Branched-chain amino acids in liver diseases

Branched chain amino acids(BCAAs)have been shown to affect gene expression,protein metabolism,apoptosis and regeneration of hepatocytes,and insulin resistance.They have also been shown to inhibit the proliferation of liver cancer cells in vitro,and are essential for lymphocyte proliferation and dendritic cell maturation.In patients with advanced chronic liver disease,BCAA concentrations are low,whereas the concentrations of aromatic amino acids such as phenylalanine and tyrosine are high,conditions that may be closely associated with hepatic encephalopathy and the prognosis of these patients.Based on these basic observations,patients with advanced chronic liver disease have been treated clinically with BCAA-rich medicines,with positive effects.

Impairment of innate immune responses in cirrhotic patients and treatment by branched-chain amino acids

It has been reported that host defense responses, such as phagocytic function of neutrophils and natural killer (NK) cell activity of lymphocytes, are impaired in cirrhotic patients. This review will concentrate on the impairment of innate immune responses in decompensated cirrhotic patients and the effect of the treatment by branched-chain amino acids (BCAA) on innate immune responses. We already reported that phagocytic function of neutrophils was significantly improved by 3-mo BCAA supplementation. In addition, the changes of NK activity were also significant at 3 mo of supplementation compared with before supplementation. Also, Fisher’s ratios were reported to be significantly increased at 3 mo of BCAA supplementation compared with those before oral supplementation. Therefore, administration of BCAA could reduce the risk of bacterial and viral infection in patients with decompensated cirrhosis by restoring impaired innate immune responses of the host. In addition, it was also revealed that BCAA oral supplementation could reduce the risk of development of hepatocellular carcinoma in cirrhotic patients. The mechanisms of the effects will also be discussed in this review article.

Synergistic renoprotective effect of a compiled branched-chain amino acids and Cymbopogon schoenanthus extract against experimentally induced oxido-nitrosative renal insult

Objective: To better investigate the protective role of branched-chain amino acids(BCAAs)and Cymbopogon schoenanthus(CS) extract against the potassium dichromate(PDC)-induced oxido-nitrosative nephrotoxic insult in the experimental rat model. Methods: Thirty male rats were randomly divided into five equal groups: The 1 st group served as control; the 2^(nd)was injected with a single dose of PDC(15 mg/kg b.w i.p.);the 3^(rd), 4^(th), and 5^(th) groups were respectively treated with BCAAs, CS, and their combination for 15 d prior to induction of renal insult via PDC single dose(15 mg/kg b.w s.c.). The experimental period was terminated in all groups 2 d after induction of renal insult. The harvested kdney samples were divided for biochemical assays and histological examination. Results: The PDC-induced nephrotoxic effect caused a depletion of renal oxidative scavengers glutathione, superoxide dismutase with consequent lipo-oxidative cellular membrane deterioration manifested by a rise in malonaldehyde, oxidized glutathione, myeloperoxidase and the concomitant increase in inflammatory response elements tumor necrosis factor α, nitric oxide, and interleukin 1 β.Moreover, the comet assay and increased 8-hydroxy-2-deoxyguanosine proved an accelerated apoptotic DNA fragmentation. These local renal changes were met with global altered blood biochemistry. The BCAAs and CS or their compiled administration showed an ameliorative effect against PDC-induced nephrotoxic in a synergistic pattern. Conclusions: Both BCAAs and CS or their combined administration afford potential competitors against renal insult induced by polyvalent anion pollutants in experimentally studied animals model. As a route for novel drug discovery, further investigation should be attempted to optimize their augmenting reno-protecting potential.

Effect of branched-chain amino acids in patients receiving intervention for hepatocellular carcinoma

AIM: To investigate the usefulness of branched-chain amino acids (BCAA) before transarterial chemoembolization (TACE) or radiofrequency ablation (RFA).

Herbicide-Resistant Mutations in Acetolactate Synthase Can Reduce Feedback Inhibition and Lead to Accumulation of Branched-Chain Amino Acids

The branched-chain amino acids (BCAAs) valine, leucine and isoleucine are essential amino acids that are critical for animal growth and development. Animals need to obtain BCAAs from their diet because they cannot synthesize them. Plants are the ultimate source of these amino acids. Acetolactate synthase (ALS) is the first common enzyme in the biosynthesis of BCAAs. The metabolic control of BCAA biosynthesis involves allosteric regulation of ALS by the end-products of the pathway, i.e., valine, leucine and isoleucine. ALS holoenzyme seems to consist of two large catalytic subunits and two small regulatory subunits. In a previous study, using homologous recombination dependent gene targeting we created rice plants in which W548Land S627I mutations were induced into the endogenous gene encoding the ALS catalytic subunit. These two amino acid substitutions conferred hypertolerance to the ALS-inhibiting herbicide bispyripac-sodium. In this study, we revealed that feedback regulation by valine and leucine was reduced by these two amino acid substitutions. Furthermore, in leaves and seeds of ALS mutants with W548Land/or S627I substitution, a 2- to 3-fold increase in BCAAs was detected. Our results suggest that the ALS catalytic subunit is also involved in feedback regulation of ALS, and that judicious modification of the regulatory and catalytic subunits of ALS-coding genes by gene targeting can lead to the efficient accumulation of BCAA in plants.

OPTICALLY ACTIVE AMINO ACIDS WITH HIGHLY BRANCHED SIDE CHAIN (I) SYNTHESIS OF D- AND L- 2-AMINO-5,5-DIMETHYLHEXANOIC ACID AND 2-AMINO-6,6-DIMETHYLHEPTANOIC ACID

The title compounds were prepared by the enzymatic resolution of the corresponding N-acetylated DL-amino acids methyl esters, which were obtained from t-butyl chloride via an 8-step synthesis.

Functional microbiomics reveals branched-chain amino acids depletion for alleviation of insulin resistance by berberine

Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.

Diagnostic value of methylated branched chain amino acid transaminase 1/IKAROS family zinc finger 1 for colorectal cancer

BACKGROUND The diagnostic value of combined methylated branched chain amino acid transaminase 1(BCAT1)/IKAROS family zinc finger 1(IKZF1)in plasma for colorectal cancer(CRC)has been explored since 2015.Recently,several related studies have published their results and showed its diagnostic efficacy.AIM To analyze the diagnostic value of methylated BCAT1/IKZF1 in plasma for screening and postoperative follow-up of CRC.METHODS The candidate studies were identified by searching the PubMed,Embase,Cochrane Library,CNKI,and Wanfang databases from May 31,2003 to June 1,2023.Sensitivity,specificity,and diagnostic accuracy were calculated by merging ratios or means.RESULTS Twelve eligible studies were included in the analysis,involving 6561 participants.The sensitivity of methylated BCAT1/IKZF1 in plasma for CRC diagnosis was 60%[95%confidence interval(CI)53-67]and specificity was 92%(95%CI:90-94).The positive and negative likelihood ratios were 8.0(95%CI:5.8-11.0)and 0.43(95%CI:0.36-0.52),respectively.Diagnostic odds ratio was 19(95%CI:11-30)and area under the curve was 0.88(95%CI:0.85-0.91).The sensitivity and specificity for CRC screening were 64%(95%CI:59-69)and 92%(95%CI:91-93),respectively.The sensitivity and specificity for recurrence detection during follow-up were 54%CONCLUSION The detection of methylated BCAT1/IKZF1 in plasma,as a non-invasive detection method of circulating tumor DNA,has potential CRC diagnosis,but the clinical application prospect needs to be further explored.

Plasma Levels of Amino Acids in Japanese Men and Their Changes after the Administration of Glucose and Sucrose

Background: It is not known whether plasma amino acids levels are different between young and old men in Japan. No research has been reported about changes in plasma levels of amino acids after the administration of glucose or sucrose to young and aged men. Objective: We want to know whether there are age differences in plasma levels of amino acids and if the administration of glucose or sucrose influences their levels. Results: Old people had lower plasma levels of most of amino acids, especially essential and branched-chain amino acids than young men. Plasma levels of amino acids were measured after the administration of 50 grams of glucose or sucrose to young (18 - 22 years old) and aged (≥50 years old) male adults. Plasma levels of total amino acids decreased after the administration of glucose. Decrease in the total amino acid levels was significant in aged men after the administration of sucrose. A significant decrease in plasma levels of total non-essential amino acids was observed at 120 min after the administration of glucose but not sucrose in both aged and young men. Both glucose and sucrose administrations resulted in a significant decrease in the plasma levels of the total essential amino acid levels and branched amino acids in young and aged men. Conclusion: These results suggest that there are age differences in plasma levels of amino acids. Upon the administration of glucose or sucrose amino acids, particularly essential amino acids, decreased in plasma. These amino acids may be transported from the blood soon after the administration of sugar (glucose or sucrose) to the tissues, such as muscles, possibly due to an increase in the insulin levels.

Supplementation of branched-chain amino acids in protein-restricted diets modulates the expression levels of amino acid transporters and energy metabolism associated regulators in the adipose tissue of growing pigs

This experiment was conducted to investigate the effects of branched-chain amino acids(BCAA)supplemented in protein-restricted diets on the growth performance and the expression profile of amino acid transporters and energy metabolism related regulators in the white adipose tissue(WAT)of different regional depots including dorsal subcutaneous adipose(DSA) and abdominal subcutaneous adipose(ASA), A total of 24 crossbred barrows(7.40 ± 0.70 kg) were randomly divided into 4 groups and were fed the following isocaloric diets for 33 days: 1) a recommended adequate protein diet(AP, 20% CP, as a positive control); 2) a low protein diet(LP, 17% CP); 3) the LP diet supplemented with BCAA(LP + B, 17% CP) to reach the same level of the AP diet group; 4) the LP diet supplemented with 2 times the amount of BCAA(LP + 2B, 17% CP). The daily gain and daily feed intake of the LP diet group were the lowest among all the treatments(P < 0.01). The feed conversion was improved markedly in the group of LP + B compared with the LP diet group(P < 0.05). No significant difference was noted for the serum biochemical parameter concentrations of glucose, triglyceride, nonesterified fatty acid and insulin among the groups(P > 0.05). Moreover, BCAA supplementation down-regulated the expression levels of amino acid transporters including L-type amino acid transporter 1 and sodium-coupled neutral amino acid transporter 2 in DSA, but up-regulated the expression level of Ltype amino acid transporter 4 in ASA(P < 0.05), Meanwhile, the energy sensor AMP-activated protein kinase α was activated in the DSA of pigs fed LP diet and in the ASA of the pigs fed AP or LP + 2B diets(P < 0.05). The mRNA expression profile of the selected mitochondrial component and mitochondrial biogenesis associated regulators in DSA and ASA also responded differently to dietary BCAA supplementation. These results suggested that the growth performance of growing pigs fed protein restricted diets supplemented with BCAA could catch up to that of the pigs fed AP diets. The results also partly demonstrated that the regulation mechanisms of BCAA are different in the adipose tissues of different depots.

Branched chain amino acids and metabolic regulation

Amino acids are fundamental nutrients required for protein synthesis. The branched chain amino acids (BCAAs) leucine, isoleucine, and valine are the most abundant of the essential amino acids. BCAAs have recently been recognized as having functions in processes other than simple nutrition. For example, metabolic diseases are characterized by higher levels of circulating BCAAs. Moreover, supplementation with or deficiency in BCAAs is closely related to the regulation of metabolic homeostasis. Indeed, leucine deprivation induces increased lipolysis and thermogenesis, which result in fat loss, as well as suppressed lipogenesis and enhanced insulin sensitivity in the liver. Accumulating evidence has indicated that several amino acid sensors, including GCN2, ATF4, mTOR, and AMPK, play pivotal roles in the regulation of lipid metabolism, glucose metabolism, and energy homeostasis. Furthermore, the hypothalamus is critical for sensing amino acid levels and mediates the metabolic adaptation of the body upon limitation of essential amino acids (EAAs) through regulating expression of the S6K1, MC4R, and CRH. In this review, we highlight recent studies investigating the cellular mechanisms linking amino acids, amino acid sensors, metabolic regulation, and metabolic diseases. Amino acid sensing and metabolic regulation have become research hotspots in the metabolic field.

同位素稀释-气相色谱-质谱法测定血清中三种支链氨基酸

建立了一种同位素稀释-气相色谱-质谱法测定血清中三种支链氨基酸含量的检测方法。采用该方法对血清中缬氨酸、亮氨酸、异亮氨酸进行定量分析,结果的相对标准偏差为0.19%~0.46%,平均回收率为99.9%~102.2%。方法重复性好、准确度高、结果准确可靠,可满足临床血清样品中三种氨基酸含量的准确检测。

BCAT1抑制剂BAY-069的合成工艺优化

BAY-069是目前体外活性最强的支链氨基酸转氨酶1(BCAT1)抑制剂,但其报道的合成路线存在原料成本较高、总收率极低和中间体结构表征不充分等缺点。本研究基于已有合成路线,重点对其合成工艺中的Ullmann偶联反应进行了系统优化。以1-硝基萘(1)为起始原料,经过7步反应和手性色谱柱手性拆分合成目标化合物BAY-069。所有中间体和目标化合物均经1 H NMR,13 C NMR和HR-MS表征。以Ullmann偶联反应为主要优化步骤的路线,其优化后的总收率为11.0%(3b→(±)-BAY-069),是原总收率1.6%(3a→(±)-BAY-069)的6.9倍。

Enhancement of precursor amino acid supplies for improving bacitracin production by activation of branched chain amino acid transporter BrnQ and deletion of its regulator gene lrp in Bacillus licheniformis

Bacitracin,a new type of cyclic peptide antibiotic,is widely used as the feed additive in feed industry.Branched chain amino acids(BCAAs)are the key precursors for bacitracin synthesis.In this research,soybean meal was served as the raw material to supply precursor amino acids for bacitracin synthesis,and enhanced production of bacitracin was attempted by engineering BCAA transporter BrnQ and its regulator Lrp in the bacitracin industrial production strain Bacillus licheniformis DW2.Firstly,our results confirmed that Lrp negatively affected bacitracin synthesis in DW2,and deletion of lrp improved intracellular BCAA accumulations,as well as the expression level of BCAA transporter BrnQ,which further led to a 14.71%increase of bacitracin yield,compared with that of DW2.On the contrary,overexpression of Lrp decreased bacitracin yield by 12.28%.Secondly,it was suggested that BrnQ acted as a BCAA importer in DW2,and overexpression of BrnQ enhanced the intracellular BCAA accumulations and 10.43%of bacitracin yield.While,the bacitracin yield decreased by 18.27%in the brnQ deletion strain DW2△brnQ.Finally,BrnQ was further overexpressed in lrp deletion strain DW2△lrp,and bacitracin yield produced by the final strain DW2△lrp::BrnQ was 965.34 U/mL,increased by 22.42%compared with that of DW2(788.48 U/mL).Collectively,this research confirmed that Lrp affected bacitracin synthesis via regulating the expression of BCAA transporter BrnQ and BCAA distributions,and provided a promising strain for industrial production of bacitracin.

Ala-Gln和BCAA对创伤大鼠营养支持作用的实验研究

目的 观察富含丙氨酰谷氨酰胺 (Ala Gln)和支链氨基酸 (BCAA)的氨基酸注射液 ,对创伤大鼠的营养支持效果。 方法 Wistar大鼠 40只 ,行创伤和中心静脉插管后 ,随机分为无氮组、正常饲料组、对照组和实验组。测定饲料摄入量、体重、氮平衡、血浆蛋白和氨基酸含量、外周血淋巴细胞转化率、伤口埋植海绵中羟脯氨酸含量、皮肤抗张力强度和小肠粘膜蛋白质及核酸。 结果 无氮组动物营养状况欠佳 ,各项指标均较差。实验组动物的血浆谷氨酰胺 (Gln)、BCAA含量、外周血淋巴细胞转化率、伤口皮肤抗张力强度和羟脯氨酸含量均显著高于对照组和正常饲料组 (P <0 .0 5 )实验组和正常饲料组动物第 8天氮平衡 ,小肠粘膜核酸和蛋白质明显高于对照组 (P <0 .0 5 )。 结论 Gln和BCAA有助于改善创伤后机体的营养及代谢状况 ,增强免疫功能 ,促进小肠粘膜细胞增殖。

复方氨基酸-20AA治疗肝硬化并发肝性脑病临床研究

目的观察第四代高支链复方氨基酸-20AA注射液治疗肝硬化并发肝性脑病的疗效和安全性。方法49例肝硬化肝性脑病患者随机分成对照组23例、治疗组26例,两组均给予去除诱因、纠正电解质紊乱和酸碱失衡、乳果糖及保肝治疗。治疗组在对照组用药基础上加用复方氨基酸-20AA注射液(丰诺安)500mL.L-1,每日1次,共用10d。监测治疗前后神志、Karnofsky评分、血氨、血清白蛋白、丙氨酸转氨酶及总胆红素的变化。结果复方氨基酸-20AA注射液显著改善患者神志、Karnofsky评分、血氨、ALT和TBIL,但血清Alb改善两组间无统计学意义。两组患者均未发现严重不良反应。结论第四代高支链复方氨基酸-20AA注射液治疗肝硬化并发肝性脑病安全、有效。

BCAA对大鼠LDH、TNF_α、Ca^(2+)-ATPase的影响初探

目的 :初步探讨BCAA对大鼠LDH、Ca2 + ATPase、TNFα 的影响。方法 :Wistar鼠 ,随机分为正常对照组、BCAA实验组。正常对照组摄食普通酪蛋白饲料 ,BCAA实验组饲料添加BCAA ,5周后处死动物取标本待测。结果 :BCAA显著增加血中TNFα 水平 ,明显增加骨骼肌LDH活力 ,显著增强心肌和骨骼肌中Ca2 + ATPase活性 ,但不影响血乳酸、肌中LDH活力和心肌及骨骼肌中糖原含量。结论 :BCAA具有调节LDH、Ca2 + ATPase活力 ,促进TNFα

不同针灸疗法对高强度军训士兵血清BACC和F-Trp的影响

目的观察不同针灸疗法对高强度军训士兵血清支链氨基酸(BACC)和色氨酸(F-Trp)的影响,探讨针灸抗疲劳的可能机制。方法将90例健康士兵随机分为A组、B组和C组,每组30例。A组采用电针足三里治疗,B组采用艾灸足三里治疗,C组不进行任何治疗。治疗2星期后,3组进行1次高强度5 km跑步训练。分别观察3组治疗前后及治疗后5 d血清BACC和F-Trp含量变化。结果 3组受试士兵治疗后血清BACC及F-Trp含量与同组治疗前比较,差异均具有统计学意义(P<0.05)。A组和B组治疗后血清BACC含量与C组比较,差异均具有统计学意义(P<0.05)。A组和B组治疗后及治疗后5 d血清F-Trp含量与C组比较,差异均具有统计学意义(P<0.05)。结论针灸疗法能有效提高军训士兵机体的抗疲劳能力,减轻大强度运动引起的肌肉损伤。

支链氨基酸增强小鼠的游泳能力对其血氨和5-羟色胺变化的研究

目的探讨支链氨基酸(Branched-chain amino acids,BCAAs)对训练小鼠抗疲劳运动能力的影响。方法50只小鼠随机分为实验组(B1、B2、B3、B4)和对照组(C)。实验组分别灌胃补充BCAAs0.45、1.25、3.75和10g/kg.d,对照组灌胃生理盐水。各组小鼠5周递增负荷游泳训练后进行力竭游泳并取材。观察BCAAs对小鼠脑组织5-羟色胺(5-HT)、血氨(PA)和力竭游泳时间的影响。结果实验组小鼠血氨含量升高,脑组织匀浆中5-HT含量下降,但力竭运动游泳时间均显著延长。结果血氨浓度随剂量的增加而增大,C与B1组相比血氨水平无显著性差异,但明显低于B2、B3、B4组(P<0.01);C组小鼠5-羟色胺浓度显著高于实验组(P<0.01),实验组间随着补充剂量的增大5-羟色胺浓度减小;实验组小鼠力竭游泳能力明显强于对照组(P<0.01)。实验组间,B2、B3组小鼠力竭时间明显长于B1组(分别为P<0.05,P<0.01),B4组力竭时间与B1、B2、B3组相比则下降。结论BCAAs能够对抗运动性疲劳的发生发展,增强运动能力,但具有量效关系。

神经元特异性烯醇化酶和白介素-6对脓毒症相关性脑病的诊断及支链氨基酸给药方式研究

目的:探讨血清神经元特异性烯醇化酶(NSE)及白介素-6(IL-6)对脓毒症相关性脑病(SAE)的诊断及支链氨基酸给药方式对SAE治疗的影响。方法:选取2018年1月—2019年6月佛山市第二人民医院重症医学科收治的68例脓毒症患者。根据有无脑病分为SAE组(52例)和非SAE组(脓毒症未合并脑病组,16例)。检测两组患者第1、3天血清NSE、IL-6水平。分析血清NSE、IL-6诊断SAE的界值、敏感度和特异度。将52例SAE患者随机分为两组,分别予口服及静脉滴注支链氨基酸治疗,比较两组患者7 d和14 d格拉斯哥昏迷量表评分(GCS)、血清NSE、IL-6指标、住ICU时间及28 d病死率。结果:SAE组第1、3天NSE和IL-6水平均明显高于非SAE组(P<0.05)。SAE组第3天NSE水平为16.98μg/L时,诊断SAE的敏感度为63.5%,特异度为87.5%;第3天IL-6水平为88.50 mg/L时,诊断SAE的敏感度为69.2%,特异度为62.5%;第3天NSE联合IL-6诊断SAE的ROC曲线下面积为0.875(95%CI:0.793~0.957)。支链氨基酸静脉滴注组GCS评分高于口服组,血清NSE、IL-6水平均低于口服组,差异均有统计学意义(均P<0.05)。结论:第3天血清NSE联合IL-6检测更能有效诊断SAE。静脉滴注支链氨基酸对SAE患者神经系统功能恢复效果优于口服组。