용에 대한 관심을 불러일으켰습니다. 

타우린이 

울혈성 심부전에 효과적인 치료법이라는 사실이 밝혀지면서 

타우린을 다른 질병에 대한 치료제로 연구하게 되었습니다. 

오늘날 타우린은 

일본에서 울혈성 심부전 치료제로 승인되었으며 

다른 여러 질병의 치료에도 가능성을 보이고 있습니다. 

이 리뷰에서는 

근육, 중추신경계 및 심혈관계 질환 치료에서 

타우린의 역할을 뒷받침하는 연구를 요약합니다. 

또한 

타우린은 

미토콘드리아 질환, 

미토콘드리아 뇌병증, 

젖산증, 

뇌졸중 유사 에피소드(MELAS) 치료에 매우 효과적이며 

당뇨병과 같은 대사 질환과 관절염 같은 

염증성 질환의 치료에 새로운 접근법을 제시합니다. 

또한 이러한 치료 작용의 근간이 되는 

타우린의 기능

(항산화, 에너지 대사, 유전자 발현, ER 스트레스, 신경 조절, 품질 관리 및 칼슘 항상성 조절)에 대해서도 

다룹니다.

Keywords: Taurine, Cytoprotection, Neurodegenerative diseases, Antioxidation, ER stress, MELAS

INTRODUCTION

Taurine is a β-amino acid found in very high concentration in most cells, with levels particularly high in excitable tissues. Although taurine possesses many functions in mammals, its cytoprotective actions have attracted the most attention, as they dramatically alter the health and nutritional status of various species. Because taurine regulates fundamental events in the cell, while altering the balance between life and death, interest in taurine’s physiological functions has grown. These findings have provided impetus for the use of taurine in infant formula, nutritional supplements and energy drinks. It also has stimulated research into its potential therapeutic uses. Although most of those studies have focused on taurine-mediated reversal of pathology in animals, there have been attempts to translate the basic science findings into clinical applications. Results of many clinical studies have been encouraging, suggesting a promising future for taurine therapy (Ginguay et al., 2016). Equally promising are studies showing the nutritional value of taurine (McCarty, 2013). In some species, such as the cat and fox, taurine is an essential nutrient (Schmidt et al., 1976; Novotny et al., 1991; Ito et al., 2008; Ripps and Shen, 2012). Not only does taurine deficiency cause pathology in those animals but it also shortens their lifespan (Ito et al., 2014a; Park et al., 2014). By contrast, taurine is classified as a conditionally essential nutrient or a functional nutrient in man (Gaull, 1986, 1989; Bouckenooghe et al., 2006). Although humans are incapable of synthesizing large amounts of taurine, the retention of taurine by human tissues is greater than that of cats or fox. Thus, unlike cats, humans do not readily develop overt signs of taurine deficiency although parenteral feeding can be associated with taurine deficiency (Arrieta et al., 2014). Nonetheless, human studies have revealed the nutritional value of taurine. Particularly noteworthy is a World Health Association study involving 50 population groups in 25 different countries throughout the world, which reports that elevated dietary taurine consumption is associated with decreased risk of hypertension and hypercholesterolemia (Yamori et al., 2004; Sagara et al., 2015). Taurine supplementation is also linked to diminished body mass index (Yamori et al., 2010) and reduced levels of inflammation markers in obese women (Rosa et al., 2014). Thus, the cytoprotective actions of taurine contribute to an improvement in the clinical and nutritional health of humans. The present review discusses the mechanisms underlying the cytoprotective activity of taurine, the influence of taurine on a wide range of diseases and the nutritional value of taurine supplementation.

소개

타우린은

대부분의 세포에서 매우 높은 농도로 발견되는 β-아미노산으로,

특히 흥분성 조직에서 수치가 높습니다.

타우린은

포유류에서 많은 기능을 가지고 있지만,

다양한 종의 건강과 영양 상태를 극적으로 변화시키기 때문에

세포 보호 작용이 가장 주목을 받고 있습니다.

타우린은

세포의 근본적인 사건을 조절하는 동시에

삶과 죽음 사이의 균형을 변화시키기 때문에

타우린의 생리적 기능에 대한 관심이 커졌습니다.

이러한 발견은

유아용 조제분유,

영양 보충제,

에너지 음료에 타우린을 사용하는 데 원동력이 되었습니다.

또한

타우린의 잠재적인 치료적 용도에 대한 연구도 활발해졌습니다.

이러한 연구의 대부분은

타우린을 매개로 한 동물의 병리 역전에 초점을 맞추었지만,

기초 과학 연구 결과를 임상 적용으로 전환하려는 시도도 있었습니다.

많은 임상 연구 결과가 고무적이며

타우린 치료의 유망한 미래를 제시하고 있습니다(Ginguay 외., 2016).

타우린의 영양학적 가치를 보여주는 연구도 마찬가지로 유망합니다(McCarty, 2013).

고양이와 여우와 같은 일부 종에서 타우린은 필수 영양소입니다(Schmidt 등, 1976; Novotny 등, 1991; Ito 등, 2008; Ripps and Shen, 2012).

타우린 결핍은

이러한 동물에게 병리를 일으킬 뿐만 아니라

수명을 단축시킵니다(Ito et al., 2014a; Park et al., 2014).

반면

타우린은

인간에게 조건부 필수 영양소 또는

기능성 영양소로 분류됩니다(Gaull, 1986, 1989; Bouckenooghe et al., 2006).

인간은

다량의 타우린을 합성할 수 없지만,

인간 조직의 타우린 보유량은 고양이나 여우보다 더 많습니다.

따라서

고양이와 달리 인간은

비경구 사료 공급이 타우린 결핍과 관련이 있을 수 있지만

타우린 결핍의 명백한 징후가 쉽게 나타나지 않습니다(Arrieta 등., 2014).

그럼에도 불구하고

타우린의 영양학적 가치는

인간을 대상으로 한 연구를 통해 밝혀졌습니다.

특히 주목할 만한 연구로는

전 세계 25개국의 50개 인구 집단을 대상으로 한 세계보건기구의 연구로,

식이 타우린 섭취 증가가 고혈압 및 고콜레스테롤혈증 위험 감소와 관련이 있다고 보고했습니다

(Yamori 외, 2004; Sagara 외, 2015).

초록 우리는 이전에 24시간 요중 타우린(Tau) 배설이 관상동맥 심장 질환(CHD) 및 뇌졸중으로 인한 사망률과 반비례한다는 사실을 밝힌 바 있습니다. 이 연구의 목적은 24시간 요중 타우/크레아티닌(Cre) 비율과 체질량 지수(BMI), 혈압(BP), 혈청 총 콜레스테롤(TC), 비만, 고혈압, 고콜레스테롤혈증 유병률을 포함한 심혈관 질환 위험 요인 간의 연관성을 조사하는 것이었습니다. 단면 분석은 세계보건기구가 조정한 심혈관 질환 및 소화기 비교 연구(1985-1994)에 참여한 22개국 50개 인구 표본의 48-56세 참가자 4,211명(남성 2,120명, 여성 2,091명)을 대상으로 실시되었습니다. 연령, 성별, 항고혈압 치료와 같은 전통적인 위험 요인을 조정한 선형 회귀 분석에 따르면 Tau/Cre는 BMI, 수축기 혈압, 이완기 혈압 및 TC와 반비례했습니다(각각 선형 추세에 대한 P <0.001). 이러한 연관성은 24시간 요중 나트륨/Cre, 칼륨/Cre, 칼슘/Cre, 마그네슘/Cre 및 코호트 효과에 대한 추가 조정 후에도 크게 달라지지 않았습니다. 전통적인 위험 요인을 조정한 후, 타우/Cre 비율의 최하위 5분위수에 속한 피험자의 비만, 고혈압, 고콜레스테롤혈증 유병률은 최상위 5분위수에 속한 피험자에 비해 각각 2.84(95% CI: 2.04, 3.96; P 경향 <0.001), 1.22(95% CI: 0.98, 1.51; P <0.05), 2.20(95% CI: 1.73, 2.80; P <0.001) 배 더 높았습니다. 이러한 연관성은 다른 24시간 소변 마커와 코호트 효과를 추가로 조정한 후에도 크게 달라지지 않았습니다. 결론적으로, Tau/Cre 수치가 높을수록 BMI, 혈압, TC, 비만, 고혈압, 고콜레스테롤혈증 등 심혈관 질환 위험 인자가 낮은 것으로 나타났습니다.

타우린 보충제는

또한 비만 여성의 체질량 지수 감소(야모리 외, 2010) 및

염증 마커 수치 감소(로사 외, 2014)와도 관련이 있습니다.

따라서

타우린의 세포 보호 작용은

인간의 임상 및 영양 건강 개선에 기여합니다.

이 리뷰에서는

타우린의 세포 보호 작용의 기본 메커니즘,

다양한 질병에 대한 타우린의 영향,

타우린 보충제의 영양학적 가치에 대해 설명합니다.

MECHANISMS UNDERLYING THE CYTOPROTECTIVE ACTIVITY OF TAURINEAntioxidant activity

Recent studies have uncovered novel mechanisms responsible for taurine-mediated cytoprotection (Table 1). One of the primary mechanisms of taurine cytoprotection appears to involve its antioxidant activity, which is mediated by three distinct events. First, taurine is a proven anti-inflammatory agent that neutralizes the neutrophil oxidant, hypochlorous acid. The product of the reaction between taurine and hypochlorous acid, taurine chloramine, also interferes with the inflammatory process (Kim and Cha, 2014; Marcinkiewicz and Kontny 2014). Second, taurine diminishes the generation of superoxide by the mitochondria (Jong et al., 2012; Schaffer et al., 2014a). In normal mitochondria, taurine forms a conjugate with a uridine residue of tRNALeu(UUR). Because the modified uridine residue is located in the Wobble position of the anticodon, the conjugation reaction is capable of enhancing the interaction of the AAU anticodon of tRNALeu(UUR) with the UUG codon of mitochondrial mRNAs. However, in certain mitochondrial diseases, the formation of the taurine conjugate is diminished, an effect that suppresses the expression‎ of specific mitochondria encoded proteins, such as NADH-ubiquinone oxidoreductase chain 6 (ND6) (Schaffer et al., 2014a). ND6 is a subunit of complex I that is required for maximal complex I activity and the proper assembly of the complex. Therefore, a reduction in ND6 biosynthesis decreases complex I activity, the utilization of NADH by the respiratory chain and mitochondrial ATP generation but it increases the generation of superoxide by the respiratory chain (Jong et al., 2012; Schaffer et al., 2016; Shetewy et al., 2016). It is widely accepted that mitochondrial oxidative stress damages macromolecules within the mitochondria, but more importantly it is capable of triggering the mitochondrial permeability transition (permeabilization of the inner mitochondrial membrane) and mitochondria-dependent apoptosis (Ricci et al., 2008, Shetewy et al., 2016). This sequence of events can be disrupted by taurine treatment. In the mitochondrial disease, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), the formation of the taurine conjugate is impaired. Taurine therapy provides a source of substrate for the taurine conjugation reaction, thereby restoring mitochondrial protein biosynthesis, improving mitochondrial function and reducing superoxide generation (Rikimaru et al., 2012; Schaffer et al., 2014b). In support of this theory, it has been shown that promoters of mitochondrial oxidative stress, including ozone, nitrogen dioxide, bleomycin, amiodarone, arsenic, iron, Adriamycin and catecholamines, to name a few, respond favorably to taurine therapy, (Schaffer et al., 2009). Third, reactive oxygen species (ROS) generated by the mitochondria can damage antioxidant enzymes that are capable of preventing oxidative stress. Because the activity of some of the antioxidant enzymes is sensitive to oxidative damage, taurine may limit oxidative stress by preventing damage to those sensitive enzymes.

타우린의 세포 보호 작용의 기초가 되는 메커니즘항산화 작용

최근 연구에 따르면

타우린 매개 세포 보호에 대한 새로운 메커니즘이 밝혀졌습니다(표 1).

타우린 세포 보호의 주요 메커니즘 중 하나는

타우린의 항산화 활성과 관련된 것으로 보이며,

이는 세 가지 다른 사건에 의해 매개되는 것으로 보입니다.

첫째,

타우린은 호중구 산화제인 차아 염소산을 중화시키는

입증된 항염증제입니다.

타우린과 차아 염소산의 반응 생성물인

타우린 클로라민도

염증 과정을 방해합니다 (Kim and Cha, 2014; Marcinkiewicz와 Kontny 2014).

둘째,

타우린은

미토콘드리아의 슈퍼옥사이드 생성을 감소시킵니다(Jong et al., 2012; Schaffer et al., 2014a).

정상적인 미토콘드리아에서

타우린은 우리딘 잔류물인 tRNALeu(UUR)와 접합체를 형성합니다.

변형된 우리딘 잔기는

안티코돈의 워블 위치에 위치하기 때문에

접합 반응은

미토콘드리아 mRNA의 UUG 코돈과 tRNALeu(UUR)의

AAU 안티코돈의 상호 작용을 강화할 수 있습니다.

그러나

특정 미토콘드리아 질환에서는

타우린 접합체의 형성이 감소하여 NADH-유비퀴논 산화환원효소 사슬 6(ND6)과 같은

특정 미토콘드리아 암호화 단백질의 발현을 억제하는 효과가 있습니다(Schaffer et al., 2014a).

ND6는 복합체 I의 하위 단위로,

복합체 I의 최대 활성과 적절한 복합체 조립에 필요합니다.

따라서

ND6 생합성이 감소하면

복합체 I 활성,

호흡기 사슬에 의한 NADH 활용 및 미토콘드리아 ATP 생성이 감소하지만

호흡기 사슬에 의한 슈퍼옥사이드 생성은 증가합니다(종 외, 2012; 샤퍼 외, 2016; 셰트위 외, 2016).

미토콘드리아 산화 스트레스가

미토콘드리아 내의 거대 분자를 손상시킨다는 것은 널리 알려져 있지만,

더 중요한 것은

미토콘드리아 투과성 전환(미토콘드리아 내부 막의 투과성화)과

미토콘드리아 의존 세포 사멸을 유발할 수 있다는 것입니다(Ricci et al., 2008, Shetewy et al., 2016).

이러한 일련의 사건은

타우린 치료로 중단될 수 있습니다.

미토콘드리아 질환,

미토콘드리아 뇌병증,

젖산증,

뇌졸중 유사 에피소드(MELAS)에서는

타우린 접합체의 형성이 손상됩니다.

타우린 요법은

타우린 접합 반응의 기질을 제공하여

미토콘드리아 단백질 생합성을 회복하고

미토콘드리아 기능을 개선하며 슈퍼옥사이드 생성을 감소시킵니다(Rikimaru 외, 2012; Schaffer 외, 2014b).

이 이론을 뒷받침하기 위해

오존, 이산화질소, 블레오마이신, 아미오다론, 비소, 철, 아드리아마이신 및 카테콜아민을 포함한

미토콘드리아 산화 스트레스 촉진제가

타우린 치료에 호의적으로 반응한다는 사실이 밝혀졌습니다(Schaffer et al., 2009).

셋째,

미토콘드리아에서 생성되는 활성 산소종(ROS)은

산화 스트레스를 예방할 수 있는 항산화 효소를 손상시킬 수 있습니다.

일부 항산화 효소의 활성은

산화적 손상에 민감하기 때문에

타우린은 이러한 민감한 효소의 손상을 방지하여

산화 스트레스를 제한할 수 있습니다.

Table 1.

Mechanisms underlying cytoprotective actions of taurine to improve clinical and nutritional health of humans

CytoprotectionFunctions of Taurine

Antioxidation	Anti-inflammation by neutralization of hypochlorous to produce taurine chloramine (Kim and Cha, 2014; Marcinkiewicz and Kontny, 2014)
	Diminishes superoxide by conjugating with uridine of tRNALeu(UUR) in mitochondria (Jong et al., 2012; Schaffer et al., 2014a)
	Generates ATP by encoding mitochondrial ND6 protein (Jong et al., 2012; Schaffer et al., 2016; Shetewy et al., 2016) Prevents mitochondrial membrane permeability and apoptosis (Ricci et al., 2008, Shetewy et al., 2016)
	Benefits mitochondrial disease, MELAS by providing substrate for taurine conjugation (Rikimaru et al., 2012; Schaffer et al., 2014b)
Energy metabolism	Activates complex I and NADH sensitive enzymes by reducing NADH/NAD+ ratio during glycolysis (Schaffer et al., 2016)
	Restores fatty acid oxidation by increasing PPARalpha levels (Schaffer et al., 2016)
	Conjugates bile acids to facilitate lipid absorption by intestines (Schaffer et al., 2016)
Gene expression‎	Changes transcription profile of metabolism-related genes (Park et al., 2006)
	Modulates genes to induce longevity (Ito et al., 2014a)
	Changes transcription factors (Schaffer et al., 2016)
	Modulates protein phosphorylation and cell signalling (Lombardini, 1996; Ramila et al., 2015)
ER stress	Attenuates ER stress by improving protein folding (Ito et al., 2015a)
	Ameliorates stroke brain injury by inhibiting ER stress (Gharibani et al., 2015)
	Protects neurons in stroke and Alzheimer’s disease (Prentice et al., 2015)
Neuromodulation	Protects CNS by agonizing GABAA, glycine and NMDA receptors (El Idrissi and L’Amoreaux, 2008; Chan et al., 2013)
	Decreases seizures by binding with GABAA receptor (L’Amoreaux et al., 2010)
	Protects against seizures by elevating glutamic acid decarboxylase (El Idrissi and L’Amoreaux, 2008)
Quality control	Protects cardiomyocytes by activating ubiquitin-proteasome system and autophagy (Jong et al., 2015)
	Attenuates toxin-mediated autophagy (Li et al., 2012; Bai et al., 2016)
Ca2+ homeostasis	Protects heart and brain during myocardial infarction and stroke by diminishing Ca2+ overload (Li et al., 2012; Bai et al., 2016)
	Taurine loss during ischemia-reperfusion protects heart by reducing hypoxia-induced Ca2+ overload (Schaffer et al., 2002)
	Taurine depletion leads to cardiomyopathy due to reduced activity of SR Ca2+ ATPase (Ramila et al., 2015)
	Protects brain neurons during epilepsy by inducing Ca2+ binding proteins (Junyent et al., 2010)
	Protects neurons against glutamate excitotoxicity by reducing glutamate-induced elevation of [Ca2+]i (Wu et al., 2005)
Osmoregulation	Serves as an organic osmolyte (Schaffer et al., 2002)

차아염소산염을 중화시켜 타우린 클로라민을 생성하여 항염증(Kim and Cha, 2014; Marcinkiewicz and Kontny, 2014)

미토콘드리아에서 tRNALeu(UUR)의 우리딘과 결합하여 슈퍼옥사이드 감소 (Jong et al., 2012; Schaffer et al., 2014a)

미토콘드리아 ND6 단백질을 암호화하여 ATP를 생성합니다 (Jong et al., 2012; Schaffer et al., 2016; Shetewy et al., 2016) 미토콘드리아 막 투과성 및 세포 사멸을 방지합니다 (Ricci et al., 2008, Shetewy et al., 2016).

타우린 접합을 위한 기질을 제공하여 미토콘드리아 질환인 MELAS에 도움이 됩니다(Rikimaru 외, 2012; Schaffer 외, 2014b).

해당 과정 중 NADH/NAD+ 비율을 감소시켜 복합체 I 및 NADH 민감성 효소를 활성화합니다 (Schaffer et al., 2016).

PPAR알파 수치를 증가시켜 지방산 산화를 회복시킵니다(Schaffer et al., 2016).

담즙산과 결합하여 장에서 지질 흡수를 촉진합니다 (Schaffer et al., 2016).

신진대사 관련 유전자의 전사 프로파일을 변화시킨다 (Park et al., 2006).

장수를 유도하는 유전자를 조절합니다 (Ito et al., 2014a).

전사인자 변화 (Schaffer et al., 2016)

단백질 인산화 및 세포 신호 전달을 조절합니다(Lombardini, 1996; Ramila 외, 2015).

단백질 폴딩을 개선하여 ER 스트레스를 완화합니다(Ito et al., 2015a).

ER 스트레스를 억제하여 뇌졸중 뇌 손상을 개선합니다(Gharibani 외., 2015).

뇌졸중 및 알츠하이머병의 신경세포 보호 (Prentice et al., 2015)

GABAA, 글리신 및 NMDA 수용체에 작용하여 CNS를 보호합니다(El Idrissi and L'Amoreaux, 2008; Chan et al., 2013).

GABAA 수용체와 결합하여 발작을 감소시킵니다 (L'Amoreaux et al., 2010).

글루탐산 탈카르복실 효소를 증가시켜 발작을 예방합니다 (El Idrissi and L'Amoreaux, 2008).

유비퀴틴-프로테아좀 시스템과 오토파지를 활성화하여 심근세포를 보호합니다(Jong et al., 2015).

독소 매개 오토파지를 약화시킵니다(Li et al., 2012; Bai et al., 2016).

Ca2+ 과부하를 감소시켜 심근경색 및 뇌졸중 시 심장과 뇌를 보호합니다(Li et al., 2012; Bai et al., 2016).

허혈-재관류 중 타우린 손실은 저산소증으로 인한 Ca2+ 과부하를 감소시켜 심장을 보호합니다 (Schaffer et al., 2002).

타우린 고갈은 SR Ca2+ ATPase의 활성 감소로 인해 심근 병증을 유발합니다 (Ramila et al., 2015).

Ca2+ 결합 단백질을 유도하여 간질 중 뇌 신경세포를 보호합니다 (Junyent et al., 2010).

글루타메이트에 의한 [Ca2+]i의 상승을 감소시켜 글루타메이트 흥분 독성으로부터 뉴런을 보호합니다 (Wu et al., 2005).

Effect on energy metabolism

Taurine deficiency-mediated impairment of complex I activity also affects energy metabolism, largely through elevations in the NADH/NAD+ ratio, which regulate energy metabolism by feedback inhibiting key dehydrogenases. The citric acid cycle is very sensitive to increases in the NADH/NAD+ ratio, as three NADH sensitive enzymes (α-ketoglutarate dehydrogenase, isocitrate dehydrogenase and citrate synthase) are subject to inhibition by elevations in the NADH/NAD+ ratio. For example, oxidation of pyruvate by the taurine deficient heart falls, as elevations in the NADH/NAD+ ratio inhibits pyruvate dehydrogenase activity and causes a deficiency in pyruvate, arising from the massive conversion of pyruvate to lactate (Schaffer et al., 2016). Thus, despite stimulation of glycolysis, glucose oxidation is significantly reduced in the taurine deficient heart, dramatically decreasing the contribution of glucose metabolism toward overall ATP biosynthesis. The rate of taurine biosynthesis by the liver is low in humans, therefore, the major source of taurine in humans is the diet. For many years, diets rich in seafood were considered an excellent source of taurine, with meat containing some but less taurine than seafood. However, the recent introduction of taurine-containing supplements, such as Bacchus-D and Red Bull, provides an alternative source of taurine. The supplements have proven to be effective therapeutic agents, at least in the case of heart failure. According to Jeejeebhoy et al. (2002), taurine is deficient in hearts of patients suffering from heart failure. Restoration of taurine levels in these patients through supplementation leads to improved contractile function. This study reinforces the view that taurine supplements are important therapeutic agents. However, the largest decline in energy metabolism occurs in fatty acid oxidation, which falls in part because of a decrease in citric acid cycle flux. Also suppressing fatty acid oxidation in taurine deficiency are the low levels of the transcription factor, PPARα (Schaffer et al., 2016). PPARα regulates several proteins and enzymes involved in fatty acid metabolism, with the most important being the long chain fatty acyl carnitine transporter complex (Schaffer et al., 2016). Another factor affecting lipid metabolism is taurine deficiency-mediated reductions in bile acid biosynthesis, as bile acids facilitate the absorption of lipids by the intestines (see section on atherosclerosis).

에너지 대사에 미치는 영향

타우린 결핍으로 인한 복합체 I 활성의 손상은

주로 주요 탈수소효소를 억제하는 피드백을 통해 에너지 대사를 조절하는

NADH/NAD+ 비율의 상승을 통해 에너지 대사에 영향을 미칩니다.

구연산 주기는

NADH/NAD+ 비율의 증가에 매우 민감한데,

이는 세 가지 NADH 민감성 효소(α-케토글루타레이트 탈수소효소, 이소시트레이트 탈수소효소 및 구연산염 합성효소)가 NADH/NAD+ 비율의 증가에 의해 억제될 수 있기 때문입니다.

예를 들어,

타우린이 결핍된 심장에 의한 피루베이트의 산화는

NADH/NAD+ 비율의 상승이 피루베이트 탈수소효소 활성을 억제하고

피루베이트가 젖산염으로 대량 전환되어

피루베이트 결핍을 유발하기 때문에 떨어집니다(Schaffer et al., 2016).

따라서

해당 작용의 자극에도 불구하고

타우린이 결핍된 심장에서는 포도당 산화가 현저히 감소하여

전체 ATP 생합성에 대한 포도당 대사의 기여도가 급격히 감소합니다.

인간의 간에서

타우린을 생합성하는 비율은 낮기 때문에

타우린의 주요 공급원은 식단입니다.

수년 동안 해산물이 풍부한 식단은

타우린의 훌륭한 공급원으로 여겨져 왔으며

육류에는 해산물보다 타우린이 일부 함유되어 있지만

타우린 함량은 적었습니다.

그러나 최근

바커스-D와 레드불과 같은 타우린 함유 보충제가 출시되면서

타우린의 대체 공급원이 되었습니다.

이 보충제는 적어도

심부전의 경우 효과적인 치료제로 입증되었습니다.

(2002)에 따르면

심부전 환자의 심장에는

타우린이 결핍되어 있다고 합니다.

이러한 환자의

타우린 수치가 보충제를 통해 회복되면

수축 기능이 개선됩니다.

이 연구는

타우린 보충제가 중요한 치료제라는 견해를 강화합니다.

그러나

에너지 대사의 가장 큰 감소는

지방산 산화에서 발생하며,

이는 부분적으로 구연산 순환 플럭스의 감소로 인해 발생합니다.

또한

타우린 결핍에서

지방산 산화를 억제하는 것은 낮은 수준의 전사인자 PPARα입니다(Schaffer et al., 2016).

PPARα는

지방산 대사에 관여하는 여러 단백질과 효소를 조절하며,

가장 중요한 것은 장쇄 지방 아실 카르니틴 수송체 복합체입니다(Schaffer et al., 2016).

지질 대사에 영향을 미치는 또 다른 요인은

담즙산이 장에서 지질의 흡수를 촉진하기 때문에

타우린 결핍으로 인한

담즙산 생합성 감소입니다(죽상동맥경화증 섹션 참조).

Regulation of gene expression‎

Park et al. (2006) were the first investigators to recognize that taurine treatment triggers genetic changes. More recently, Ito et al. (2014a) have identified several taurine sensitive genes that contribute to a wide range of cellular functions (cell cycle progression, cell signaling, death and survival, amino acid metabolism, protein biosynthesis, protein folding and aging). Taurine-mediated changes in transcription factor content have also been reported (Schaffer et al., 2016). Although taurine is known to modulate protein phosphorylation and cell signaling (Lombardini, 1996; Ramila et al., 2015), it remains to be determined if alterations in protein phosphorylation are involved in taurine-mediated genetic changes.

유전자 발현 조절

Park 등(2006)은

타우린 처리가 유전적 변화를 유발한다는 사실을

최초로 밝혀낸 연구자입니다.

최근에는 Ito 등(2014a )이

광범위한 세포 기능

(세포 주기 진행, 세포 신호 전달, 세포 사멸 및 생존, 아미노산 대사, 단백질 생합성, 단백질 접힘 및 노화)에 기여하는

타우린 민감성 유전자를 여러 개 확인했습니다.

타우린을 매개로 한

전사인자 함량의 변화도 보고되었습니다(Schaffer et al., 2016).

타우린은

단백질 인산화와 세포 신호를 조절하는 것으로 알려져 있지만(Lombardini, 1996; Ramila 외, 2015),

단백질 인산화 변화가 타우린 매개 유전자 변화에 관여하는지 여부는 아직 밝혀지지 않았습니다.

Modulation of ER stress

Another important mechanism of taurine cytoprotection is attenuation of endoplasmic reticular (ER) stress. ER stress is an important regulatory mechanism designed to restore ER function and re-establish a balance between protein degradation and protein biosynthesis/folding. When a cell experiences excessive ER stress, pathways are stimulated that can kill the cell. A common initiator of ER stress is the accumulation of defective proteins, whose levels increase as a result of improper protein folding, inadequate protein degradation or ER dysfunction. To restore ER function and the balance between protein degradation and protein biosynthesis/folding, unfolded or misfolded proteins activate three stress sensors (PERK, ATF6 and IRE1) that initiate distinct pathways known as the unfolded protein response (UPR) pathways. Together, the UPR pathways are capable of suppressing protein biosynthesis, enhancing protein degradation, generating chaperones to improve protein folding and initiating either autophagy or apoptosis. During a stroke, taurine decreases glutamate toxicity, thereby reducing both oxidative stress and calcium overload. However, taurine also suppresses two of the three UPR pathways. Although the mechanisms underlying the actions of taurine against ER stress and the UPR pathways remain to be determined, it is relevant that taurine deficiency is associated with ER stress (Ito et al., 2015a). It has been proposed that taurine might alter protein folding, either by reducing oxidative stress or providing a better osmotic environment for protein folding (Ito et al., 2015a). The initial studies describing the effect of taurine on ER stress used cellular and animal models of stroke (Gharibani et al., 2013, 2015). According to the authors of those studies, ER stress, along with oxidative stress and mitochondrial dysfunction, are characteristic features of stroke and neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s diseases (Prentice et al., 2015). During stroke, massive amounts of the neurotransmitter, glutamate, are released which overstimulates postsynaptic neurons leading to a neuroexcitotoxic response, characterized by oxidative stress, calcium overload, ER stress and in some cases cell death (Prentice et al., 2015).

ER 스트레스 조절

타우린 세포 보호의 또 다른 중요한 메커니즘은

소포체(ER) 스트레스의 약화입니다.

ER 스트레스는

ER 기능을 회복하고

단백질 분해와 단백질 생합성/접힘 사이의 균형을 회복하기 위해 고안된

중요한 조절 메커니즘입니다.

세포가

과도한 ER 스트레스를 받으면

세포를 죽일 수 있는 경로가 자극을 받습니다.

ER 스트레스의 일반적인 시작은

결함이 있는 단백질의 축적으로,

부적절한 단백질 폴딩,

부적절한 단백질 분해 또는 ER 기능 장애로 인해 그 수치가 증가합니다.

ER 기능과 단백질 분해와 단백질 생합성/접힘 사이의 균형을 회복하기 위해,

접히지 않거나 잘못 접힌 단백질은

세 가지 스트레스 센서(PERK, ATF6 및 IRE1)를 활성화하여

접힌 단백질 반응(UPR) 경로로 알려진 별개의 경로를 시작합니다.

UPR 경로는

단백질 생합성을 억제하고

단백질 분해를 촉진하며

단백질 폴딩을 개선하는 샤프론을 생성하고

자가포식 또는 세포 사멸을 개시할 수 있습니다.

뇌졸중이 발생하는 동안

타우린은

글루타메이트 독성을 감소시켜

산화 스트레스와 칼슘 과부하를 모두 감소시킵니다.

그러나

타우린은 또한

세 가지 UPR 경로 중 두 가지 경로를 억제합니다.

타우린이

ER 스트레스와 UPR 경로에 작용하는 근본적인 메커니즘은 아직 밝혀지지 않았지만,

타우린 결핍이 ER 스트레스와 관련이 있는 것으로 알려져 있습니다(Ito et al., 2015a).

타우린이

산화 스트레스를 줄이거나

단백질 폴딩에 더 나은 삼투압 환경을 제공함으로써

단백질 폴딩을 변화시킬 수 있다고 제안되었습니다(Ito et al., 2015a).

타우린이

ER 스트레스에 미치는 영향을 설명하는 초기 연구에서는

뇌졸중의 세포 및 동물 모델을 사용했습니다(Gharibani 등., 2013, 2015).

이러한 연구의 저자에 따르면

ER 스트레스는

산화 스트레스 및 미토콘드리아 기능 장애와 함께

뇌졸중 및 알츠하이머, 헌팅턴병, 파킨슨병을 포함한

신경 퇴행성 질환의 특징적인 특징입니다(Prentice et al., 2015).

뇌졸중이 발생하면

다량의 신경전달물질인 글루타메이트가 방출되어

시냅스 후 뉴런을 과도하게 자극하여

산화 스트레스,

칼슘 과부하,

ER 스트레스 및 경우에 따라 세포 사멸을 특징으로 하는

신경 흥분 독성 반응을 유발합니다(Prentice et al., 2015).

Taurine as an inhibitory neuromodulator

Although ER stress assumes an important role in the cytoprotective actions of taurine in the central nervous system (CNS), another important mechanism affecting the CNS is the neuromodulatory activity of taurine. Toxicity in the CNS commonly occurs when an imbalance develops between excitatory and inhibitory neurotransmitters. GABA is one of the dominant inhibitory neurotransmitters, therefore, reductions in either the CNS levels of GABA or the activity of the GABA receptors can favor neuronal hyperexcitability. Taurine serves as a weak agonist of the GABAA, glycine and NMDA receptors (El Idrissi and L’Amoreaux, 2008; Chan et al., 2013). Therefore, taurine can partially substitute for GABA by causing inhibition of neuronal excitability. However, the regulation of the GABAA receptor by taurine is complex. While acute taurine administration activates the GABAA receptor, chronic taurine feeding promotes the downregulation of the GABAA receptor (L’Amoreaux et al., 2010) and the upregulation of glutamate decarboxylase, the rate-limiting step in GABA biosynthesis (El Idrissi and L’Amoreaux, 2008). Therefore, complex interactions within the GABAeric system, as well as in the glycine and NMDA receptors, largely define the actions of taurine in the CNS.

억제성 신경 조절제로서의 타우린

ER 스트레스는

중추신경계(CNS)에서 타우린의 세포 보호 작용에 중요한 역할을 하지만,

CNS에 영향을 미치는 또 다른 중요한 메커니즘은

타우린의 신경조절 작용입니다.

중추신경계의 독성은

일반적으로 흥분성 신경전달물질과 억제성 신경전달물질 사이에

불균형이 발생할 때 발생합니다.

가바는

대표적인 억제성 신경전달물질 중 하나이므로

가바의 CNS 수치나 가바 수용체의 활성이 감소하면

신경세포의 과흥분성이 촉진될 수 있습니다.

타우린은

GABAA,

글리신 및 NMDA 수용체의 약한 작용제로 작용합니다(El Idrissi and L'Amoreaux, 2008; Chan et al., 2013).

따라서

타우린은

신경세포 흥분성 억제를 유발하여

GABA를 부분적으로 대체할 수 있습니다.

그러나

타우린에 의한 GABAA 수용체의 조절은 복잡합니다.

급성 타우린 투여는

GABAA 수용체를 활성화하는 반면,

만성 타우린 공급은 GABAA 수용체의 하향 조절을 촉진하고(L'Amoreaux et al., 2010),

GABA 생합성의 속도 제한 단계인

글루타메이트 탈카르복실효소의 상향 조절을 촉진합니다(El Idrissi and L'Amoreaux, 2008).

따라서

글리신 및 NMDA 수용체뿐만 아니라

GABA에릭 시스템 내의 복잡한 상호 작용이 CNS에서

타우린의 작용을 크게 정의합니다.

Regulation of quality control processes

Taurine also regulates quality control processes, such as the ubiquitin-proteasome system and autophagy. These processes either rejuvenate damaged cells and subcellular organelles or eliminate them through degradation or cell death. In taurine deficient cells, a reduction in the activity of the proteasome leads to an accumulation of ubiquitinated proteins, an effect abolished by the mitochondrial specific antioxidant, mitoTEMPO (Jong et al., 2015). Taurine deficiency is also associated with diminished autophagy, a condition that allows damaged cells and organelles to accumulate (Jong et al., 2015). Inactivation of these quality control processes is extremely damaging to cells and tissue. However, excessive autophagy is also damaging because it can elevate cell death. Although there have only been a few studies examining the effect of taurine treatment on autophagy, the actions of taurine are compatible with its cytoprotective activity, as taurine attenuates toxin-mediated autophagy (Li et al., 2012; Bai et al., 2016).

품질 관리 과정의 조절

타우린은

유비퀴틴-프로테아좀 시스템과

오토파지와 같은 품질 관리 과정도 조절합니다.

이러한 과정은

손상된 세포와 세포 소기관을 재생하거나

분해 또는 세포 사멸을 통해 제거합니다.

타우린이 결핍된 세포에서

프로테아좀의 활성이 감소하면

미토콘드리아 특이적 항산화제인 미토템포에 의해 제거되는

유비퀴틴화된 단백질이 축적됩니다(Jong et al., 2015).

타우린 결핍은 또한

손상된 세포와 세포 소기관이 축적되는 상태인

자가포식 감소와 관련이 있습니다(Jong et al., 2015).

이러한 품질 관리 프로세스의 비활성화는

세포와 조직에 극심한 손상을 입힙니다.

그러나

과도한 자가포식도

세포 사멸을 촉진할 수 있기 때문에 해롭습니다.

타우린 처리가 자가포식에 미치는 영향을 조사한 연구는 거의 없지만,

타우린이 독소 매개 자가포식을 약화시키기 때문에

타우린의 작용은 세포 보호 활동과 양립할 수 있습니다(Li et al., 2012; Bai et al., 2016).

Modulation of Ca2+ homeostasis

Excessive accumulation of Ca2+ by the heart and brain during a myocardial infarction or stroke, is also cytotoxic. Not only does high [Ca2+]i activate proteases and lipases, but it also initiates the mitochondrial permeability transition, an event that permeabilizes the inner mitochondrial membrane and provokes the release of pro-apoptotic factors from the mitochondria that kill the cell (Rasola and Bernadi, 2011, Shetewy et al., 2016). Taurine protects the cell by diminishing Ca2+ overload through three mechanisms (Schaffer et al., 2014b; Prentice et al., 2015). First, the loss of taurine from cells during an ischemia-reperfusion insult appears to be mediated by the taurine transporter, as taurine loss is also accompanied by the loss of Na+ from the cell. Consequently, upon taurine release, less Na+ is available for Ca2+ entry via the Na+/Ca2+ exchanger, which minimizes the degree of Ca2+ overload (Schaffer et al., 2002). Second, taurine indirectly regulates the activity of the sarcoplasmic reticular Ca2+ ATPase, which is responsible for maintaining cytosolic Ca2+ homeostasis through the removal of Ca2+ from the cytosol (Ramila et al., 2015). This action of taurine involves alterations of protein phosphorylation, however, the mechanism by which taurine modulates protein phosphorylation has not been ascertained and warrants further study. Third, taurine treatment is associated with changes in the presence of calbindin D28k, calretinin and parvalbumin (Junyent et al., 2010). Fourth, taurine inhibits glutamateinduced Ca2+ influx through the L-, P/Q- and N-type voltage gated Ca2+ channels, as well as the NMDA receptor channel (Wu et al., 2005).

Ca2+ 항상성 조절

심근경색이나 뇌졸중이 발생하는 동안

심장과 뇌에 Ca2+가 과도하게 축적되면

세포 독성을 유발합니다.

높은 [Ca2+]i는 프로테아제와 리파아제를 활성화할 뿐만 아니라

미토콘드리아 내부 막을 투과성화하고

미토콘드리아에서 세포를 죽이는 세포 사멸 인자의 방출을 유발하는

미토콘드리아 투과성 전환을 시작합니다(Rasola and Bernadi, 2011, Shetewy et al., 2016).

타우린은

세 가지 메커니즘을 통해

Ca2+ 과부하를 감소시켜 세포를 보호합니다(Schaffer et al., 2014b; Prentice et al., 2015).

첫째,

허혈-재관류 손상 시 세포에서 타우린 손실은

타우린 수송체에 의해 매개되는 것으로 보이는데,

타우린 손실은 세포에서 Na+의 손실도 동반하기 때문입니다.

결과적으로

타우린이 방출되면

Na+/Ca2+ 교환기를 통해 Ca2+가 유입되는 데 사용할 수 있는

Na+가 줄어들어 Ca2+ 과부하 정도가 최소화됩니다(Schaffer 등., 2002).

둘째,

타우린은 세포질에서 Ca2+를 제거하여

세포질 Ca2+ 항상성을 유지하는 역할을 하는

세포질 망상 Ca2+ ATPase의 활성을 간접적으로 조절합니다(Ramila et al., 2015).

타우린의 이러한 작용은

단백질 인산화의 변화를 수반하지만,

타우린이 단백질 인산화를 조절하는 메커니즘은 아직 밝혀지지 않았으며 추가 연구가 필요합니다.

셋째,

타우린 치료는

칼빈딘 D28k, 칼레티닌 및 파발부민의 존재 변화와 관련이 있습니다(Junyent 등, 2010).

넷째,

타우린은

L-, P/Q- 및 N-형 전압 게이트 Ca2+ 채널과 NMDA 수용체 채널을 통해

글루타메이트에 의한 Ca2+ 유입을 억제합니다(Wu et al., 2005).

Osmoregulation

The concentration of taurine within most cells is quite high. In response to elevations in an osmotic load, intracellular taurine levels increase while they decrease in response to hypo-osmotic stress. These are important mechanisms to protect the cell from excessive stretching in response to osmotic imbalances. Because taurine serves as an organic osmolyte, it also modulates the levels of other osmolytes, such as Na+, which not only carries a charge (unlike taurine which is a neutral zwitterion) but is also involved in many important cellular functions, such as transport and membrane potential (Schaffer et al., 2002). In the kidney, taurine serves as a weak diuretic and natriuretic agent, important properties for normal renal function.

오스모레귤레이션

대부분의 세포 내 타우린 농도는 상당히 높습니다.

삼투압 부하가 증가하면

세포 내 타우린 수치가 증가하고

저삼투압 스트레스에 반응하여

세포 내 타우린 수치가 감소합니다.

이는

삼투압 불균형에 반응하여

세포가 과도하게 늘어나지 않도록 보호하는 중요한 메커니즘입니다.

타우린은

유기 삼투물질로 작용하기 때문에

중성 양이온인 타우린과 달리 전하를 운반할 뿐만 아니라

수송 및 막 전위와 같은 많은 중요한 세포 기능에 관여하는

Na+와 같은 다른 삼투물질의 수준도 조절합니다(Schaffer 등, 2002).

신장에서 타우린은

약한 이뇨제 및 나트륨 이뇨제 역할을 하며

정상적인 신장 기능에 중요한 역할을 합니다.

TAURINE-MEDIATED PROTECTION AGAINST PATHOLOGY AND DISEASEEffect of taurine on the central nervous system

Stroke: Stroke, whose incidence is on the rise, is presently a leading cause of death and disability. Under pathological conditions, such as ischemic stroke and hypo-osmotic stress, taurine is released from various cells in the central nervous system (CNS) and function as a neuroprotective agent (Albrecht and Schousboe, 2005). For many brain areas, concentrations of taurine are below 1 mM, which are adequate to activate glycine receptors but not most GABA receptors; the GABA receptors of the ventrobasal thalamus are an exception, as they exhibit especially high affinity for taurine. Taurine plays an important role in neuronal development in the cerebral cortex (Furukawa et al., 2014). Although concentrations of taurine below 1 mM do not activate the GABA receptor in many regions of the CNS, taurine deficiency leads to impaired GABAergic inhibition in the striatum, a condition associated with the development of a disease mimicking hepatic encephalopathy (Sergeeva et al., 2007).

A major cause of cellular damage and death during stroke is the release of large amounts of glutamate, which overstimulate glutamate receptors, resulting in hyper-excitability (Prentice et al., 2015). Among the damaging events associated with glutamate toxicity are calcium overload, oxidative stress, ATP depletion and mitochondrial dysfunction (Abramov and Duchan, 2008; Prentice et al., 2015). The combination of calcium excess and oxidative stress is capable of triggering the mitochondrial permeability transition and the release of pro-apoptotic factors that initiate mitochondrial apoptosis. Apoptosis can also be initiated by caspase 12, CHOP (C/EBP homologous protein) and JNK, which are end products of unfolded protein response (UPR) pathways that arise from ER stress. Interestingly, taurine is also released from brain slices in response to glutamate receptor stimulation (Saransaari and Oja, 2010). The release of taurine helps counteract the adverse effects of glutamate toxicity by reducing [Ca2+]i, increasing the Bcl-2/Bad ratio and suppressing ER stress (Wu and Prentice, 2010). Moreover, taurine reduces cell swelling in rat brain cortical slices subjected to a hypoxic-reoxygenation insult (Ricci et al., 2009). However, it remains to be determined whether taurine-mediated increases in ATP generation and suppression of mitochondrial ROS generation might also contribute to the reductions in the severity of stroke. There is reason to believe that the mitochondrial actions of taurine should reverse stroke-mediated suppression of complex I activity. Taurine might also attenuate another source of ROS in stroke, namely those from NADPH oxidase (Abramov et al., 2007), as taurine treatment is known to reduce the levels of the substrate, NADPH (Schaffer et al., 2016) and mediate the downregulation of Nox2/Nox4 (Han et al., 2016). Using an animal model of focal cerebral ischemia, Gharibani et al. (2015) found that the combination of taurine and a NMDA partial antagonist (5-methyl-N,N-diethylthiolcarbamate-sulfoxide) reduced apoptosis and ER stress while the partial antagonist alone exhibited no neuroprotection.

While there is abundant evidence that taurine is effective in treating stroke in animals (Menzie et al., 2013), only a few studies have addressed its effect on the risk of stroke in humans. In a prospective-case study based on the New York University Women’s Health Study, which examined 14,274 women, no association was observed between serum taurine levels and stroke risk (Wu et al., 2016). However, among non-smokers there may be a link that deserves further consideration, particularly in light of evidence that the incidence of stroke was reduced 90% in a genetic model of stroke (stroke-prone spontaneously hypertensive rats) fed a diet rich in taurine (Yamori et al., 2009). Clearly, clinical studies examining the effectiveness of taurine against stroke in humans is warranted (Fig. 1).

타우린을 매개로 한 병리 및 질병 예방타우린이 중추 신경계에 미치는 영향

뇌졸중:

발병률이 증가하고 있는 뇌졸중은 현재 사망과 장애의 주요 원인입니다.

허혈성 뇌졸중 및 저삼투압 스트레스와 같은 병리학적인 조건에서

타우린은 중추신경계(CNS)의 다양한 세포에서 방출되어 신경 보호제로서 기능합니다(Albrecht and Schousboe, 2005).

많은 뇌 영역에서 타우린의 농도는 글리신 수용체를 활성화하는 데 적합한 1mM 미만이지만 대부분의 GABA 수용체는 활성화하지 못하며, 복측 시상의 GABA 수용체는 타우린에 특히 높은 친화력을 나타내므로 예외입니다. 타우린은 대뇌 피질의 신경세포 발달에 중요한 역할을 합니다(후루카와 외., 2014). 타우린 농도가 1mM 미만이면 중추신경계의 여러 영역에서 GABA 수용체가 활성화되지 않지만, 타우린 결핍은 간성 뇌병증을 모방하는 질환의 발병과 관련된 상태인 선조체의 GABAergic 억제 장애로 이어집니다 (Sergeeva et al., 2007).

뇌졸중 중 세포 손상 및 사망의 주요 원인은 다량의 글루타메이트가 방출되어 글루타메이트 수용체를 과도하게 자극하여 과흥분성을 유발하는 것입니다(Prentice et al., 2015). 글루타메이트 독성과 관련된 손상 중에는 칼슘 과부하, 산화 스트레스, ATP 고갈 및 미토콘드리아 기능 장애가 있습니다(Abramov and Duchan, 2008; Prentice et al., 2015). 칼슘 과잉과 산화 스트레스의 조합은 미토콘드리아 투과성 전환과 미토콘드리아 세포 사멸을 개시하는 세포 사멸 촉진 인자의 방출을 촉발할 수 있습니다. 세포 사멸은 또한 ER 스트레스로 인해 발생하는 UPR(언폴딩 단백질 반응) 경로의 최종 산물인 카스파제 12, CHOP(C/EBP 동종 단백질) 및 JNK에 의해 시작될 수 있습니다. 흥미롭게도 타우린은 글루타메이트 수용체 자극에 반응하여 뇌 조각에서도 방출됩니다(Saransaari와 Oja, 2010). 타우린의 방출은 [Ca2+]i를 감소시키고 Bcl-2/Bad 비율을 증가시키며 ER 스트레스를 억제하여 글루타메이트 독성의 부작용을 상쇄하는 데 도움이 됩니다(Wu and Prentice, 2010). 또한 타우린은 저산소-재산소화 자극을 받은 쥐의 뇌 피질 절편에서 세포 부종을 감소시킵니다(Ricci et al., 2009). 그러나 타우린을 매개로 한 ATP 생성의 증가와 미토콘드리아 ROS 생성의 억제가 뇌졸중의 중증도 감소에 기여할 수 있는지는 아직 밝혀지지 않았습니다. 타우린의 미토콘드리아 작용이 뇌졸중을 매개로 한 복합체 I 활성 억제를 역전시킬 수 있다고 믿을 만한 근거가 있습니다. 타우린 치료는 기질인 NADPH의 수준을 감소시키고(Schaffer et al., 2016) Nox2/Nox4의 하향 조절을 매개하는 것으로 알려져 있기 때문에 타우린은 뇌졸중에서 또 다른 ROS의 원천, 즉 NADPH 산화효소(Abramov et al., 2007)를 약화시킬 수도 있습니다(Han et al., 2016). 국소 뇌 허혈의 동물 모델을 사용하여 Gharibani 등(2015)은 타우린과 NMDA 부분 길항제(5-메틸-N,N-디에틸티올카바메이트-설폭사이드)의 조합이 세포 사멸과 ER 스트레스를 감소시키는 반면 부분 길항제만으로는 신경 보호 효과가 나타나지 않는다는 것을 발견했습니다.

타우린이 동물의 뇌졸중 치료에 효과적이라는 증거는 풍부하지만(Menzie 등, 2013), 사람의 뇌졸중 위험에 미치는 영향을 다룬 연구는 소수에 불과합니다. 14,274명의 여성을 대상으로 한 뉴욕대학교 여성 건강 연구를 기반으로 한 전향적 사례 연구에서는 혈청 타우린 수치와 뇌졸중 위험 사이의 연관성이 관찰되지 않았습니다(Wu et al., 2016). 그러나 비흡연자 중에서도 타우린이 풍부한 식단을 먹인 뇌졸중 유전 모델(뇌졸중이 발생하기 쉬운 자연 고혈압 쥐)에서 뇌졸중 발생률이 90% 감소했다는 증거에 비추어 볼 때 추가적으로 고려해야 할 연관성이 있을 수 있습니다(Yamori 등, 2009). 분명히 타우린의 뇌졸중 예방 효과를 검증하는 임상 연구가 필요합니다(그림 1).

Fig. 1.

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Taurine-mediated protection against pathology and disease. High concentrations of taurine in most cells regulate physiological function of excitable tissues and mitochondria. Taurine protects CNS by decreasing ER stress and antagonizing neurotransmitter receptors of GABAA, glycine and NMDA. Protection of the cardiovascular system by taurine occurs through regulation of cell signaling, such as Ca2+ transport, ROS generation and protein phosphorylation. Supplementation of taurine ameliorates symptoms of MELAS and diabetes mellitus. The anti-inflammatory activity of taurine involves either the formation of taurochloramine in neutrophils or the attenuation of nitric oxide and prostaglandin E2 in inflammatory diseases, such as rheumatoid arthritis and osteoarthritis. Taurine depletion or taurine transporter KO leads to cardiac and skeletal muscle dysfunction. Taurine prevents sarcopenia in aged person by minimizing gradual muscle loss.

타우린을 매개로 한 병리 및 질병 예방. 

대부분의 세포에서 고농도의 타우린은 

흥분 조직과 미토콘드리아의 생리적 기능을 조절합니다. 

타우린은 

ER 스트레스를 감소시키고 

GABAA, 

글리신 및 NMDA의 신경전달물질 수용체를 길항하여 

CNS를 보호합니다. 

타우린에 의한 심혈관계 보호는 

Ca2+ 수송, ROS 생성 및 단백질 인산화와 같은 

세포 신호의 조절을 통해 이루어집니다. 

타우린을 보충하면 

MELAS와 당뇨병의 증상이 개선됩니다. 

타우린의 항염증 활성은 

호중구에서 타우로클로라민을 형성하거나 

류마티스 관절염 및 골관절염과 같은 염증성 질환에서

 산화 질소와 프로스타글란딘 E2를 약화시키는 것과 관련이 있습니다. 

타우린 고갈 또는 타우린 수송체 KO는 

심장 및 골격근 기능 장애로 이어집니다. 

타우린은 

점진적인 근육 손실을 최소화하여 

노인의 근감소증을 예방합니다.

CNS: central nervous system; FXS: fragile X syndrome; SSDD: succinic semialdehyde dehydrogenase deficiency; MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Neurodegenerative diseases, such as Alzheimer’s, Huntington’s and Parkinson’s disease: The neurodegenerative diseases share many of the pathological features of stroke caused by glutamate-mediated activation of N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) inotropic glutamate receptors and metabotropic glutamate receptors (Hara and Snyder, 2007). A major cause of cell death from glutamate-mediated hyperexcitability in neurodegenerative diseases appears to involve the collapse of the mitochondrial membrane potential (Abramov and Duchen, 2008). Activation of glutamate receptors leads to calcium overload and an increase in ROS production. Because mitochondrial function is adversely affected by neurodegeneration, one would expect that mitochondrial ROS generation should be a major cause of cellular damage. Indeed, respiratory chain defects have been detected in degenerative diseases, although the site of the defect is disease specific, with Parkinson’s disease affecting complex I, Huntington’s disease affecting complex II and Alzheimer’s disease affecting complex IV (Damiano et al., 2010; Alleyne et al., 2011). Interestingly, one of the animal models of Parkinson’s disease is generated by treating rodents with the complex I inhibitor, rotenone (Cannon et al., 2009). Taurine deficiency and rotenone actions are similar, as both lead to reductions in complex I activity, inhibition of NADH dehydrogenase activity, reductions in respiratory activity and elevations in NADH. Because a primary physiological function of taurine is the maintenance of complex I activity, there is reason to believe that taurine therapy should reduce the severity of Parkinson’s disease (Alkholifi et al., 2015). Indeed, it has recently been reported that reduced plasma taurine content is associated with motor severity in Parkinson’s disease (Zhang et al., 2016). Moreover, a single blind, randomized, controlled study of 47 patients with Parkinson’s disease revealed effectiveness in reducing excessive sleepiness upon treatment with the taurine analog, homotaurine (Ricciardi et al., 2015).

알츠하이머병, 헌팅턴병, 파킨슨병과 같은 신경 퇴행성 질환:

신경 퇴행성 질환은

글루타메이트 매개 N-메틸-D-아스파르트산염(NMDA) 수용체,

α-아미노-3-하이드록시-5-메틸-4-이소사카졸프로피온산(AMPA)

이소트로픽 글루타메이트 수용체 및 대사성 글루타메이트 수용체의 활성화로 인한

뇌졸중의 많은 병리적 특징을 공유합니다(Hara and Snyder, 2007).

신경 퇴행성 질환에서

글루타메이트 매개 과흥분성으로 인한

세포 사멸의 주요 원인은 미토콘드리아 막 전위의 붕괴와 관련이 있는 것으로 보입니다(Abramov and Duchen, 2008).

글루타메이트 수용체의 활성화는

칼슘 과부하와 ROS 생성의 증가로 이어집니다.

미토콘드리아 기능은

신경 퇴화에 의해 악영향을 받기 때문에

미토콘드리아 ROS 생성이 세포 손상의 주요 원인이 될 것으로 예상할 수 있습니다.

실제로

퇴행성 질환에서 호흡 사슬 결함이 발견되었지만,

결함 부위는 질환별로 다르며 파킨슨병은 복합체 I에,

헌팅턴병은 복합체 II에,

알츠하이머병은 복합체 IV에 영향을 줍니다(Damiano 외, 2010; Alleyne 외, 2011).

흥미롭게도 파킨슨병의 동물 모델 중 하나는 설치류를 복합체 I 억제제인 로테논으로 치료하여 생성됩니다(Cannon et al., 2009). 타우린 결핍과 로테논의 작용은 유사하며, 둘 다 복합체 I 활성의 감소, NADH 탈수소효소 활성의 억제, 호흡 활동의 감소 및 NADH의 상승으로 이어집니다.

타우린의 주요 생리적 기능은

복합체 I 활성의 유지이므로

타우린 요법이 파킨슨병의 중증도를 감소시킬 수 있다고 믿을 만한 근거가 있습니다(Alkholifi 등., 2015).

실제로

최근 혈장 타우린 함량 감소가

파킨슨병의 운동 중증도와 관련이 있다는 보고가 있습니다(Zhang et al., 2016).

또한

파킨슨병 환자 47명을 대상으로 한 단일 맹검, 무작위, 대조 연구에서는

타우린 유사체인 호모타우린으로 치료했을 때

과도한 졸음을 줄이는 효과가 있는 것으로 나타났습니다(Ricciardi et al., 2015).

Fragile X Syndrome and succinic semialdehyde dehydrogenase deficiency: Fragile X syndrome is a genetic disease characterized by behavioral disorders and moderate to severe intellectual disabilities. The learning deficit (memory retention) of the fragile X mouse responds favorably to chronic oral administration of taurine (0.05% w/v) for 4 weeks, an effect seemingly linked to taurine’s GABAergic activity (Neuwirth et al., 2015).

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal genetic disease involving a key enzyme in GABA catabolism. Patients with SSADH deficiency showed symptoms such as ataxia, hypotonia, language deficits, and intellectual disability. Nearly half of the SSADH patients suffer from seizures. Because the disease is associated with disruption of GABA homeostasis, the effect of taurine therapy on symptoms of the disease before and after treatment have been examined. In a single case study of a 2-year old boy, taurine therapy (200 mg/kg/day) for 12 months improved social behavior, coordination and activity (Saronwala et al., 2008). However, in a subsequent open-label study of 18 SSADH deficient subjects administered taurine (50-200 mg/kg/day) for a period up to one year there was no major improvement in adaptive behavior with taurine (Pearl et al., 2014). Clearly, a controlled, randomized double-blind study of a larger number of patients receiving either placebo or taurine therapy is warranted.

취약성 X 증후군과 숙신산 세미알데히드 탈수소효소 결핍증:

취약성 X 증후군은 행동 장애와 중등도에서 중증의 지적 장애를 특징으로 하는 유전 질환입니다. 취약 X 마우스의 학습 결손(기억력 유지)은 4주 동안 타우린(0.05% w/v)을 만성 경구 투여하면 양호한 반응을 보이는데, 이는 타우린의 GABAergic 활성과 관련이 있는 것으로 보입니다(Neuwirth et al., 2015).

숙신 세미알데히드 탈수소효소(SSADH) 결핍증은 GABA 이화 작용의 핵심 효소와 관련된 희귀 상염색체 유전 질환입니다. SSADH 결핍 환자는 운동 실조, 근긴장 저하, 언어 결핍, 지적 장애 등의 증상을 보입니다. SSADH 환자의 거의 절반이 발작을 겪습니다. 이 질환은 GABA 항상성 파괴와 관련이 있기 때문에 치료 전후에 타우린 치료가 질환의 증상에 미치는 영향이 조사되었습니다. 2세 남아를 대상으로 한 한 사례 연구에서 12개월 동안 타우린 요법(200 mg/kg/일)을 실시한 결과 사회적 행동, 조정력 및 활동이 개선되었습니다(Saronwala et al., 2008). 그러나 이후 18명의 SSADH 결핍 환자를 대상으로 최대 1년 동안 타우린(50-200 mg/kg/일)을 투여한 오픈 라벨 연구에서는 타우린을 통한 적응 행동이 크게 개선되지 않았습니다(Pearl et al., 2014). 따라서 위약 또는 타우린 치료를 받는 더 많은 수의 환자를 대상으로 한 통제된 무작위 이중 맹검 연구가 필요합니다.

Epilepsy: Imbalances between excitatory and inhibitory neurotransmitters underlie the mechanism of seizures. Taurine is an abundant amino acid in the brain, where it serves as an inhibitory neuromodulator (Oja and Saransaari, 2013). Although taurine levels can suppress specific types of seizures, taurine deficiency is not required for initiation of seizures. In animal studies, taurine administration has been found to abolish seizures evoked by a wide range of stimulants, including [D-Ala,Met ]-enkphalinamide, opioids, kainite, isoniazid, picrotoxin, penicillin and hypoxia. Nonetheless, clinical trials examining the effect of taurine treatment on human epilepsy have been mixed, with only about 1/3 of the patients responding favorably to taurine therapy (Barbeau and Donaldson, 1974; Bergamini et al., 1974; Konig et al., 1977; Rumpl et al., 1977; Mantovani and DeVivo 1979; Airaksinen et al., 1980).

The dominant inhibitory neurotransmitter in the brain is GABA, therefore, regulation of neuroexcitability by GABA plays a prominent role in preventing neuronal hyperexcitability and seizures (L’Amoreaux et al., 2010). Taurine serves as an agonist of the GABAA receptor, an action that enhances chloride influx into postsynaptic neurons, which causes hyperpolarization that inhibits hyperexcitability. Suppression of kainic acid, isoniazid and picrotoxin-mediated seizures has been attributed to the actions of taurine on the GABAeric system (El Idrissi et al., 2003; El Idrissi and L’Amoreaux, 2008; Junyent et al., 2009; L’Amoreaux et al., 2010). Like GABA, glycine is a major inhibitory neurotransmitter that activates chloride conductance and hyperpolarizes neurons. The inhibitory neuromodulator activity of taurine also extends to the glycine receptor, as the binding of taurine to the glycine receptor evokes chloride current and suppresses neuronal firing (Wu et al., 2008).

뇌전증:

흥분성 신경전달물질과

억제성 신경전달물질 사이의 불균형은

발작의 메커니즘의 근간을 이룹니다.

타우린은

뇌에 풍부한 아미노산으로,

억제성 신경 조절제 역할을 합니다(Oja and Saransaari, 2013).

타우린 수치는 특정 유형의 발작을 억제할 수 있지만,

타우린 결핍이 발작의 시작에 반드시 필요한 것은 아닙니다.

동물 연구에서 타우린 투여는 [D-Ala,Met]-엔크팔린아마이드, 오피오이드, 카이나이트, 이소니아지드, 피크로톡신, 페니실린 및 저산소증을 포함한 광범위한 자극제에 의해 유발된 발작을 없애는 것으로 밝혀졌습니다. 그럼에도 불구하고 타우린 치료가 인간 간질에 미치는 영향을 조사한 임상 시험은 혼합되어 있으며, 환자의 약 1/3만이 타우린 치료에 호의적으로 반응했습니다(Barbeau and Donaldson, 1974; Bergamini 외, 1974; Konig 외, 1977; Rumpl 외, 1977; Mantovani and DeVivo 1979; Airaksinen 외, 1980).

뇌의 지배적 인 억제 신경 전달 물질은 GABA이므로 GABA에 의한 신경 흥분성 조절은 신경 세포 과흥분성 및 발작을 예방하는 데 중요한 역할을합니다 (L' Amoreaux et al., 2010). 타우린은 시냅스 후 뉴런으로의 염화물 유입을 증가시켜 과분극을 유발하여 과흥분성을 억제하는 GABAA 수용체의 작용제로서 작용합니다. 카인산, 이소니아지드 및 피크로톡신 매개 발작의 억제는 타우린이 GABA 시스템에 작용하는 것으로 알려져 있습니다(El Idrissi 등, 2003; El Idrissi와 L'Amoreaux, 2008; Junyent 등, 2009; L'Amoreaux 등, 2010). 글리신은 GABA와 마찬가지로 염화물 전도도를 활성화하고 뉴런을 과분극시키는 주요 억제성 신경전달물질입니다. 타우린의 글리신 수용체에 대한 타우린의 결합은 염화물 전류를 유발하고 신경세포 발화를 억제하기 때문에 타우린의 억제성 신경 조절제 활성은 글리신 수용체까지 확장됩니다(Wu et al., 2008).

Retinal degeneration: The landmark studies showing that taurine is an essential nutrient for cats focused on the link between taurine deficiency and the development of photoreceptor loss and retinal degeneration (Schmidt et al., 1976; Hayes et al., 1975). More recently, Hadj-Said et al. (2016) found that taurine deficiency also causes nuclear ganglion cell degeneration and loss. Moreover, the anti-epileptic agent, vigabatrin, can provoke retinal degeneration, including both photoreceptor and ganglion cell loss, accompanied by taurine deficiency (Heim and Gidal, 2012; Froger et al., 2014). In two patients with succinic semialdehyde dehydrogenase deficiency exhibiting abnormal ERGs at baseline and after 6 months of vigabatrin treatment, taurine therapy partially prevents retinal damage triggered by vigabatrin treatment (Horvath et al., 2016). Because taurine is required for normal retinal ganglion cell survival (Froger et al., 2012), it has been proposed that taurine therapy may serve an important role in the prevention of retinal degeneration (Froger et al., 2014).

망막 변성: 타우린이 고양이에게 필수 영양소라는 것을 보여주는 획기적인 연구들은 타우린 결핍과 광수용체 손실 및 망막 변성 사이의 연관성에 초점을 맞추었습니다(Schmidt 등, 1976; Hayes 등, 1975). 최근에는 Hadj-Said 등(2016) 이 타우린 결핍이 핵 신경절 세포의 변성과 손실을 유발한다는 사실을 발견했습니다. 또한 항간질제인 비가바트린은 타우린 결핍과 함께 광수용체 및 신경절 세포 손실을 포함한 망막 변성을 유발할 수 있습니다(Heim and Gidal, 2012; Froger et al., 2014). 석신 세미알데히드 탈수소효소 결핍증이 있는 두 명의 환자에서 베이스라인과 비가바트린 치료 6개월 후 비정상적인 ERG를 보인 결과, 타우린 치료가 비가바트린 치료로 유발된 망막 손상을 부분적으로 예방했습니다(Horvath 등, 2016). 타우린은 정상적인 망막 신경절 세포 생존에 필요하기 때문에(Froger et al., 2012), 타우린 요법이 망막 퇴행 예방에 중요한 역할을 할 수 있다고 제안되었습니다(Froger et al., 2014).

Effect of taurine on the cardiovascular system

Congestive heart failure: Taurine has been approved for the treatment of congestive heart failure in Japan (Azuma et al., 1992). Like other heart failure medication, taurine not only diminishes the common symptoms of congestive heart failure (breathlessness on exertion and edema) but also eliminates or decreases the need for administering other heart failure medication, such as digoxin (Azuma et al., 1992). Although taurine exerts a mild positive inotropic effect on the hypodynamic heart and promotes natriuresis and diuresis, the major therapeutic effect of chronic taurine administration appears to involve a reduction in the actions of norepinephrine and angiotensin II, which are known to decrease myocardial performance through elevations in afterload pressure, ventricular remodeling and fluid remodeling (Ito et al., 2014b). Taurine is effective in reducing the adverse actions of norepinephrine through its ability to both decrease catecholamine overflow (through alterations in Ca2+ transport) and diminish cell signaling (through changes in Ca2+ transport, ROS content and protein phosphorylation). Although recent studies have shown that taurine therapy improves exercise capacity of patients with heart failure (Ahmadian et al., 2017), it remains to be determined whether taurine supplementation also reduces the risk of developing overt heart failure in the general population. Moreover, the possibility that taurine supplementation might lower the mortality rate of heart failure patients has not been examined. There is reason to believe that taurine might prolong lifespan of heart failure patients because it elevates high energy phosphate content of the heart, which is an important determinant of mortality among patients suffering from congestive heart failure (Schaffer et al., 2016).

Hypertension: Supplementation with taurine prevents the development of hypertension in several animal models (Fujita and Sato, 1986; Ideishi et al., 1994; Dawson et al., 2000; Harada et al., 2004; Hagar et al., 2006; Hu et al., 2009). In those models, taurine-mediated reductions in blood pressure appear to be mediated by a combination of diminished [Ca2+]i, oxidative stress, sympathetic activity and inflammatory activity, as well as an improvement in renal function (Sato et al., 1991; Dawson et al., 2000; Harada et al., 2004; Hagar et al., 2006; Mozaffari et al., 2006; Hu et al., 2009; Han and Chesney, 2012; Maia et al., 2014; Katakawa et al., 2016).

Two recent clinical studies support the view that taurine therapy reduces blood pressure in hypertensive subjects (Katakawa et al., 2016; Sun et al., 2016). Katakawa attributed the beneficial effects of taurine therapy against hypertension in humans to improved endothelial function secondary to a decline in oxidative stress. By comparison, Sun et al. (2016) focused on the vasodilatory effects of pre-hypertensive patients receiving taurine therapy. The most important feature of the study reported by Sun et al. (2016) was its size and design, as it is a single-center, double-blind, randomized, placebo-controlled trial of 120 pre-hypertensive subjects aged 18–75 with systolic pressure varying from 120–139 mm Hg and diastolic pressure from 80–89 mm Hg. After administration of taurine (1.6 g/day) for 12 weeks, systolic pressure of the pre-hypertensive subjects was reduced 7.2 mm Hg and diastolic pressure fell 4.7 mm Hg while pre-hypertensive subjects treated with placebo exhibited no significant reduction in blood pressure over the same treatment period (Sun et al., 2016). The taurine effect was greater in pre-hypertensive subjects with higher blood pressure than with the subjects with lower blood pressure at the time of initial taurine administration. The administration of taurine resulted in a 1.5-fold increase in plasma taurine concentration, an effect correlated with the improvement in blood pressure. This observation was consistent with an earlier epidemiological study by Yamori et al. (2010), who found that individuals with elevated amounts of taurine intake exhibit lower blood pressure values than individuals consuming less taurine. Moreover, Ogawa et al. (1985) had previously observed that plasma taurine content is reduced in essential hypertension. The human studies are consistent with animal studies showing that taurine deficiency accelerates the onset of hypertension in rats lacking a kidney and maintained on a high salt diet (Mozaffari et al., 2006). Moreover, a negative correlation has been detected between plasma taurine content and blood pressure in spontaneously hypertensive rats (Nara et al., 1978). In their clinical study, Sun et al. (2016) attributed the taurine-mediated reduction in blood pressure to improved flow- and nitroglycerin-mediated dilation, a change not observed in the placebo treated group. In addition to elevating plasma taurine content, the taurine treated group exhibited elevated H2S content, the latter that promotes hypotension by inhibiting transient receptor potential channel 3 (TRPC3)-induced signaling in the vasculature. Further studies are warranted to compare the importance of H2S content on blood pressure control relative to the other common regulators of vascular function, such as Ca2+, neurohumoral factors and nitric oxide.

Atherosclerosis: Atherosclerosis is the primary cause of pathology in stroke, myocardial infarction and peripheral artery disease. The process of atherosclerosis is complex, involving multiple factors and steps (Moore and Tabas, 2011). One of the key steps in the initiation of atherosclerosis is the uptake of the cholesterol-enriched lipoprotein, LDL, by the intima of the arterial wall. Also recruited in the arterial wall are monocytes, which normally exhibit little adhesion to endothelial cells and are not readily accumulated by smooth muscle. However, upon exposure to inflammatory factors and chemoattractants (chemokines), monocytes begin to adhere to endothelial cells, where they are taken up by the intima of the arterial wall. Upon exposure to factors, such as macrophage-colony factor, most of the monocytes in the early atheromata are differentiated into macrophages. Within the intima, LDL can undergo oxidation and glycation, which individually enhance the uptake of the lipoprotein by macrophages. While the uptake and handling of LDL by macrophages is considered an early event in the formation of foam cells, it is now apparent that there are multiple pathways involved in foam cell formation and atherosclerosis (Moore and Tabas, 2011).

Taurine treatment diminishes atherogenesis through several possible mechanisms. First, in most, but not all studies, taurine supplementation accelerates the regression in serum cholesterol levels in atherogenic animals (Petty et al., 1990; Murakami et al., 1996, 2010). During the regression period, hepatic cholesterol levels fall more rapidly in taurine treated animals, largely because of an increase in 7α-hydroxylase activity, which accelerates the degradation of cholesterol. Because there is a correlation between lower serum cholesterol and the dose of taurine used during treatment, the upregulation of the CYP7A1 gene in the liver is thought to regulate serum cholesterol levels (Yokogoshi et al., 1999; Lam et al., 2006; Murakami et al., 2010). At the same time, taurine treatment is associated with diminished activity of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting step of cholesterol biosynthesis (Bellentani et al., 1987). Second, exposure of hepatic cells for 24 hrs with medium containing taurine leads to a decline in the biosynthesis of cholesterol esters and triglycerides. Because the hepatic content of triglycerides and cholesterol esters is a determinant of lipoprotein assembly in the endoplasmic reticulum of the liver, taurine specifically decreases the assembly and secretion of lipoproteins containing the structural protein, apolipoprotein B100 (Yanagita et al., 2008; Murakami et al., 2010). Apolipoprotein B100 is the primary structural protein of both LDL and its precursor, VLDL. Third, taurine protects endothelial cells of vascular tissue from glucose-induced and oxidized LDL-induced toxicity, which is an early step in the development of atherosclerosis (Ulrich-Merzenich et al., 2007). It has also been suggested that taurine protects endothelial cells from homocysteine-induced ER stress and apoptosis by reducing hyperhomocysteinemia (Zulli et al., 2009). While oxidative stress is a primary adverse response to hyperglycemia and homocysteinemia, oxidized LDL-induced toxicity has been attributed to the accumulation of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase (Tan et al., 2007). Fourth, taurine suppresses platelet-derived growth factor-BB (PDGF-BB) induced vascular smooth muscle cell proliferation, which plays an important role in atherosclerosis (Yoshimura et al., 2005). Taurine appears to alter the activity of a phosphatase that dephosphorylates the PDGF-β receptor, which is a potent chemoattractant and proliferative factor for vascular smooth muscle cells. However, taurine does not suppress phorbol ester-induced activation of the Raf/MEK/ERK pathway of vascular smooth muscle proliferation, leading to the suggestion that taurine’s actions are specific for the PDGF-β pathway. Nonetheless, the field remains controversial. According to Terashima et al. (2003), taurine suppresses mesenchymal cell proliferation by inhibiting ERK activity and immediate early gene expression‎. Clearly, studies clarifying the effect of taurine on smooth muscle cell proliferation are warranted. Fifth, taurine diminishes the expression‎ of LOX-1, which mediates the uptake of oxidized LDL by endothelial cells and decreases the rate of stenosis in oxidatively stressed rabbits subjected to balloon injury of the iliac artery (Gokce et al., 2011). The authors also recognized the important role of taurine-mediated attenuation of oxidative stress in their findings. Finally, the possibility that taurine-mediated inhibition of atherosclerosis may involve its anti-inflammatory activity deserves consideration.

The epidemiological WHO-CARDIAC study showed that dietary taurine intake is correlated with reduced mortality of ischemic heart disease patients (Yamori et al., 2001). In support of that study, Elvevoll et al. (2008) found that taurine enhances the beneficial effects of n-3 fatty acid supplementation on total cholesterol, LDL cholesterol and triglycerides. Recently, Katakawa et al. (2016) attributed the diminished risk of atherogenesis in humans maintained on a diet supplemented with taurine and magnesium to reductions in oxidative stress and improvement in endothelial function. These studies have revealed the importance of taurine supplementation in human health.

Ischemia-reperfusion injury: Several actions of taurine (antioxidant, modulation of [Ca2+]i. osmoregulation, protein phosphorylation and high energy phosphate regulation) alter the outcome of an ischemia-reperfusion insult. A discussion of the differing effects of these factors in various models of ischemia-reperfusion injury and of the importance of taurine treatment and loss during an ischemia-reperfusion insult, appeared in a recent review (Schaffer et al., 2014b). Because of variable effects, it is unlikely that taurine would be adopted as an acute cardioprotective agent to diminish infarct size and minimize injury during a myocardial infarction. Rather, taurine’s use may be restricted to cardiac transplantation and bypass surgery. Several investigators have reported a benefit of taurine as a component of cardioplegic solutions (Oriyanhan et al., 2005) or of loading hearts with taurine prior to their use as donor hearts (Venturini et al., 2009; Sahin et al., 2011). Besides reducing oxidative stress and swelling, taurine loss during an ischemia-reperfusion insult leads to a decrease in [Na+]i, which not only diminishes osmotic stress but also Ca2+ overload (Schaffer et al., 2002; Modi and Suleiman, 2004). In addition, rapid intravenous infusion of taurine before bypass surgery protects against oxidative stress and cellular necrosis (Milei et al., 1992).

Myocardial arrhythmias: One of the earliest reported cardiovascular actions of taurine is its antiarrhythmic actions against a broad range of pro-arrhythmic agents (digoxin or related cardiac glycoside, epinephrine, ouabain, CsCl, hypokalemia)(Read and Welty, 1963; Chazov et al., 1974). This effect is likely related to the modulation of [K+]i, [Na+]i and [Ca2+]i. According to a clinical report, oral administration of taurine and L-arginine dramatically reduced cardiac arrhythmias of three subjects. Thus, under appropriate conditions, taurine is a very effective antiarrhythmic agent (Eby and Halcomb, 2006). Nonetheless, taurine is presently not used in the treatment of cardiac arrhythmias.

Role of taurine in metabolic diseases

Mitochondrial disease, MELAS: A remarkable similarity exists between the symptoms of taurine deficiency and that of the mitochondrial disease, MELAS (Schaffer et al., 2013). Indeed, the characteristic symptoms of MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) are also present in taurine deficiency. This is not surprising, as the pathophysiology of the two conditions is similar. MELAS is caused by specific point mutations in the region of DNA that codes for tRNALeu(UUR) (Schaffer et al., 2014a). The mutations appear to alter the structure of the tRNA, preventing the conjugation of taurine with the uridine base of tRNALeu(UUR) (Kirino et al., 2005). Modification of the uridine base alters the interaction of the UUG codon with the AAU anticodon of tRNALeu(UUR), thereby altering UUG decoding (Kurata et al., 2003). Taurine deficiency also appears to reduce the formation of the taurine conjugate, 5-taurinomethyluridine-tRNALeu(UUR), but the effect is related to a reduction in mitochondrial taurine content (Schaffer et al., 2014a). Taurine deficiency reduces the expression‎ of UUG-dependent proteins, with one of the most UUG-dependent mitochondria encoded protein being ND6, a subunit of complex I. Because ND6 plays a prominent role in the assembly of complex I, taurine-mediated reductions in ND6 levels lead to several features seen in MELAS, including lactic acidosis, reduced complex I activity and diminished oxygen consumption. Impaired respiratory chain function causes elevations in superoxide generation and reduced ATP generation, effects that likely play a central role in the development of the myopathy and encephalopathy of MELAS (Fig. 2). Seizures, which are another symptom of MELAS, could depend on the inhibitory neuromodulatory activity of taurine although the mitochondrial activity of taurine might also be a determinant of seizures.

Fig. 2.

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Comparison of MELAS and taurine deficiency in mitochondria. The mitochondrial disease, MELAS, is caused by specific point mutations in mitochondrial DNA (mtDNA) that codes for tRNALeu(UUR). Most of the point mutations of MELAS with 80% frequency occur at A3243G while mutations at T3271C exist with 10% frequency. In mtDNA, ND genes are shown in red color and tRNA genes are depicted as blue circles. The gene of tRNALeu(UUR) responsible for MELAS is located adjacent to ND1. The mutation in MELAS alters the structure of the tRNALeu(UUR) preventing the conjugation of taurine with the uridine base of the UAA anti-codon from forming 5-taurinomethyluridine (τm5U). MELAS patients also show reduced aminoacylation of taurine deficient tRNALeu(UUR) by leucine catalyzed by aminoacyl-tRNA synthetase (AS). Both reduced aminoacylation of tRNALeu(UUR) by leucine and formation of the taurine conjugate of τm5UAA-tRNALeu(UUR) prevent decoding of mitochondrial UUG-dependent proteins, including ND6, which is one of 44 protein subunits of complex I of the electron transport chain located in the mitochondria inner membrane. On the other hand, taurine deficiency has normal aminoacylation of tRNALeu(UUR) by leucine, but exhibits reduced formation of the taurine conjugate of τm5UAA-tRNALeu(UUR), which also prevents decoding of mitochondrial ND6 mRNA, resulting in increased superoxide generation and reduced ATP generation. MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; ND6: NADH-ubiquinone oxidoreductase chain 6; mt IS: motochodrial intermembrane space; mtIM: mitochondrial inner membrane; LS: light strand; HS: heavy strand.

Because of the direct link between taurine content and the development of MELAS, it is not surprising that patients with MELAS respond favorably to taurine therapy (Rikimaru et al., 2012). In one such case study, laboratory tests revealed that a 29-year-old woman presented at the hospital with stroke-like episodes had a MELAS-like A3243G point mutation in a left biceps brachii muscle biopsy. Anticonvulsants, both phenytoin and valproate, were administered over the next 7 months but failed to halt the epileptic and stroke-like episodes. Shortly after beginning oral taurine supplementation, which increased blood taurine content about 5-fold, the epileptic and stroke-like episodes completely ceased. Also corrected by taurine therapy was lactic acidosis. In a related case study, a 21-year-old male was admitted to a hospital with right homonymous hemianopsia. He was diagnosed with A3243G-linked MELAS and lactic acidosis. Anticonvulsion therapy was used over the next several years, but the patient still experienced several stroke-like episodes, including sensory aphasia and visual impairment. After taurine supplementation, which elevated blood levels approximately 10-fold, the stroke-like episodes ceased. The same group examined the effect of taurine treatment on cytoplasmic hybrids (cybrids) harboring a 3243G-MELAS mutation; incubation of the cybrids for 4 days with medium containing 40 mM taurine partially normalized oxygen consumption and mitochondrial membrane potential, which were suppressed in the A3243G containing cybrids. Taurine treatment also attenuated the degree of oxidative stress in cybrids harboring the 3243 mutant. Thus, taurine therapy not only abolishes stroke-like episodes in MELAS patients but also restores normal mitochondrial respiratory function. These data reveal promise for the use of taurine as a therapeutic agent against MELAS.

Diabetes mellitus: Diabetes mellitus is a disease characterized by elevated blood glucose and either a decrease in plasma insulin (type 1 diabetes) or resistance to the actions of insulin (type 2 diabetes). Type 1 diabetes is an autoimmune disease that is caused by T-cell-mediated destruction of pancreatic β-cells that dramatically reduces insulin biosynthesis. Thus, the disease is characterized by hypoinsulinemia and hyperglycemia. By contrast, type 2 diabetes is a progressive disorder characterized initially by insulin resistance, in which the actions of insulin at target organs are reduced, although in later stages of the disease insulin secretion is also impaired. Diabetes is associated with multiple complications, including cardiovascular disease, neuropathy, nephropathy, retinopathy, foot ulcers, skin lesions and hearing impairment. Although restrictions in the degree of hyperglycemia are central to the control of these complications, several downstream factors can contribute to the severity of the complications. One of the most important of these factors is ROS. According to seminal studies by Brownlee (2005), it was proposed that glucose oxidation, which involves pyruvate metabolism by the mitochondria, produces ROS, which in turn enhances flux through several damaging pathways (advanced glycosylation end product generation, protein kinase C activation, polyol formation and hexosamine pathway stimulation) involved in the development of diabetic complications.

Two important concepts arose from the work of Brownlee (2005). First, his unifying hypothesis provided a logical link between glucose-mediated oxidative damage and several pathways implicated in diabetic complications. Moreover, it introduced the insightful idea that mitochondria-derived ROS play an important role in the development of certain diabetic complications. However, it did not take into consideration the effect of diabetes-mediated oxidative stress on mitochondrial function itself (Higgins and Coughlan, 2014; Malik et al., 2015; Coughlan et al., 2016; Czajka and Malik, 2016).

The major source of ROS in most diabetic tissues is complexes I and III of the respiratory chain. Interestingly, ROS generated by complex I remain within the matrix of the mitochondria while complex III-derived ROS are distributed between the matrix and extra-mitochondrial locations. In the matrix, ROS provokes damage, as evidenced by decreased activity of the oxidant-sensitive enzyme, aconitase, increased mitochondrial DNA oxidation and if severe enough, death via apoptosis (Ricci et al., 2008; Lindblom et al., 2015). Although complex III-mediated ROS generation can affect targets outside of the mitochondria, the intra-mitochondrial effects appear most important in the development of diabetic complications. In leptin deficient, obese, type 2 diabetic db/db mice, elevations in mitochondrial ROS production of the heart lead to reduced ATP production, as respiratory function and energy metabolism are impaired, which in turn diminishes myocardial performance (Boudini et al., 2007). Respiration and ATP generation are also defective in diabetic renal mesangial and tubular cells. Because ATP is required for reabsorption in the proximal tubules while energy deficiency leads to renal failure, hyperglycemia-mediated mitochondrial damage and ATP deficiency appear to play a prominent roles in the development of the diabetic nephropathy (Higgins and Coughlan, 2014; Czajka and Malik, 2016; Hallan and Sharma, 2016).

Mitochondrial DNA damage, which has been detected in humans suffering from diabetes melllitus (Malik et al., 2015), invariably alters the expression‎ of mitochondria encoded proteins, leading to diminished respiratory chain activity. As a result, more ROS is produced, which triggers further mitochondrial DNA damage, ultimately leading to a vicious cycle of damage. Evidence of severe mitochondrial structural changes and dysfunction (morphology, biogenesis, respiratory chain function, fatty acid and citric acid cycle metabolism, oxidative stress, apoptosis and uncoupling activity) support a role of mitochondrial damage in the development of diabetic complications (Sivitz and Yorek, 2010; Aon et al., 2015; Lindblom et al., 2015; Hallan and Sharma, 2016).

Plasma and platelet taurine levels are reduced in subjects with type 1 diabetes (Franconi et al., 1995). Based on 711 overweight, diabetic subjects, plasma taurine levels are related to the decline in insulin sensitivity (Zheng et al., 2016). In fact, most of the major targets of diabetes (kidney, retina and neurons) undergo hyperglycemic-mediated reductions in taurine content (Schaffer et al., 2009). Nonetheless, at an early age, the metabolic pattern of subjects with diabetes is very different from that of the taurine deficient mouse (Ito et al., 2015b; Schaffer et al., 2016). The initial defect in type 1 diabetes is insulinopenia, which reduces glucose metabolism and elevates fatty acid metabolism, while taurine deficient mice exhibit impaired respiratory chain function, increased glycolysis and decreased glucose and fatty acid oxidation (Schaffer et al., 2016). Nonetheless, taurine is required for normal β-cell viability, therefore, the number of pancreatic β-cells is reduced in 12-month-old TauTKO mice (Ito et al., 2015b). Moreover, the properties of the diabetic animal are altered with age, as mitochondrial oxidative injury leads to impaired respiratory chain function in the late phases of the disease. Also affecting mitochondrial function and biogenesis is diet and physical activity (Santos et al., 2014). Therefore, upon aging and dietary modification, the diabetic and taurine phenotypes adopt similar features. In this regard it is interesting that Han et al. (2015) claim that taurine deficiency is a necessary requirement for the development of an appropriate model of diabetic nephropathy.

There is overwhelming evidence that taurine therapy reduces pathology associated with diabetes, obesity and the metabolic syndrome (Schaffer et al., 2009; Ito et al., 2012; Imai et al., 2014; Murakami, 2015; Chen et al., 2016). In many animal studies, particularly of type II diabetes, taurine treatment diminishes the degree of hypoglycemia, an effect that in turn attenuates diabetic complications (Nakaya et al., 2000; Winiarska et al., 2009; Das and Sil, 2012; Kim et al., 2012; Chiang et al., 2014; Koh et al., 2014). Several mechanisms may contribute to the regulation of hyperglycemia in diabetic animals treated with taurine. First, taurine improves respiratory function and increases ATP production, effects that should improve pancreatic β-cell function and insulin secretion (Sivitz and Yorek, 2010; Schaffer et al., 2016). Second, hyperglycemia and lipidemia are associated with elevations in mitochondrial ROS generation. In pancreatic β-cells, fatty acid-mediated ROS generation appears to decrease insulin secretion, an effect attenuated by taurine treatment (Oprescu et al., 2007). Third, mitochondrial dysfunction can provoke insulin resistance (Sivitz and Yorek, 2010). Haber et al. (2003) found that taurine treatment prevents hyperglycemia-induced insulin resistance and oxidative stress. Together, these findings indicate that taurine protects against type 2 diabetes-mediated complications, but the mechanism by which taurine diminishes the development of the complications of type 2 diabetes remain unclear, largely because it is virtually impossible to separate the mitochondrial actions of taurine from its effects on insulin secretion and action.

On the other hand, in the streptozotocin-induced model of type 1 diabetes, plasma glucose levels remain unaltered by taurine treatment while the severity of the diabetic complications are diminished. Because diabetic status in the streptozotocin model of type 1 diabetes is unaffected by taurine, one can readily establish the mechanism underlying taurine’s effectiveness against the development of diabetic complications. According to several investigators, taurine-mediated reductions in the severity of type 2 diabetic complications are more closely linked to improvements in cellular stresses (ER, oxidative and inflammatory) and mitochondrial dysfunction (Schaffer et al., 2009; Ito et al., 2012; Imai et al., 2014). Trachtman et al. (1995) were the first group to recognize the benefit of taurine treatment against the development of diabetic complications. They reported that male rats administered streptozotocin developed a diabetic nephropathy characterized by elevated glomerular filtration rate, glomerular hypertrophy and proteinuria and albuminuria. Administration of taurine (1% in the drinking water) reduced proteinuria by 50% and dramatically suppress glomerular hypertrophy and tubointerstitial fibrosis without affecting blood glucose. Because the amino acid also abolished the elevation in renal cortical malondialdehyde, a marker of oxidative stress, and of advanced glycoloxidation products, a marker of advanced glycosylation end products, the protective effects of taurine were attributed to suppression of oxidative stress and advanced glycosylation. Recently, the effectiveness of taurine therapy against the development of diabetic nephropathy has been confirmed (Pandya et al., 2013; Koh et al., 2014). In a related study, Ikubo et al. (2011) found that streptozotocin-treated diabetic rats developed vascular defects that were associated with oxidative stress without a change in blood glucose. Interestingly, taurine also protects against apoptosis in cellular models of glucose toxicity (Ulrich-Merzenich et al., 2007).

Obesity is a disorder characterized by insulin resistance, hyperlipidemia, hyperglycemia and inflammatory responses related to enlarged adipocytes. Taurine has been effective in decreasing body weight of obese animals and in suppressing inflammatory responses. These effects and their mechanism are not reviewed here but are covered in a complete review by Murakami (2015).

Role of taurine in inflammatory diseases: Arthritis is a term used to describe over 100 diseases, the most common being rheumatoid arthritis and osteoarthritis. The major symptoms of arthritis are joint stiffness and pain with inflammation of the joints, the tissues surrounding the joint and connective tissue. Rheumatoid arthritis is characterized by synovial inflammation and proliferation, bone erosions and thinning of articular cartilage.

The distinctive features of the acute inflammatory phase, which can last up to several days, are vascular dilation, microvascular leakage and leukocyte recruitment, the latter mediated by adhesion factors that facilitate the interaction of leukocytes with activated endothelium. Acute inflammation, which is triggered by damaged or diseased tissue, as well as irritants and pathogens, is an early phase in the repair of damage and the removal of microorganisms and harmful agents by the innate immune system. During acute inflammation, leukocytes adhere to the endothelium prior to transmigrating across the endothelium into the interstitium. Chemotactic factors and cytokines recruit the neutrophils to the site of inflammation. Activation of the leukocytes, in particular neutrophils and mononuclear phagocytes, leads to the secretion of a host of proinflammatory mediators, including microbicidal peptides, cationic microbial proteins, lytic enzymes, ROS and lysosomal granule constituents. When these proinflammatory mediators are released into phagolysosomes, they destroy engulfed microbes and other pathogens. However, when they are released into the extracellular millieu, they can cause tissue damage. In rheumatoid arthritis, activation of the inflammatory process is part of the autoimmune disorder contributing to joint deformation, erosion of bone and disruption of the cartilagebone interface.

The content of taurine in the neutrophil is high, representing about 50% of the total free amino acid pool. The two primary functions of taurine in the neutrophil are anti-inflammatory and antioxidant actions. ROS are produced by the neutrophil as a weapon to kill pathogens, with one of those ROS being hypochlorous acid (HOCl). Myeloperoxidase-catalyzes the formation of taurine chloramine (TauCl) from taurine and HOCl. Because TauCl is a less potent oxidant than HOCl, the neutralization of HOCl represents one of the important antioxidant mechanisms of taurine. The myelperoxidase-catalyzed reaction is also responsible for the anti-inflammatory activity of taurine, as TauCl inhibits the production of proinflammatory cytokines (Marcinkiewicz et al., 1995; Park et al., 1997; Barua et al., 2001), attenuates elevations in nitric oxide and prostaglandin E2 (Park et al., 2000; Chorazy-Massalska et al., 2004; Kim et al., 2007), decreases the activity of matrix metalloproteinases and initiates leukocyte apoptosis to terminate acute inflammation (Klamt and Shacter, 2005). For a detailed discussion of the anti-inflammatory and anti-arthritic actions of taurine please refer to the extensive review by Marcinkiewicz and Kontny (2014).

Effect of taurine on muscle

Modulation of muscle contraction: Taurine deficiency leads to impaired contractile function of both cardiac and skeletal muscle (Cuisinier et al., 2000). Hamilton et al. (2006) found that exposure to the taurine transport inhibitor, guanidinoethanesulfonate, led to a 60% reduction in extensor digitorum longus taurine content, which was associated with a decrease in peak force contraction. More severe muscular dysfunction is seen in taurine transporter knockout mice, whose muscle taurine content is reduced by over 90%, which leads to a decline in muscle mass and muscular dysfunction (Warskulat et al., 2004; Ito et al., 2008; Ito et al., 2014b). Also associated with severe taurine deficiency are histological changes, including disruption of the myofibrils.

There are abundant reports that taurine administration enhances exercise performance of both humans (Ishikura et al., 2011; Balshaw et al., 2013; Ra et al., 2013, 2016) and animals (Goodman et al., 1985; Dawson et al., 2002; Yatabe et al., 2003; Sugiura et al., 2013; da Silva et al., 2014). Besides improving contractile function of rodents, taurine administration was found to increase the time until exhaustion, reduce exercise-induced fatigue and diminish damage from intense exercise. When taurine is administered prior to heavy exercise, the levels of pro-inflammatory factors are reduced and exercising muscle is protected (Kato et al., 2015). Also noteworthy is a trial of 36 male subjects that were administered either a branched-chain amino acid supplement, a taurine supplement, placebo or the combination of taurine and branched-chain amino acid supplements (Ra et al., 2013). The least muscle damage after eccentric exercise was observed in the combination group, as muscle soreness was diminished two days after exercise and there was less lactate dehydrogenase and aldolase released into the blood. Interestingly, serum levels of 8-hydroxydeoxyguanosine, a measure of DNA oxidative damage, were also reduced in the combination group, implicating the antioxidant activity of taurine in the beneficial effects of the combination supplement. The authors suggested that taurine potentiates the beneficial effect of the branched-chain amino acid supplement. The likely candidates for the protective activity of taurine are suppression of oxidative stress and inflammation. In another study by the same laboratory, the end point of the study was arterial stiffness after eccentric exercise (Ra et al., 2016). Serum malondialdehyde remained elevated for 4 days after exercise in the control placebo group while oxidative stress was decreased in the taurine treated group. There was a parallel between the increase in malondialdehyde and arterial stiffness, which led the authors to suggest that taurine-mediated reductions in oxidative stress helped attenuate the degree of arterial stiffness. For a more complete review of the role of taurine in muscle function and disorders, please refer to DeLuca et al. (2015).

Sarcopenia: Sarcopenia, which is the gradual loss of skeletal muscle tissue related to an imbalance between protein biosynthesis and degradation. Because sarcopenia occurs with aging and leads to physical impairment among the elderly it is a serious health problem. Interestingly, taurine deficiency is associated with a reduction in cell size (Schaffer et al., 1998; Ito et al., 2008). In a recent review, Scicchitano and Sica (2016) raised the possibility that taurine might counteract the adverse effects of sarcopenia. This is an interesting condition that could extend the utilization of taurine to another application.

Duchenne muscular dystrophy: Encouraging results have been reported using taurine therapy for the treatment of mdx mice, a model for Duchenne muscular dystrophy, which is a fatal muscle wasting disease characterized by oxidative stress and inflammation (Terrill et al., 2016b). In humans suffering from the disease, there are no symptoms at birth, however, symptoms in the form of waddling gait and difficulty climbing steps, begin to appear at a young age. The primary cause of the disease in humans are mutations in dystrophin, a cytoskeletal protein that connects the cytoskeleton and the extracellular matrix, while in the mdx mouse model of Duchenne muscular dystrophy the mutations are replaced by inadequate expression‎ of dystrophin.

In the disease, structural changes within the sarcolemma increase the permeability of the cell membrane and facilitate the accumulation of Ca2+, contributing to the development of Ca2+ overload in which the rate of [Ca2+]i rise after depolarization is enhanced, peak [Ca2+]i is increased and the relaxation phase is prolonged (Blake et al., 2002). Because the protease inhibitor, leupeptin, abolishes the exaggerated increase in [Ca2+]i, it has been proposed that proteases contribute to the severity of the disorder. Another factor that contributes to the development of the disorder is a lack of nNOS, which normally produces nitric oxide to ensure adequate vasodilation. Because nitric oxide levels fall in an oxidatively stressed environment, it has been proposed that oxidative stress and acute inflammation may also contribute to pathology of the disease.

Taurine has a potential to disrupt several of the steps in the development of Duchenne’s muscular dystrophy, in part by restoring taurine levels that decline in the muscle disorder (Terrill et al., 2015, 2016b). ln fact, addition of 4% taurine to mouse chow of mdx mice after 14 days of age increases muscle taurine content, an effect correlated with reductions in inflammation (neutrophil infiltration) and mitigation of severe bouts of myocyte necrosis after exercise (Terrill et al., 2016a). According to DeLuca et al. (2003) taurine treatment also significantly enhances forelimb strength of exercising dmx mice. This effect of taurine is largely attributed to an improvement in Ca2+ homeostasis, although taurine supplementation has no effect on the expression‎ of key E-C coupling proteins (Horvath et al., 2016). Creatine treatment is nearly as effective as taurine in enhancing muscle strength, indicating that delivery of more energy to the muscle prevents the decline in muscle function. In this regard, the effect of taurine on improvement in high-energy phosphate metabolism and respiratory chain function may also contribute to its beneficial actions (Schaffer et al., 2016).

Myotonic dystrophy: Myotonia is a condition characterized by delayed relaxation following skeletal muscle contraction. Conte-Camerino et al. (1989) found that acute administration of taurine was effective in attenuating myotonic discharges by 20,25 diazacholesterol-treated rats but not by rats treated with anthracene-9-carboxylic acid. The positive effect of taurine against the 20,25 diazacholesterol model of myotonia was attributed to an improvement in flux through voltage-gated chloride channels of extensor digitorum longus myofibers. It has been suggested that the actions of anthracene-9-carboxylate preclude an effect of taurine. Taurine requires functional chloride channels, but anthracene-9-carboxylate inhibits those channels.

Several clinical trials examining the effect of chronic taurine therapy on the severity of myotonia have been eval‎uated. In a double-blind, single crossover study of 9 patients with dystrophia myotonica, chronic taurine therapy diminished the severity of myotonia while decreasing potassium-induced hyperexcitability (Durelli et al., 1983). The possibility that taurine might also be effective against sodium channel myotonia and paramyotonia congenita has also been proposed, as taurine modulates sodium transients of the Nav1.4 channel (DeLuca et al., 2015).

Taurine also increases the sensitivity of myofibrils to Ca2+ (Dutka et al., 1985), an effect also seen in the TauTKO heart, where it has been attributed to enhanced phosphorylation of troponin (Ramila et al., 2015). It is also possible that taurine affects muscular activity of the sarcoplasmic reticular Ca2+ pump, an effect in the heart caused by alterations in the phosphorylation state of the regulator protein, phospholamban (Ramila et al., 2015).

CONCLUSION

Taurine, 2-aminoethanesulfonic acid, is an endogenous end metabolite that is distributed in various tissues at high concentration. It is a sulfur-containing amino acid synthesized from cysteine and is excreted without any further metabolism. Since the first discovery of taurine in 1827, many of its functions have been elucidated in experiments focusing on skeletal muscle, the retina and the central nervous and cardiovascular systems. The cytoprotective actions of taurine contribute to the improvement in the clinical and nutritional health of humans through various mechanisms, including antioxidation, energy production, neuromodulation, Ca2+ homeostasis and osmoregulation. The combination of one or more of these cytoprotective effects of taurine act to diminish the pathology and symptoms of a host of diseases ranging from those of the CNS, cardiovascular system, skeletal muscle and defective metabolism. Many CNS-related diseases, including stroke, neurodegeneration, FXS, SSDD and epilepsy, respond favorably to taurine therapy. Taurine treatment also diminishes the severity of inflammatory diseases and abnormalities of the circulatory system, such as heart failure, hypertension, atherosclerosis, ischemia-reperfusion injury, myocardial arrhythmias, diabetes mellitus and arthritis. The phenotype of taurine depletion resembles that of the mitochondrial disease, MELAS, as both conditions affect the activity of the respiratory chain. Also characteristic of the taurine transporter KO mouse is impaired skeletal muscle contraction and sarcopenia. Therefore, taurine therapy is likely to improve cardiac and skeletal muscular dysfunction in conditions, such as MELAS, diminished muscle contraction, sarcopenia, Duchenne muscular dystrophy and myotonic dystrophy. Because taurine is a naturally occurring substance that exhibits few adverse side effects and plays a fundamental role in the function of most mammalian cells, the future of taurine as an effective therapeutic agent and a nutritional supplement is seemingly bright. Although clinical eval‎uation of taurine has been limited to a few diseases, it has already been approved for use in congestive heart failure. Therefore, taurine is an essential neutraceutical with diverse cytoprotective and therapeutic actions.

결론
타우린, 2- 아미노에탄설폰산은 다양한 조직에 고농도로 분포하는 내인성 말단 대사 산물입니다. 시스테인에서 합성된 황 함유 아미노산으로 더 이상의 대사 과정 없이 배설됩니다. 1827년 타우린이 처음 발견된 이후 골격근, 망막, 중추신경계 및 심혈관계에 초점을 맞춘 실험을 통해 타우린의 많은 기능이 밝혀졌습니다. 타우린의 세포 보호 작용은 항산화, 에너지 생산, 신경 조절, Ca2+ 항상성 및 산소 조절 등 다양한 메커니즘을 통해 인간의 임상 및 영양 건강을 개선하는 데 기여합니다. 타우린의 이러한 세포 보호 효과 중 하나 이상의 조합은 중추신경계, 심혈관계, 골격근, 신진대사 결함 등 다양한 질병의 병리 및 증상을 완화하는 역할을 합니다. 뇌졸중, 신경 퇴행, FXS, SSDD, 간질 등 많은 CNS 관련 질환이 타우린 치료에 호의적인 반응을 보입니다. 타우린 치료는 또한 심부전, 고혈압, 죽상 동맥 경화증, 허혈 재관류 손상, 심근 부정맥, 당뇨병 및 관절염과 같은 순환계의 염증성 질환 및 이상의 심각성을 감소시킵니다. 타우린 고갈의 표현형은 미토콘드리아 질환인 멜라스의 표현형과 유사하며, 두 질환 모두 호흡기 사슬의 활성에 영향을 미치기 때문입니다. 또한 타우린 수송체 KO 마우스의 특징은 골격근 수축 장애와 근감소증입니다. 따라서 타우린 요법은 MELAS, 근육 수축 감소, 근감소증, 듀센 근이영양증 및 근이영양증과 같은 질환에서 심장 및 골격근 기능 장애를 개선할 수 있습니다. 타우린은 부작용이 거의 없고 대부분의 포유류 세포의 기능에 근본적인 역할을 하는 자연 발생 물질이기 때문에 효과적인 치료제와 영양 보충제로서의 타우린의 미래는 밝아 보입니다. 타우린에 대한 임상 평가는 몇 가지 질병으로 제한되어 있지만, 이미 울혈성 심부전에 대한 사용이 승인되었습니다. 따라서 타우린은 다양한 세포 보호 및 치료 작용을 하는 필수 중성 의약품입니다.

Acknowledgments

The year 2017 represents the 190th anniversary since the discovery of taurine by the German scientists, Friedrich Tiedemann and Leopold Gmelin in 1827. This article was prepared in honor of the 190th anniversary of taurine’s discovery. The authors of this article, Stephen Schaffer, president of the International Taurine Society, and Ha Won Kim, president of the Korean Taurine Society, would like to express our appreciation for the support from Dong-A Pharmaceutical Company, Ltd, Korea.

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