Effects of a nitric oxide donor and nitric oxide s

I苯磺酸钙联合硫辛酸对糖尿病合并肾损伤患者糖脂代谢及肾功能的影响刘鲁豫1,刘爱霞1*，王露露S张效科2（1.陕西中医药大学附属医院内分泌科，咸阳712000；2.陕西中医药大学，咸阳712046%摘要：目的研究凳苯磺酸钙联合硫辛酸对糖尿病合并肾损伤（DN）患者糖脂代谢及肾功能的影响°方法按照就诊序号，将132例DN患者均分为A组（硫辛酸治疗）与B组（凳苯磺酸钙联合硫辛酸治疗），比较2种治疗方案对患者糖脂代谢及肾功能的影响°结果治疗后，2组患者空腹血糖（FPG）、餐后2h血糖（p2hPG）及糖化血红蛋白（HbAlc）水平与治疗前比较无显著性变化，治疗后2组FPG、p2hPG及HbAlc水平组间比较差异无统计学意义（P〉0.05）；治疗后，2组总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）及低密度脂蛋白胆固醇（LDL-C）水平与治疗前相比，均未发生显著性变化，治疗后2组TC、TG、HDL-C及LDL-C水平比较差异无统计学意义（P〉0.05）；治疗后,组血肌肝（CC、24h尿白蛋白排泄量（UAE）及尿素氮（BUN）水平较同组治疗前显著下降（P V0.05）,且B组患者治疗后Cr和UAE水平均显著低于A组（P<0.05）,2组治疗后BUN水平比较差异无统计学意义（P〉0.05）；治疗后，A组血清内皮素（ET）、血清一氧化氮（NO）及血浆纤溶酶原激活剂抑制物-1CPAI-1）水平与治疗前比较差异无统计学意义（P〉0.05）B组血清ET水平均较同组治疗前显著下降（P<0.05）血清NO 及血浆PAI-1水平均较同组治疗前显著上升（P<0.05）,B组患者治疗后血清ET水平显著低于A组（P<0.05）,血清NO及血浆PAI-1水平显著高于A组（P V0.05）；治疗后2组血清胱抑素-C（CysC）及尿N-乙酰氨基葡糖5酶（NAG）水平均较同组治疗前显著下降（P V0.05）,且B组血清CysC及尿NAG水平显著低于A组（P<0.05）结论凳苯磺酸钙联合硫辛酸治疗DN的效果优于单用硫辛酸，凳苯磺酸钙可能通过改善患者血管内皮细胞功能发挥肾脏保护作用°关键词：凳苯磺酸钙；硫辛酸；糖尿病合并肾损伤；糖脂代谢；肾功能DOI：10.3969/j.issn.10042407.202101030中图分类号：R977文献标志码:A文章编号：10042407（2021）01-0140-05Effects of calcium dobesilate combined with thioctic acid on glucose and lipid me­tabolism and renal function in diabetic nephropathy patientsLIU Luyu1,LIU Aixia1*, WANG Lulu1,ZHANG Xiaoke2(1.Department of Endocrinology,Affiliated Hospital of Shaanxi Univer­sity of Chinese Medicine,Xianyang712000,China；2.Shaanxi University of Traditional Chinese Medicine,Xianyang712046,China)Abstract:To investigate the effects of calcium dobesilate combined with thioctic acid on glucose and lipid metabolism and renal function in patients with diabetic nephropathy(DN).According to admission order,132DN patients were divided into2groups according to group A(thioctic acid)and group B(calcium dobesilate combined with thioctic acid).Then the effect of the2treatment methods o n glucose and lipid metabolism and renal function were compared.The levels of fasting plasma glucose(FPG),postprandial2h plasma glucose(p2hPG)and glycosylated hemoglobin(HbAlc)after treatment showed no sig­nificant changes with those before treatment,and the post-treatment FPG,p2hPG and HbAlc levels had no statistic difference be­tween the groups(P〉0.05).After treatment,the levels of total cholesterol(TC),triglyceride(TG),high-density lipoprotein cho­lesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)had no significant changes in both groups,and the post-treat­ment TC,TG,HDL-C and LDL-C showed no statistic difference between the groups(P〉0.05).After treatment,the levels of serum creatinine(Cr),24h urinary albumin excretion(UAE)and blood urea nitrogen(BUN)were decreased in both groups(P< 0.05).The levels of Cr and UAE in group B were significantly lower than those in group A(P<0.05),and no significant difference was found in BUN levels between groups after treatment(P〉0.05).The levels of serum endothelin(ET),serum nitric oxide(NO)and plasma plasminogen activator inhibitor-1(PAI-1)in group A had no significant di f erence before and after treatment(P〉0.05).In group B,t he serum ET level was decreased,and serum NO and plasma PAI-1levels were increased after treatment(P<0.05).Compared with group A,group B had lower ET level as well as higher serum NO and plasma PAI-1levels after treatment(P<0.05).After treatment,the levels of serum cystatin-C(CysC)and urine N-acetyl--D-glucosaminidase (NAG)were decreased in b oth groups,and were lower in group B than in group A(P<0. 05).Calcium dobesilate combined with lipoic acid is better than lipoic acid alone in the treatment of DN,calcium dobesilate may play a renal protective role byimpYovingthefunctionofvasculaYendothelialcels.Key words:calcium dobesilate；thioctic acid；diabetic nephYopathy；glucose and lipid metabolism；enalfunction基金项目：国家自然科学基金项目（编号=81774304）作者简介：刘鲁豫，女，硕士，主治医师通信作者：刘爱霞，女，硕士，主治医师糖尿病（DM）是世界范围内的常见病、多发病,随着病情的不断发展，DM将诱发大量并发症，其中糖尿病合并肾损伤（DN）是最为严重的并发症之一+DM诱发的肾损伤，是导致终末期肾病（ESRD）的主要原因减缓肾脏损伤、保护肾功能，在防止ESRD、改善患者预后中具有重要作用。

important role in the pathological complications seen in atherosclerosis and coronary heart disease. Research presented here suggests that astaxanthin may be useful as part of an antioxidant therapy to alleviate hypertension (Figure 1).
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the significant improvement of blood flow (N=10, p<0.05) in humans treated with 6 mg astaxanthin for 10 days (Figure 4).
Mechanism of Anti-hypertension
The antihypertensive mechanism may be in part explained by the changes of vascular reactivity and hemorheology.
Microchannel Array Flow Analysis (MC-FAN) measured a significant increase of blood flow of 11% (Figure 3) in the astaxanthin treated group (N=6-7, p<0.05). Although plasma fluidity is largely influenced by fibrinogen, in this study, the fibrinogen levels did not change and therefore, the improved deformation and reduced blood aggregation are the likely mechanisms (Hussein et al., 2005b). This is supported by Miyawaki et al., (2005) who also used the MC-FAN to demonstrate

冻干制剂中精氨酸的作用英文回答：Arginine is a conditionally essential amino acid that plays a significant role in the synthesis of proteins, creatine, and nitric oxide. In freeze-dried formulations, arginine serves several important functions:Protein synthesis: Arginine is a key component of protein molecules and is involved in the protein synthesis process. It is particularly important for the synthesis of muscle proteins, which are crucial for muscle growth and repair.Creatine synthesis: Arginine is a precursor for the synthesis of creatine, a compound that is stored in muscle cells and provides energy during muscle contractions. Creatine supplementation has been shown to improve athletic performance and muscle strength.Nitric oxide production: Nitric oxide (NO) is a signaling molecule that plays a crucial role in vasodilation, blood flow regulation, and immune function. Arginine is a substrate for the enzyme nitric oxide synthase (NOS), which converts arginine into NO. Increased NO production can improve blood flow and oxygen delivery to tissues, enhance nutrient transport, and reduce inflammation.pH buffering: Arginine has a buffering capacity and can help to maintain a stable pH environment within freeze-dried formulations. This is important to ensure thestability and activity of other components in the formulation.中文回答：精氨酸是一种条件必需氨基酸，在蛋白质、肌酸和一氧化氮的合成中起着重要的作用。

㊃综㊀述㊃硫化氢及其外源性供体对心血管疾病治疗潜力的研究进展李甜甜1,郭丽1∗,张书虎2(1佳木斯大学附属第一医院心血管内科,佳木斯154002;2哈尔滨医科大学附属第二医院老年病科,哈尔滨150086)ʌ摘㊀要ɔ㊀硫化氢(H 2S)被认为是继一氧化碳㊁一氧化氮后的第3大内源性气体信号分子,可在哺乳动物组织中合成,并能自由地穿过细胞膜,在包括心血管系统在内的多系统中发挥多种生物作用㊂心血管疾病是世界范围内死亡的主要原因,其具体发病机制尚未完全明确㊂近年来,越来越多的研究支持内源性H 2S 和外源性H 2S 供体化合物对动脉粥样硬化㊁心肌肥厚㊁心力衰竭和缺血/再灌注损伤等心血管疾病发挥保护作用,本文综述了此方面的研究进展,重点介绍了H 2S 以及各种外源性H 2S 供体在治疗心血管疾病中的潜力㊂ʌ关键词ɔ㊀硫化氢;心血管疾病;动脉粥样硬化;心肌肥大;心力衰竭;缺血/再灌注损伤ʌ中图分类号ɔ㊀R540.4㊀㊀㊀㊀㊀ʌ文献标志码ɔ㊀A㊀㊀㊀㊀ʌDOI ɔ㊀10.11915/j.issn.1671-5403.2020.05.094收稿日期:2019-06-22;接受日期:2019-08-06通信作者:郭丽,E-mail:597847372@Progess in research on therapeutic potential of hydrogen sulfide and its exogenous donors in cardiovascular diseasesLI Tian-Tian 1,GUO Li 1∗,ZHANG Shu-Hu 2(1Department of Cardiology,First Affiliated Hospital of Jiamusi University,Jiamusi 154002,China;2Department of Geriatrics,Second Affiliated Hospital of Harbin Medical University,Harbin 150086,China)ʌAbstract ɔ㊀Hydrogen sulfide (H 2S)is ranked after carbon monoxide and nitric oxide as the third largest endogenous gas signalingmolecule.It can be synthesized in mammalian tissues and can freely pass through cell membrane.It can exerted a variety of biologicaleffects in multiple systems including the cardiovascular system.Cardiovascular diseases are the leading cause of death worldwide,and its specific pathogenesis is not fully understood.In recent years,more and more studies have supported the protective effects of endoge-nous H 2S and exogenous H 2S donor compounds on such cardiovascular diseases as atherosclerosis,myocardial hypertrophy,heart failure and ischemia /reperfusion injury.In this paper,we review the research progress in this area,highlighting the potential of H 2S and vari-ous exogenous H 2S donors in the treatment of cardiovascular diseases.ʌKey words ɔ㊀hydrogen sulfide;cardiovascular disease;atherosclerosis;cardiac hypertrophy;heart failure;ischemia /reperfusioninjuryCorresponding author :GUO Li ,E-mail :597847372@㊀㊀硫化氢(hydrogen sulfifide,H 2S)是一种无色㊁有臭鸡蛋味的水溶性气体[1],是继一氧化碳㊁一氧化氮后被发现的第3种重要的内源性气体信号分子[2,3],主要由胱硫醚β-合成酶(cystathionine beta-synthase,CBS )㊁胱硫醚γ-裂解酶(cyst-athionine gamma-lyase,CSE)产生,也可在α-酮戊二酸存在下的情况下通过非依赖性3-巯基-丙酮酸硫转移酶(3-mercapto-pyruvate sulfate transferase,3-MST)或半胱氨酸氨基转移酶(cysteine aminotransferase,CAT)产生[4]㊂在人类心血管系统中,CSE 是主要的H 2S 生成酶;而在大鼠冠状动脉中产生H 2S 的酶主要是3-MST㊂H 2S 可以在哺乳动物组织中合成,并能够在各种系统中自由穿过细胞膜而发挥多种生物效应[3]㊂目前大量研究报道了H 2S 在动脉粥样硬化㊁心脏重塑和心肌缺血/再灌注损伤中的治疗作用,其相关机制包括抗氧化㊁抑制细胞凋亡㊁促进血管生成㊁抗炎㊁调节离子通道等[5],本文将重点讨论H 2S 及其外源性供体在动脉粥样硬化㊁心脏重塑㊁心力衰竭和心肌缺血/再灌注损伤中的治疗潜力㊂1㊀动脉粥样硬化㊀㊀动脉粥样硬化的病理基础为脂质代谢紊乱,动脉粥样硬化的发展涉及多种机制,包括内皮细胞损伤和功能障碍㊁炎症细胞聚集㊁泡沫细胞形成㊁平滑肌细胞增殖和迁移㊁钙化㊁纤维帽破裂和血栓形成等[6]㊂在CSE基因过表达的载脂蛋白E(apoli-poprotein E,ApoE)敲除鼠的主动脉组织中,内源性H2S生成增加,动脉粥样硬化斑块变小,血脂降低,由此可知CSE基因的激活减轻了ApoE(-/-)鼠动脉粥样硬化的严重程度[7]㊂新型的外源性H2S供体GYY4137可通过降低主动脉细胞间黏附分子-1 (intercellular cell adhesion molecule-1,ICAM-1)㊁肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)和血凝集素样氧化低密度脂蛋白受体1(lectin-like oxidized low density lipoprotein receptor-1,LOX-1)的表达,增加内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)磷酸化来减轻ApoE(-/-)鼠主动脉粥样硬化斑块程度,改善主动脉内皮依赖性舒张功能[8]㊂硫氢化钠(sodiumhydrosulfide,NaHS)减轻动脉粥样硬化大鼠模型中动脉粥样硬化斑块的严重程度,降低内皮细胞内皮缩血管肽-1(endothelin-1, ET-1)的生成㊂H2S可通过半胱氨酸S-硫醇清除自由基并抑制氧化应激,发挥其细胞保护作用,从而抑制动脉粥样硬化[9,10]㊂H2S还能够通过上调血浆中一氧化氮的水平来抑制小鼠动脉粥样硬化以及血管平滑肌细胞(vascular smooth muscle cells,VSMCs)的增殖和迁移㊂高脂饮食可显著降低动脉粥样硬化大鼠模型中血浆H2S和心钠素(atrial natriuretic peptide,ANP)水平,升高肾上腺髓质素(adreno-medullin,ADM)水平,而在采用NaHS治疗8周后,可逆转动脉粥样硬化大鼠模型中的上述变化[11]㊂H2S诱导谷胱甘肽过氧化物酶1的S-硫化反应,并通过促进谷胱甘肽合成进一步降低脂质过氧化作用和增强主动脉抗氧化防御能力[12]㊂在ApoE(-/-)鼠实验中,NaHS或GYY4137通过直接S-硫化作用减少动脉粥样硬化斑块面积,减轻巨噬细胞浸润和主动脉炎症,降低血浆脂质水平[13]㊂在振荡剪应力诱导的动脉粥样硬化模型中,CSE表达下调,而在应用NaHS后可通过激活内皮型eNOS,降低细胞间ICAM-1的表达,从而抑制振荡剪应力诱导的动脉粥样硬化㊂雌激素通过上调CSE的活性增加肝脏和血管中H2S的产生,从而抑制雌性小鼠的动脉粥样硬化[14]㊂㊀㊀VSMCs在动脉粥样硬化和侵入性干预后再狭窄等疾病中起着重要作用㊂S-双氯芬酸是一种新的含有H2S的分子,可抑制VSMCs增殖,故其可能在血管损伤后再狭窄中起保护作用㊂有研究证明,在家兔中诱导动脉粥样硬化病变,并以类似于球囊血管成形术的方式对家兔进行治疗后再用NaHS进行处理,结果显示NaHS可显著抑制新生内膜中VSMCs的增殖,而在加入DL-脯氨酰甘氨酸后, VSMCs增殖明显㊂因此,H2S可减轻球囊血管成形术后内膜增生,抑制再狭窄的发生[15]㊂2㊀心脏肥大和心力衰竭㊀㊀心脏重塑是心脏大小㊁形状㊁结构和功能的渐进性病理变化,其特征在于进行性心脏肥大㊁心室扩张㊁心肌细胞纤维化㊁凋亡㊁血管功能障碍以及最终心力衰竭,预防或逆转心脏重塑是治疗心力衰竭的关键㊂心脏重塑机制复杂,受包括肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)㊁自噬㊁凋亡㊁炎症㊁基质金属蛋白酶㊁转录和转录后修饰等在内的多种因素影响[16]㊂多项研究表明,H2S在心脏重塑过程中扮演重要角色㊂2.1㊀H2S对肾素-血管紧张素受体激动剂所致心脏重构的影响㊀㊀过度刺激β-肾上腺素能受体(β-adrenergic receptor,β-AR),可在心肌细胞中产生肥大效应,并能够迅速降低内源性H2S水平㊂葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase,G-6-PD)是产生还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotina-mide adenine dinucleotide phosphate,NADPH)的限速酶,H2S可使G-6-PD活性增强而抑制肾上腺素能受体过度刺激引起的心肌肥厚[17]㊂H2S能抑制异丙肾上腺素(isoprenaline,ISO)诱导的心肌重构,抑制心肌细胞凋亡㊂ZYZ-802是一种新合成的HS-NO 杂合分子,可分解成H2S和一氧化氮,通过提高血管内皮生长因子(vascular endothelial growth factor, VEGF)和环鸟苷5ᶄ-单磷酸鸟苷水平来减轻ISO诱导的心力衰竭[18]㊂H2S还通过抑制肥大细胞浸润和肾素脱颗粒来抑制局部肾素水平,从而改善ISO 诱导的心力衰竭㊂2.2㊀H2S对压力超负荷所致心脏重塑的影响㊀㊀Krüppel样因子5(Krüppel-like factor5,KLF5)在心血管系统中发挥多种功能㊂在将小鼠KLF5基因敲除后可减轻其体内血管紧张素Ⅱ诱导的炎性血管反应和心肌肥厚[19]㊂GYY4137通过特异性蛋白1的S-巯基化调节KLF5转录活性,抑制自发性高血压大鼠模型的心脏重构[20]㊂GYY4137还抑制心肌成纤维细胞α-平滑肌肌动蛋白(alpha-smooth muscle actin,α-SMA)的表达,抑制高血压大鼠的心肌纤维化[21]㊂动物和人体研究表明,当左心室肥厚时,连接蛋白43(connexin43,Cx43)表达的变化和间隙连接的破坏是心律失常发生和发展的基础㊂H2S通过降低心脏Ang-Ⅱ的活性和上调Cx43的表达,明显抑制腹主动脉缩窄引起的心肌肥厚和纤维化㊂CSE基因敲除小鼠经横主动脉缩窄手术后心肌肥厚明显加重,而CSE基因高表达的小鼠心肌肥厚则明显减轻㊂此外,H2S还通过扩张血管和影响细胞外胶原代谢而改善慢性心力衰竭大鼠的心功能㊂H2S可诱导基质金属蛋白-2(matrix metallopro-teinases-2,MMP-2),从而增强VEGF的合成和血管生成,降低抗血管生成因子水平,并减轻压力超负荷小鼠心内纤维化和心脏重塑[22]㊂2.3㊀H2S对缺血性损伤所致心脏重塑的影响㊀㊀H2S通过抑制氧化应激㊁增加线粒体生物合成和减少细胞凋亡而改善缺血性心力衰竭[23],对心肌梗死后左室肥厚有良好的抑制作用㊂S-炔丙基半胱氨酸(S-propargyl-cysteine,SSPRC)是一种新型的内源性H2S控释制剂,通过维持谷胱甘肽(gluta-thione GSH)和超氧化物歧化酶(superoxide dismutase,SOD)等抗氧化分子的水平,降低心力衰竭大鼠左冠状动脉阻塞风险[24]㊂2.4㊀H2S对其他类型心脏重构的影响㊀㊀在糖尿病性心肌病小鼠体内,H2S水平低于正常水平㊂H2S能够改善小鼠心肌的能量代谢,还可通过减少炎症㊁氧化应激和细胞凋亡来缓解病糖尿病性心肌病的发展㊂高同型半胱氨酸血症(hyper-homocysteinemia,HHcy)中同型半胱氨酸水平的升高是心脏病理重构的诱导因素㊂HHcy通过促进MEF2C-HDAC1复合物的形成,使肌细胞增强因子2c(myocyte enhancer factor2c,MEF2C)失活,抑制心肌细胞miR-133a而引起心肌肥厚㊂H2S通过激活心肌细胞MEF2C和诱导miR-133a抑制心肌肥厚[25]㊂在被动吸烟建立的大鼠左室重构模型中可知,H2S能够通过磷脂酰肌醇3激酶/蛋白激酶B (phosphatidylinositol3kinase/protein kinase B, PI3K/AKT)依赖的核因子E2相关因子(nuclear factor E2related factors,Nrf2)信号激活而产生抗氧化作用,从而降低心室重构[26]㊂NaHS通过K-通道和PI3K/AKT信号通路刺激大鼠心房钠尿肽的分泌,从而降低心房压力,减轻心力衰竭症状㊂3㊀缺血/再灌注损伤㊀㊀缺血性心脏病主要是由冠状动脉的动脉粥样硬化病变引起的心脏的供血减少,其中以心肌梗死最为严重,且死亡率较高㊂再灌注对改善缺血是必要的,但也会造成不可逆的心肌损伤㊂NaHS通过降低促炎细胞因子和诱导型eNOS㊁上调Akt/eNOS的表达来防止大鼠缺血/再灌注心脏损害[27]㊂NaHS 通过热休克蛋白72的上调㊁磷酸化Akt和雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)的增加㊁线粒体通透性转换(mitochondria permeability transition,MPT)孔开口的抑制㊁心肌线粒体膜电位的增加㊁以及激活蛋白激酶C(protein kinase C, PKC)调节细胞内Ca2+超载来减少缺血/再灌注诱导的大鼠心脏梗死的面积㊂H2S通过增强糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)磷酸化和提高β-catenin浓度抑制急性心肌梗死造成的细胞死亡[28]㊂GYY4137可通过增强PI3K/Akt信号,降低大鼠心肌梗死面积的大小,抑制氧化应激和炎性因子的释放,减轻细胞凋亡㊂线粒体特异性H2S 供体AP39通过抑制线粒体通透性转换孔(mito-chondrial permeability transition pore,MPTP)开启和线粒体活性氧(reactive oxygen species,ROS)产生,显著降低了大鼠心肌缺血/再灌注损伤引起的梗死面积[29]㊂4㊀总结及展望㊀㊀总之,H2S对动脉粥样硬化㊁心脏肥大㊁心力衰竭和心肌缺血具有重要的保护作用,其机制包括抑制氧化应激反应㊁恢复线粒体功能㊁调节自噬㊁抗凋亡以及增加血管生成等㊂然而,这些保护作用的证据主要来自动物和细胞模型,尚缺乏强有力的临床证据㊂H2S在全身自由循环,可在不同细胞间穿梭,并作用于各种细胞靶点,其作用并不局限于心血管,因此使用H2S供体需要考虑其对整体生理和病理的影响,以避免H2S在某些特殊情况下引起的不良反应㊂随着研究的不断深入,越来越多的富含H2S 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