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BACKGROUND: Hyperhomocysteine (HHcy) plays an important role in promoting inflammation and cell death of tubular epithelial cells. However, the role of HHcy and Astragaloside IV (AS-IV) in sepsis associated acute kidney injury (S-AKI) remain unclear. PURPOSE: A significant aspect of this study aimed to elucidate the effect of AS-Ⅳ treatment on HHcy-exacerbated S-AKI and reveal its potential mechanism. METHODS: Male C57BL/6 J mice fed with specific diet containing 2% methionine were established as in vivo models, and AS-Ⅳ was orally administrated continuously for 3 weeks, and then LPS (10 mg·kg-1 bodyweight) was given by a single intraperitoneal injection. The renal morphological changes were evaluated by HE and PAS staining. RNA-sequencing analysis was applied to select key signaling. The NRK-52E cells exposed to Hcy or combined with LPS were used as in vitro models. The mRNA and protein expression levels of Gpr97-TPL2 signaling were examined by qRT-PCR and western blotting assays. RESULTS: In vivo, HHcy mice developed more severe renal injury and prevalent tubular inflammation after LPS injection. In vitro, the levels of NGAL, Gpr97 and TPL2 were significantly increased in NRK-52E cells induced by Hcy (1.6 mM) or in combination with LPS. Notably, the effects of Hcy on TPL2 signaling was abolished by transfecting TPL2 siRNA or treating TPL2 inhibitor, without alterations in Gpr97. However, the enhancement of Gpr97-TPL2 signaling induced by Hcy was counteracted by Gpr97 siRNA. Subsequently, our findings demonstrated that AS-Ⅳ treatment can improve renal function in HHcy-exacerbated S-AKI mice. Mechanistically, AS-Ⅳ alleviated renal tubular damage characterized by abnormal increases in KIM-1, NGAL, TPL2, Gpr97, Sema3A and TNF-α, and decreases in survivin in vivo and in vitro mainly through suppressing the activation of Gpr97-TPL2 signaling. CONCLUSION: The present study suggested that HHcy-exacerbated S-AKI was mediated mechanically by activation of Gpr97-TPL2 signaling for the first time. Furthermore, our research also illustrated that AS-Ⅳ protected against HHcy-exacerbated S-AKI by attenuating renal tubular epithelial cells damage through negatively regulating Gpr97-TPL2 signaling, proposing a natural product treatment strategy for HHcy-exacerbated S-AKI.

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Objective@#To investigate the relationship between total homocysteine (tHcy) levels and sarcopenia among the elderly, so as to provide insights into the prevention and treatment of sarcopenia.@*Methods@#The elderly aged 65 years and older who participated in the physical examination of Shibantan Township Health Center in Xindu District, Chengdu City from April to June 2021 was selected as the study subjects. The elderly with sarcopenia (diagnosed according to the diagnostic criteria of the Asian Sarcopenia Working Group in 2019) and non-sarcopenia were matched 1︰1 by gender and age (±2 years). Demographic information, skeletal muscle mass, skeletal muscle strength and tHcy were collected through questionnaire surveys, physical examination and laboratory testing. Multivariable conditional logistic regression model was used to explore the relationship between tHcy and sarcopenia.@*Results@#A total of 320 individuals, including 160 sarcopenia patients and 160 non-sarcopenia individuals, were investigated. There were 138 males (43.13%) and 182 females (56.87%), with a median age of 71.00 (interquartile range, 6.00) years. There were 57 drinkers (17.81%), 78 smokers (24.37%), 173 cases of hypertension (54.06%) and 124 cases of hyperhomocysteinemia (38.80%). Multivariable conditional logistic regression analysis showed that elevated tHcy was associated with an increased risk of sarcopenia (OR=1.107, 95%CI: 1.024-1.197), after adjusting for smoking, alcohol consumption, hypertension, waist circumference, neck circumference, body mass index, platelet count and high density lipoprotein cholesterol.@*Conclusion@#Elevated tHcy is associated with sarcopenia, and intervention should be carried out for the elderly with higher tHcy.

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The objective of this study is to investigate the relationship between altered plasma trace elements, particularly selenium (Se), with Hyper-homocysteinemia (HhCys) as a predictive factor of insulin secretion dysfunction. The study is carried out on adult Psammomys obesus, divided in 4 experimental groups: (I) Normoglycemic/Normoinsulinemic; (II) Normoglycemic/Hyperinsulinemic; (III) Hyperglycaemic/Hyperinsulinemic and (IV) Hyperglycaemic/Insulin deficiency with ketoacidosis. The data showed that a drastic depletion of Se plasma levels is positively correlated with HhCys (>15 µmol/L; p < .001), concomitantly with decreased GPx activity, GSH levels, and GSH/GSSG ratio in group IV both in plasma and liver. In contrast, SOD activity is increased (p ≤ .001) in group IV both in plasma and liver. However, plasma Cu and Mn levels increased, while plasma Zn levels decreased in group IV (p < .001). Our study confirms the increase of plasma hCys levels seemed to be a major contributing factor to antioxidant capacities and alters the availability of selenium metabolism by interference with homocysteine synthesis in the insulin secretion deficiency stage.

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Hyperhomocysteine (HHcy) is known as a risk factor for coronary artery disease (CAD). Despite the knowledge that gut microbiota related metabolism pathway shares metabolites with that of Hcy, little has been shown concerning the association between HHcy and gut microbiota. To explore their relationship in the context of CAD, 105 patients and 14 healthy controls were recruited from one single medical center located in Beijing, China. Their serum and fecal samples were collected, with multi-omics analyses performed via LC/MS/MS and 16S rRNA gene V3-V4 region sequencing, respectively. Participants from the prospective cohort were divided into CAD, CAD & HHcy and healthy controls (HC) groups based on the diagnosis and serum Hcy concentration. The results revealed significant different metabolic signatures between CAD and CAD & HHcy groups. CAD patients with HHcy suffered a heavier atherosclerotic burden compared to CAD patients, and the difference was closely associated to betaine-homocysteine S-methyltransferase (BHMT)-related metabolites and trimethylamine N-oxide (TMAO)-related metabolites. Dimethylglycine (DMG) exhibited a strong positive correlation with serum total Hcy (tHcy), and TMAO and trimethylysine (TML) were associated with heavier atherosclerotic burden. Multiple other metabolites were also identified to be related to distinct cardiovascular risk factors. Additionally, Clostridium cluster IV and Butyricimonas were enriched in CAD patients with elevated tHcy. Our study suggested that CAD patients with elevated tHcy were correlated with higher atherosclerotic burden, and the impaired Hcy metabolism and cardiovascular risk were closely associated with BHMT-related metabolites, TMAO-related metabolites and impaired gut microbiota homeostasis.

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BACKGROUND: Ischemic stroke (IS) is a serious global health burden. In order to improve our understanding of the risk factors associated with IS, we investigated the combined effect of the methylation of five genes related to the metabolism of homocysteine on developing IS. METHODS: Quantitative methylation-specific PCR was used to measure the levels of promoter methylation in hypertensive and stroke patients. The cutoff value calculated by the maximum Youden index was used to classify the levels of gene methylation as hypomethylation and hypermethylation. Logistic regression was used to explore the relationship between gene methylation and IS. RESULTS: The methylation levels of the genes encoding methylenetetrahydrofolate dehydrogenase 1 [MTHFD1], cystathionine ß-synthase [CBS], and dihydrofolate reductase [DHFR] in hypertensive patients were higher than those in stroke patients (all p < 0.01). MTHFD1 hypermethylation, CBS hypermethylation, and DHFR hypermethylation were protective factors for stroke after adjustment for confounding factors. Compared with individuals carrying none of the biomarkers, the ORs [95% CIs] for stroke of those with 1 and 2 elevated biomarkers were 4.068 [1.670-9.913] and 15.345 [6.198-37.994] after adjustment for confounding factors. The participants with a larger number of biomarkers had an increased risk of stroke (p for trend <0.001). For the combination biomarkers, the area under the curve of the receiver operating characteristic was 0.716. CONCLUSION: A significant linear relationship between the number of elevated biomarkers and the risk of stroke has been observed, suggesting that elevations of these biomarkers could be used for potentially predicting the disease.

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Objective:To study the effect of Shuangshen Xionglian （SSXL） granules on vasculopathy and phosphatidylinositol 3 kinase （PI3K）/serine threonine kinase （Akt）/nitrogen oxide synthase （eNOS） signal in hyperhomocysteinemia chronic kidney disease rats. Method:Rats were randomly divided into 5 groups： sham operation group， model group， and high， medium and low-dose （8， 4， 2 g·kg-1） SSXL groups. The model of hyperhomocysteinemia chronic kidney disease in rats was established with high methionine feed combined with 5/6 nephrectomy. After 5/6 nephrectomy， continuous intragastric administration lasted for four weeks. Arterial blood pressure was measured at the 4th and 8th weeks after operation. At the end of the 8th week after the operation， blood was collected to determine serum creatinine， urea nitrogen， homocysteine （Hcy）， methionine and blood lipid. Western blot was used to detect the expressions of PI3K/Akt/eNOS pathway-related proteins， such as p-p85， p-Akt and p-Ser177 in thoracic aorta， and serum NO and eNOS were measured. The changes of endothelium-dependent relaxation and non-endothelium-dependent relaxation were measured by the method of isolated thoracic aorta ring. Pathological htoxylin eosin （HE） staining was used to observe the changes of renal tissue and thoracic aorta. Result:At the 8th week of the experiment， compared with the sham operation group， arterial systolic blood pressure， serum urea nitrogen， creatinine， Hcy， methionine， total cholesterol and low-density lipoprotein of the model group were significantly increased. Four weeks later after administration， arterial systolic blood pressure， serum urea nitrogen， Hcy， methionine， serum total cholesterol and serum low-density lipoprotein were significantly reduced in each dose group （P<0.05， P<0.01）. The creatinine in the SSXL 8， 4 g·kg-1 group was significantly reduced （P<0.05）. The nitric oxide content of SSXL in each dose groups were increased compared with that in the model group （P<0.05， P<0.01）， and the serum eNOS activity of the SSXL in the SSXL 8 g·kg-1 group was significantly increased compared with that in the model group （P<0.05）. The endothelium dependent and non-endothelium dependent vasodilation of thoracic aortic rings in the model group were significantly damaged. The cumulative concentration of acetylcholine （1×10-5.5~1×10-4 mmo1·L-1） in the SSXL 8 g·kg-1 group was significantly improved （P<0.05， P<0.01）. The diastolic degree of the vascular ring in the SSXL 8 g·kg-1 group was significantly higher than that in the model group （P<0.05）. Western blot results showed that the expressions of p-85， p-Akt and p-Ser177 in blood vessels increased in the sham group compared with those in the model group （P<0.01）. Compared with the model group， the phosphorylation level of this pathway was increased in the SSXL groups， and the expressions of p-Akt and p-Ser177 in the SSXL 8 g·kg-1 group were significantly increased （P<0.05）. The pathological results showed that the pathological changes of thoracic aorta and renal tissue in the dosages of SSXL were significantly reduced compared with those in the model group. Conclusion:SSXL granules can improve hyperhomocysteine and dyslipidemia in rats of chronic kidney disease with hyperhomocysteine， reduce serum creatinine， urea nitrogen levels and arterial systolic blood pressure， and improve vascular morphology and diastolic function， which may be related to the regulation of the PI3K/Akt/eNOS signaling pathway.

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BACKGROUND: Hyperhomocysteinemia, a thrombotic risk factor, may have several causes. Among the genetic causes of hyperhomocysteinemia, there are polymorphisms in the enzymes methylenetetrahydrofolate reductase (C677T) and cystathionine ß-synthase (C699T, C1080T, and 844ins68). Although the frequency of hyperhomocysteinemia in our country is high, there is no evidence about the frequencies of these polymorphisms. METHODS: We analyzed 80 healthy individuals from several regions in our country. We evaluated the fasting and post-oral methionine load plasma Hcy and the genotypes in order to obtain the allele frequencies of the polymorphisms C677T of methylenetetrahydrofolate reductase and C699T, C1080T, and 844ins68 of the cystathionine ß-synthase. RESULTS: No individual had deficiency of folic acid, vitamins B12, or B6, but 80% had post-oral methionine load hyperhomocysteinemia. We found a significant increase in the Hcy plasma concentration associated with age and gender. Only the polymorphism C1080T was significantly associated with hyperhomocysteinemia. CONCLUSION: There is an association between fasting and post-oral methionine load plasma Hcy concentrations with the allelic frequencies of the polymorphisms C669T, 844ins68, and C1080T of the cystathionine ß-synthase and C667T of the methylenetetrahydrofolate reductase in healthy Mexican individuals. As compared with individuals with normal fasting or post-oral methionine load Hcy plasma levels, only C1080T was significantly associated with hyperhomocysteinemia.

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OBJECTIVE: The relationship between total plasma homocysteine (tHcy) and exercise remains controversial. This study aimed to investigate the association between regular aerobic exercise and hyperhomocysteine (hHcy) in patients with hypertension. METHODS: A total of 497 hypertensive patients from 7 communities of Nanjing were enrolled in this cross-sectional study. All participants were asked to complete standard questionnaires by themselves. Physical and laboratory examination were performed within 1 week after enrollment. The association between regular aerobic exercise and hHcy in hypertensive patients was estimated by a multiple logistic regression analysis. RESULTS: Of the 497 patients, 210 had a regular aerobic exercise habit and 274 of them were detected with hHcy. Multivariate analysis revealed that exercisers have less risk of hHcy (adjusted odds ratio [OR] 0.42, 95% confidence interval [CI] 0.26-0.66) as compared to non-exercisers controlling for the established and potential confounders. Intensity, frequency, and total energy expenditure of aerobic exercise were found to be independently associated with lower hHcy risk in hypertensive patients. Gender subgroup analyses showed that this inverse relationship between regular aerobic exercise and hHcy exists in both male and female groups (adjusted OR 0.41 95%CI 0.21-0.80, and adjusted OR 0.40 95%CI 0.20-0.80, respectively). CONCLUSIONS: Regular aerobic exercise has a negative association with hHcy in this cross-sectional study. That suggests a hypothesis that doing aerobic exercise might decrease the risk of hHcy in hypertensive patients.

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BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, which is associated with malnutrition and hyperhomocysteine. The current study aimed to analyze the relationship between malnutrition and hyperhomocysteine in AD patients, and effects of diet intervention with betaine on the disease. METHODS: The nutritional statuses of the AD patients were assessed by short form mini nutritional assessment (MNA-SF). The levels of Hcy, tau hyperphosphorylation, synaptic proteins, blood inflammatory factors were measured by enzymatic cycling assay, Western blot and ELISA. The cognitive function was measured by AD assessment scale (ADAS-cog). RESULTS: There was a significant difference in mental status between normal people and AD patients (P<.05). Overall, malnutrition was reported in a larger proportion of AD patients and high level of Hcy was closely associated with malnutrition. Betaine decreased the levels of phosphorylated tau, elevated PP2Ac activity and inhibited Aß accumulation (P<.05). The levels of IL-lß and TNF-α were significantly higher in the untreatment group while much lower in the intervention group (P<.05). After intervention of betaine treatment, the expression level of Hcy can be restored and betaine can effectively suppress inflammation as well as trigger an increase in memory-related proteins. ADAS-Cog suggested that significant improvement was found after the intervention of betaine. CONCLUSIONS: AD was associated with both malnutrition and higher levels of Hcy. Betaine could restore Hcy expression to normal level in AD patient, which might ameliorate memory deficits.

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Homocysteine, a sulfur-containing amino acid derived from the methionine metabolism, is located at the branch point of two pathways of the methionine cycle, i.e. remethylation and transsulfuration. Gene abnormalities in the enzymes catalyzing reactions in both pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is associated with increased risk for congenital disorders, including neural tube closure defects, heart defects, cleft lip/palate, Down syndrome, and multi-system abnormalities in adults. Since hyperhomocysteinemia is known to affect the extent of DNA methylation, it is likely that abnormal DNA methylation during embryogenesis, may be a pathogenic factor for these congenital disorders. In this review we highlight the importance of homocysteinemia by describing the genes encoding for enzymes of homocysteine metabolism relevant to the clinical practice, especially cystathionine-ß-synthase and methylenetetrahydrofolate reductase mutations, and the impairment of related metabolites levels. Moreover, a possible correlation between hyperhomocysteine and congenital disorders through the involvement of abnormal DNA methylation during embryogenesis is discussed. Finally, the relevance of present and future diagnostic tools such as tandem mass spectrometry and next generation sequencing in newborn screening is highlighted.

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Objective To observe the efficacy of folic acid combined with mecobalamine for the treatment of vascular mild cogni-tive impairment (VMCI) in patients with cerebral small vessel disease (SVD) and hyperhomocysteinemia(Hcy) .Methods A total of 84 VMCI patients with cerebral small vessel disease and Hcy were randomly divided into combination group and control group . Two groups received conventional therapy for 6 months .Besides ,the combination group received folic acid combined with mecobal-amin .The level of plasma Hcy and ADAS-cog score were observed before and after 3 months and 6 months treatment .Results Af-ter treatment ,plasma Hcy significantly lower in the combination group (P0 .05) .However ,after 6 months treatment ,the ADAS-cog scores decreased obviously than that in the before treatment group (P0 .05) .After 3 months treatment ,there was no significant difference on ADAS-cog score between combination group and control group (P>0 .05) ,however ,there had significant difference between the two groups after 6 months treatment(P<0 .05) .Conclusion The level of plasma Hcy could be reduced by adding folic acid and mecobalamin .Treatment of hyperhomocysteinemia may delay the progression of vascular cognitive impairment w hich caused by cerebral small vessel disease .

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INTRODUCTION: Treatment with B-vitamins and betaine reduces the high risk of thrombosis in patients with homocystinuria, a metabolic syndrome that is characterized by severe hyperhomocysteinemia (HHcy). In contrast, there is no clear demonstration that B-vitamins reduce the risk of thrombosis in patients with mild HHcy: for this reason, many question the clinical utility of measuring total Hcy (tHcy) in patients with thrombosis. However, thrombosis may be the first clinical manifestation of homocystinuria in patients reaching adulthood without signs and symptoms of the syndrome. AIM: 1) to measure the prevalence of severe, previously undiagnosed, HHcy among patients with thrombosis 2) to profile these patients on the basis of their characteristics. METHODS: Six Italian Thrombosis Centers completed a first questionnaire, reporting tHcy levels in patients with thrombosis who underwent thrombophilia screening, and a second questionnaire, reporting the characteristics of patients with severe HHcy (tHcy>100µmol/L). RESULTS: Of 19,678 cross-sectionally collected patients with thrombosis who underwent thrombophilia screening in the last 12.5years (median value, range 6-17), 38 had severe HHcy (0.2%). Their median age at diagnosis was 47years (range 19-83) and the median level of tHcy was 130µmol/L (range 101-262). Venous thromboembolism (71%) was more frequent than arterial thromboembolism (26%); recurrent thrombosis occurred in 42% of cases. CONCLUSIONS: Measurement of tHcy in adult patients with thrombosis may reveal the presence of severe HHcy. Since treatment of patients with severe HHcy decreases the risk of thrombosis, measurement of tHcy in patients with thrombosis may prove clinically useful.

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