Effects of four-week lasting aerobic treadmill training on hepatic injury biomarkers, oxidative stress parameters, metabolic enzymes activities and histological characteristics in liver tissue of hyperhomocysteinemic rats.

Disruptions in homocysteine (Hcy) metabolism may increase the liver's susceptibility to developing conditions such as alcoholic liver disease, viral hepatitis, hepatocellular carcinoma (HCC), and cirrhosis. The aim of this study was to examine effects of aerobic treadmill training on hepatic injury biomarkers in sera, oxidative stress parameters, the activity of metabolic enzymes, and histological characteristics in the liver tissue of rats with experimentally induced hyperhomocysteinemia. Male Wistar albino rats were divided into four groups (N = 10, per group): C-saline 0.2 mL/day sc. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; H-homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; CPA-saline 0.2 mL/day sc. 2×/day for 14 days + aerobic treadmill training for 28 days; and HPA-homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + aerobic treadmill training for 28 days. The serum albumin concentration was decreased in both physically active (PA) groups compared to sedentary groups. Concentration of malondialdehyde in liver tissue homogenates was lower in both PA groups compared to the H group. The total lactate dehydrogenase and malate dehydrogenase activities were significantly elevated in the HPA group compared to the C and H groups. Activities of aminotransferases in sera samples, and activities of catalase and superoxide dismutase in liver tissue did not significantly differ between groups. No significant histological changes were found in liver tissue in groups. This study demonstrated that aerobic treadmill training can reduce lipid peroxidation in liver tissue under hyperhomocysteinemic conditions, providing a protective effect. However, hyperhomocysteinemia can alter energy metabolism during aerobic exercise, shifting it toward anaerobic pathways and leading to elevated lactate dehydrogenase activity in the liver. Given that conditions like hyperhomocysteinemia are associated with an increased risk of cardiovascular diseases and liver damage, understanding how exercise influences these dynamics could guide therapeutic approaches.

Homocysteine Blood Levels and Mandatory Folic Acid Fortification in Serbia.

INTRODUCTION/OBJECTIVE: The current study aims to investigate the blood Hcy levels in patients with CAD and hypertension in Serbia, a country with a high incidence and mortality of both diseases. METHODS: The level of Hcy in the Serbian population was assessed in 123 patients with chronic coronary artery disease (CAD) and hypertension. There were 53 patients with chronic CAD and 70 patients with hypertension (HTA), but without CAD. RESULTS: The Hcy levels were high in both groups of patients (the mean Hcy level of 16.0 ± 7.0 µmol/L) without a statistical difference between the patients in the CAD (14.9 ± 7.3 µmol/L) and hypertension (16.7 ± 6.7 µmol/L) groups. Hypercholesterolemia was found in 81% of the patients with CAD and 92.0% of the patients with HTA, as a common concern across both clinical conditions. It was also found that not a single conventional risk factor (diabetes, hypertension, the smoking status, the family history of CAD, and hyperlipidemia) may individually influence Hcy levels. By contrast, the low levels of vitamin B12 may be related to the high levels of Hcy. CONCLUSION: Given the fact that it is known that various factors interact and influence Hcy levels and associated cardiovascular risks, specific dietary habits, lifestyle and the other Serbia-specific possible factors were done.

Comparative study of oxidative stress in cancer patients occupationally exposed to the mixture of pesticides.

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Reviews indicated a positive relationship between exposure to pesticides and the development of cancers. In the present study, we have estimated the level of oxidative stress markers in serum samples of pesticide exposure and unexposed cancer patients as compared to normal control. We have found a significant decrease in peroxygenase (PON) and arylesterase (ARE) activity and substantial increases in homocysteine levels in both cancer groups. The level of heme biosynthesis rate-limiting enzymes delta-aminolevulinic acid dehydratase (δ-ALA-D) also significantly decreased compared to control. The statistical comparison between the cancer groups does not show significant changes. We concluded the involvement of oxidative stress in carcinogenesis in both cancer group patients. However, more study is needed to put homocysteine as a novel marker for a variety of diseases on a single platform.

Genome-wide Association Study Identifies Genetic Polymorphisms for Folate-related Biomarkers in Chinese Preconception Women.

BACKGROUND: SNP allele frequencies, dietary habits, folate status and their associations vary across ethnic populations. Little is known about the SNPs accounting for variations of folate-related biomarkers for Chinese preparing-for-pregnant females. OBJECTIVE: We aimed to identify SNPs contributing to RBC and serum folate, vitamin B-12, and homocysteine levels in Chinese female preconception population. METHODS: A GWAS was conducted on 1000 randomly selected preconception Chinese women from SPCC. SNPs were genotyped using Illumina chips, and associations with biomarkers were assessed using simple linear regression models under the assumption of an additive genetic model. Genome-wide significance was considered at P < 10-7. RESULTS: The MTHFR rs1801133 was the major genetic coding variant contributing to RBC folate, serum folate and homocysteine concentrations (P=2.28×10-16; P=8.85×10-8, and P=2.46×10-13). It is associated with increased RBC folate (ß=0.154 per additional risk allele after log transform), decreased serum folate (ß=-0.951 per additional risk allele) and increased serum homocysteine concentrations (ß=1.153 per additional risk allele). The predominant SNP associated with serum folate was rs147162222 in NTRK2 (P=2.55×10-8) while the one associated with homocysteine was rs77025184 located between PDE7B and LINC00271 (P=4.91×10-17). For vitamin B-12, FUT2 rs1047781 was the dominant genetic variant (P=1.59×10-10). The numbers of signals with P value <10-7 for RBC folate, serum folate, vitamin B-12 and homocysteine were 12, 18, 8 and 614 respectively. CONCLUSIONS: This study represents the first GWAS focusing on folate-related biomarkers in a Chinese preparing-for-pregnant female population. The contributions of dominent SNPs to each biomarker were partly different from other populations. The study detected rs1801133 (C677T) in MTHFR as the predominant genetic variant contributing to RBC folate and rs1047781 (A385T) in FUT2 as the primary one explaining vitamin B-12. Notably, the intronic rs147162222 and non-coding rs77025184 were both first detected as the predominant SNPs for serum folate and homocysteine respectively.

Age-Dependent Effects of Homocysteine on Erectile Dysfunction Risk Among U.S. Males: A NHANES Analysis.

Erectile dysfunction (ED) is a common problem that seriously impacts men's quality of life and mental health. Earlier studies have indicated that homocysteine (HCY) levels might be linked to the risk of ED, although these studies are limited by small sample sizes and insufficient correction for confounding factors. This study uses data from the 2001-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the relationship between HCY levels and ED risk in U.S. adult males. The analysis involved using a weighted generalized linear model to assess main effects and restricted cubic splines (RCS) to explore nonlinear relationships. Results showed that the association between HCY and ED was not statistically significant after adjusting for covariates. However, interaction analyses between age and the HCY-ED relationship showed that as age increases, the impact of HCY on ED strengthens. Based on this, subgroup analysis by age was carried out, revealing that in people aged 50 and above, HCY levels were significantly positively correlated with ED, especially when HCY levels exceeded 9.22 µmol/L, significantly increasing the risk of ED. Sensitivity analysis further confirmed the robustness of these findings. This study indicates that controlling HCY levels, especially in middle-aged and older men, might help prevent and treat ED, providing a foundation for future preventive strategies.

Endothelial Dysfunction Does Not Occur after Acute, Elevated Homocysteine Exposure of the Lumen of the Iliac Artery of the Anaesthetised Pig.

INTRODUCTION: Elevated luminal homocysteine has been linked with cardiovascular disease; however, whether there is a direct effect of homocysteine on blood vessel endothelium is not clear. In this study, the acute effect of luminal homocysteine on iliac artery endothelial function was assessed in the anaesthetised pig. METHODS: Hyperhomocysteinaemic blood was injected into an occluded segment of the iliac in the anaesthetised pig for 20 min, and the effect on atrial diameter during the occlusion and during the reactive hyperaemia assessed. RESULTS: No significant changes in arterial diameter or pressure were observed during the incubation period at homocysteine concentrations of 10, 20, 40 and 100 µM. There was also no difference in the magnitude of the iliac diameter increase in the response to reactive hyperaemia when the incubation period was completed. CONCLUSION: There is no evidence of endothelial dysfunction in response to an acute 20-min elevation in homocysteine in an intact conduit artery.

Investigation of Hemorheological Parameters in Ischemic Stroke Patients.

BACKGROUND: The aim of this study is to determine whether there are any changes in hemorheological parameters, including whole blood viscosity (WBV), plasma viscosity, erythrocyte aggregation, and erythrocyte deformability, in acute ischemic stroke patients, and to establish their relationship with stroke etiology. The study also aims to observe the changes in these parameters, if any, over time and after treatment, and to assess the correlation between risk factors for ischemic stroke and neuroimaging findings. METHODS: This was a prospective observational study including 70 patients diagnosed with acute ischemic stroke within the first 3 days of the onset of symptoms and 96 healthy controls. Stroke patients were categorized based on TOAST criteria, and hemorheological parameters were measured at admission and on the fifth day post-treatment. Erythrocyte aggregation and deformability were measured using a laser ektacytometer, and viscosity assessment was conducted with a rotational viscometer. RESULTS: Stroke patients exhibited significant differences from the control group in aggregation amplitude, aggregation index, and aggregation half-time (p = 0.001, p = 0.013, p = 0.009, respectively) and showed elevated maximum value of elongation index (p = 0.000). No significant differences in WBV and plasma viscosity were observed between the groups. Post-treatment, the small vessel occlusion subgroup demonstrated a notable reduction in WBV. Additionally, homocysteine levels showed a positive correlation with scattered white matter lesions in basal ganglia and infratentorial regions (p = 0.002, p = 0.039, respectively). CONCLUSIONS: Increased predisposition to erythrocyte aggregation may contribute to the occurrence of acute ischemic stroke. Moreover, gaining the ability of erythrocytes to deform and increase blood flow may serve as a compensatory mechanism in the chronic vascular disease process. The risk factors for ischemic stroke may exhibit connections to specific areas within the brain.

Homocysteine decreases VEGF, EGF, and TrkB levels and increases CCL5/RANTES in the hippocampus: Neuroprotective effects of rivastigmine and ibuprofen.

Homocysteine (Hcy) is produced through methionine transmethylation. Elevated Hcy levels are termed Hyperhomocysteinemia (HHcy) and represent a risk factor for neurodegenerative conditions such as Alzheimer's disease. This study aimed to explore the impact of mild HHcy and the neuroprotective effects of ibuprofen and rivastigmine via immunohistochemical analysis of glial markers (Iba-1 and GFAP). Additionally, we assessed levels of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), chemokine ligand 5 (CCL5/RANTES), CX3C chemokine ligand 1 (CX3CL1), and the NGF/p75NTR/tropomyosin kinase B (TrkB) pathway in the hippocampus of adult rats. Mild chronic HHcy was induced chemically in Wistar rats by subcutaneous administration of Hcy (4 mg/kg body weight) twice daily for 30 days. Rivastigmine (0.5 mg/kg) and ibuprofen (40 mg/kg) were administered intraperitoneally once daily. Results revealed elevated levels of CCL5/RANTES and reduced levels of VEGF, EGF, and TrkB in the hippocampus of HHcy-exposed rats. Rivastigmine mitigated the neurotoxic effects of HHcy by increasing TrkB and VEGF levels. Conversely, ibuprofen attenuated CCL5/RANTES levels against the neurotoxicity of HHcy, significantly reducing this chemokine's levels. HHcy-induced neurochemical impairment in the hippocampus may jeopardize neurogenesis, synapse formation, axonal transport, and inflammatory balance, leading to neurodegeneration. Treatments with rivastigmine and ibuprofen alleviated some of these detrimental effects. Reversing HHcy-induced damage through these compounds could serve as a potential neuroprotective strategy against brain damage.

Mechanism of action and impact of thiol homeostasis on efficacy of an enzyme replacement therapy for classical homocystinuria.

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is characterized by elevated plasma and tissue homocysteine levels. There is no cure, but HCU is typically managed by methionine/protein restriction and vitamin B6 supplementation. Enzyme replacement therapy (ERT) based on human CBS has been developed and has shown significant efficacy correcting HCU phenotype in several mouse models by bringing plasma total homocysteine below the clinically relevant 100 µM threshold. As the reactive nature of homocysteine promotes disulfide formation and protein binding, and ERT is unable to normalize plasma total homocysteine levels, the mechanism of action of ERT in HCU remains to be further characterized. Here we showed that only a reduced homocysteine serves as a substrate for CBS and its availability restricts the homocysteine-degrading capacity of CBS. We also demonstrated that cells export homocysteine in its reduced form, which is efficiently metabolized by CBS in the culture medium. Availability of serine, a CBS co-substrate, was not a limiting factor in our cell-based model. Biological reductants, such as N-acetylcysteine, MESNA or cysteamine, increased the availability of the reduced homocysteine and thus promoted its subsequent CBS-based elimination. In a transgenic I278T mouse model of HCU, administration of biological reductants significantly increased the proportion of protein-unbound homocysteine in plasma, which improved the efficacy of the co-administered CBS-based ERT, as evidenced by significantly lower plasma total homocysteine levels. These results clarify the mechanism of action of CBS-based ERT and unveil novel pharmacological approaches to further increase its efficacy.

Nicotinamide N-methyltransferase (NNMT): A key enzyme in cancer metabolism and therapeutic target.

Emerging research has positioned Nicotinamide N-methyltransferase (NNMT) as a key player in oncology, with its heightened expression frequently observed across diverse cancers. This increased presence is tightly linked to tumor initiation, proliferation, and metastasis. The enzymatic function of NNMT is centered on the methylation of nicotinamide (NAM), utilizing S-adenosylmethionine (SAM) as the methyl donor, which results in the generation of S-adenosyl-L-homocysteine (SAH) and methyl nicotinamide (MNAM). This metabolic process reduces the availability of NAM, necessary for Nicotinamide adenine dinucleotide (NAD+) synthesis, and generates SAH, precursor to homocysteine (Hcy). These alterations are theorized to foster the resilience, expansion, and invasiveness of cancer cells. Furthermore, NNMT is implicated in enhancing cancer malignancy by affecting multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), cancer-associated fibroblasts (CAFs) and 5-Methyladenosine (5-MA), epithelial-mesenchymal transition (EMT), and epigenetic mechanisms. Upregulation of NNMT metabolism plays a key role in the formation and maintenance of the tumour microenvironment. While the use of small molecule inhibitors and RNA interference (RNAi) to target NNMT has shown therapeutic promise, the full extent of NNMT's influence on cancer is not yet fully understood, and clinical evidence is limited. This article systematically describes the relationship between the functional metabolism of NNMT enzymes and the cancer and tumour microenvironments, describing the mechanisms by which NNMT contributes to cancer initiation, proliferation, and metastasis, as well as targeted therapies. Additionally, we discuss the future opportunities and challenges of NNMT in targeted anti-cancer treatments.

Food-sourced guanidinoacetic acid and methylation cycle biomarkers in individuals aged one year and older: a population-based cross-sectional study.

PURPOSE: Several preliminary studies suggest dietary guanidinoacetic acid (GAA) might impact methyl group availability and/or methylation biomarkers, fueling ongoing debates. This study aimed to explore the relationship between dietary GAA intake and plasma indicators of the methylation cycle in individuals aged one year and older, using data from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). METHODS: Dietary information was obtained from individuals who completed a 24-hour Dietary Recall, with total daily intake of GAA calculated by aggregating all relevant food items. Relevant variables related to the methylation cycle, such as red blood cell (RBC) folate and serum folate, vitamin B12, total homocysteine (tHCy), and methylmalonic acid (MMA), were identified from the NHANES 2001-2002 laboratory assessments. RESULTS: A total of 9,115 individuals (51.3% females) were included in the final analysis. Linear regression unveiled a significant association between higher GAA intake and diminished RBC folate (p < 0.001), serum folate (p < 0.001), and MMA levels (p = 0.007). It also revealed an elevation in tHCy levels with increased GAA intake (p < 0.001). These associations remained significant even after adjusting for demographic variables and dietary factors pertinent to the methylation cycle (p < 0.05). CONCLUSION: Our findings suggest that dietary exposure to GAA (resulting in conversion to creatine) could be considered a nutritional factor associated with the consumption of methyl groups in the general population.

Predictive value of combining urinary N-acetyl-ß-D-glucosaminidase and serum homocysteine for contrast-induced nephropathy in patients after percutaneous coronary intervention.

Background: Contrast-induced nephropathy (CIN) can lead to serious complications following percutaneous coronary intervention (PCI). Urine N-Acetyl-ß-D-glucosaminidase (uNAG) and serum homocysteine (sHCY) are both potential predictors for CIN detection, but their combination has not been explored. We aimed to combine uNAG and sHCY as predictors for the early detection of CIN and for prognosis prediction in patients after PCI. Methods: A total of 232 consecutive patients who underwent PCI at a university hospital were recruited for this study. According to the European Society of Urology and Reproduction (ESUR) criterion, CIN is defined as an elevation of serum creatinine (sCr) by ≥25% or ≥0.5 mg/dl from baseline within 48 h. We assessed the use of individual biomarkers (uNAG and sHCY) measured around PCI and their combinations for CIN detection and prognosis prediction. Receiver operating characteristic curves (ROC) and area under the curve (AUC) were used to evaluate the predictive efficiency of potential predictors. Results: In total, 54 (23.28%) patients developed CIN. Concentrations of uNAG and sHCY increased significantly in CIN subjects (p < 0.05) than non-CIN. CIN could be predicted by uNAG and sHCY but not by creatinine at an early stage. At pre-PCI, 0, 12, 24, and 48 h after PCI, the AUC-ROC value of uNAG in calculating total CIN was 0.594, 0.603, 0.685, 0.657, and 0.648, respectively. The AUC-ROC value of sHCY in calculating total CIN was 0.685, 0.726, 0.771, 0.755, and 0.821, respectively. The panel of uNAG plus sHCY detected CIN with significantly higher accuracy than either individual biomarker alone and earlier than sCr. For detecting total CIN, this panel yielded AUC-ROCs of 0.693, 0.754, 0.826, 0.796, and 0.844 at pre-PCI, 0, 12, 24, and 48 h after PCI, respectively, which were superior to those of the individual biomarkers. For predicting the incidence of major adverse cardiovascular events (MACE) within 30 days to 12 months, the AUC-ROC values for uNAG and sHCY measured before discharge were 0.637 and 0.826, respectively. The combined panel yielded an AUC-ROC of 0.832. The combined detection did not significantly enhance the predictive capability for MACE in patients with CIN. The CIN group and the non-CIN group showed no significant difference in the Coronary Heart Disease Intensive Care Unit (CCU) stay time, hospital stay time, demand for renal replacement therapy, CCU mortality rate, and in-hospital mortality rate. Conclusions: The uNAG and sHCY panel demonstrated better sensitivity and specificity for predicting the diagnosis and prognosis of CIN in patients after PCI, earlier than sCr. The combination of these biomarkers revealed a significantly superior discriminative performance for CIN detection and prognosis compared to using uNAG or sHCY alone.

Differential effects of environmental exposures on clinically relevant endophenotypes between sexes.

Sex and gender differences play a crucial role in health and disease outcomes. This study used data from the National Health and Nutrition Examination Survey to explore how environmental exposures affect health-related traits differently in males and females. We utilized a sex-stratified phenomic environment-wide association study (PheEWAS), which allowed the identification of associations across a wide range of phenotypes and environmental exposures. We examined associations between 272 environmental exposures, including smoking-related exposures such as cotinine levels and smoking habits, and 58 clinically relevant blood phenotypes, such as serum albumin and homocysteine levels. Our analysis identified 119 sex-specific associations. For example, smoking-related exposures had a stronger impact on increasing homocysteine, hemoglobin, and hematocrit levels in females while reducing serum albumin and bilirubin levels and increasing c-reactive protein levels more significantly in males. These findings suggest mechanisms by which smoking exposure may pose higher cardiovascular risks and greater induced hypoxia for women, and greater inflammatory and immune responses in men. The results highlight the importance of considering sex differences in biomedical research. Understanding these differences can help develop more personalized and effective health interventions and improve clinical outcomes for both men and women.

Thermal treatment under oxidative conditions increases the antioxidant and antiglycation activity of Chilean Tórtola beans (Phaseolus vulgaris).

The influence of oxygen on the thermal treatment (TT) of secondary metabolite-enriched extracts (SMEEs) from Tórtola beans and procyanidin C1 (PC1) on the inhibition of advanced glycation end products (AGEs) generation in proteins was investigated. SMEE was incubated at 4 °C (control) or thermally treated at 60 °C for 2 h, at either 0 % O2 (I) or 20 % O2 (II). Treatments I and II increased the content of procyanidin dimers B2. Treatment II was more effective than the control or treatment I in preventing homocysteine oxidation and AGEs generation. TT of PC1 at 0 % or 20 % O2 generated procyanidin dimers and tetramers. PC1 TT at 20 % O2 exhibited higher oxidation potentials and lower IC50 values of fluorescent AGEs than those of controls or TT at 0 % O2. These findings indicate that SMEE from Tórtola beans after treatment II changes the degree of polymerization and oxidation procyanidins, thereby increasing their antiglycation activity.

APOE gene polymorphism in ischemic stroke patients from Huizhou and its correlation with blood lipids and homocysteine.

OBJECTIVES: To investigate the correlation between apolipoprotein E (APOE) gene polymorphisms and ischemic stroke and its relationship with blood lipids and homocysteine (HCY) level in Huizhou City. MATERIALS AND METHODS: In this analytical cross-sectional study, we selected 2612 patients who underwent APOE genotyping from November 2019 to November 2021 at the Third People's Hospital of Huizhou. Among them, 2014 were ischemic stroke patients and 598 were non-stroke patients. The independent variables were ischemic stroke, different genotypes, and different alleles, while the dependent variables were blood lipid levels and HCY levels. RESULTS: The distribution frequency of ε4 allele in stroke group was higher than that in non-stroke group (P < 0.05). Compared with ε4 allele carriers in the stroke group, the levels of lipid total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in ε2 and ε3 allele carriers were significantly lower, while the levels of high-density lipoprotein cholesterol (HDL-C) were significantly higher (P < 0.01). The levels of lipid Lipoprotein a (LPa) and small dense low-density lipoprotein (sdLDL) in ε2 allele carriers in stroke group were significantly lower than those of ε4 allele carriers (P < 0.05). Logistics regression analysis showed that age, TC, HCY level and allele ε4 were positively correlated with the risk of ischemic stroke (P < 0.01), TG level was positively correlated with the risk of ischemic stroke in females (P < 0.01). CONCLUSIONS: APOE gene polymorphism is associated with ischemic stroke, and ε4 allele carriers have a higher risk than ε3 allele carriers.

Discovery of a novel methionine biosynthetic route via O-phospho-l-homoserine.

Methionine (Met), a sulfur-containing amino acid, is essential for the underlying biological processes in living organisms. In addition to its importance as a starting building block for peptide chain elongation in protein biosynthesis, Met is a direct precursor of S-adenosyl-l-methionine, an indispensable methyl donor molecule in primary and secondary metabolism. Streptomyces bacteria are well known to produce diverse secondary metabolites, but many strains lack canonical Met pathway genes for l-homocysteine, a direct precursor of Met in bacteria, plants, and archaea. Here, we report the identification of a novel gene (metM) responsible for the Met biosynthesis in Streptomyces strains and demonstrate the catalytic function of the gene product, MetM. We further identified the metO gene, a downstream gene of metM, and showed that it encodes a sulfur-carrier protein (SCP). In in vitro analysis, MetO was found to play an important role in a sulfur donor by forming a thiocarboxylated SCP. Together with MetO (thiocarboxylate), MetM directly converted O-phospho-l-homoserine to l-homocysteine. O-Phospho-l-homoserine is also known as an intermediate for threonine biosynthesis in bacteria and plants, and MetM shares sequence homology with threonine synthase. Our findings thus revealed that MetM seizes O-phospho-l-homoserine from the threonine biosynthetic pathway and uses it as an intermediate of the Met biosynthesis to generate the sulfur-containing amino acid. Importantly, this MetM/MetO pathway is highly conserved in Streptomyces bacteria and distributed in other bacteria and archaea.IMPORTANCEMethionine (Met) is a sulfur-containing proteinogenic amino acid. Moreover, Met is a direct precursor of S-adenosyl-l-methionine, an indispensable molecule for expanding the structural diversity of natural products. Because Met and its derivatives benefit humans, the knowledge of Met biosynthesis is important as a basis for improving their fermentation. Streptomyces bacteria are well known to produce diverse and valuable natural products, but many strains lack canonical Met pathway genes. Here, we identified a novel l-homocysteine synthase (MetM) in Streptomyces and demonstrated that it converts O-phospho-L-homoserine to l-homocysteine using a thiocarboxylated sulfur-carrier protein as a sulfur donor. Since the metM is distributed in other bacteria and archaea, our pioneering study contributes to understanding Met biosynthesis in these organisms.

Breastfeeding and biomarkers of folate and cobalamin status in Norwegian infants: a cross-sectional study.

Folate and vitamin B12 (cobalamin) are essential for growth and development. This cross-sectional study aims to describe folate and vitamin B12 status according to infant age and breastfeeding practices in Norwegian infants. Infants aged 0-12 months (n = 125) were recruited through public health clinics. We registered breastfeeding status and measured serum concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA). The associations between infant age, breastfeeding, and biomarker concentrations were estimated in regression models. The mean (SD) age was 24 (16) weeks, and 42% were exclusively breastfed, 38% were partially breastfed, and 21% were weaned. Overall, median (IQR) folate, cobalamin, tHcy, and MMA concentrations were 47 (35-66) nmol/L, 250 (178-368) pmol/L, 6.99 (5.69-9.27) µmol/L, and 0.35 (0.24-0.83) µmol/L, respectively. None of the infants were folate deficient, 15% were vitamin B12 deficient (< 148 pmol/L), and 23% had low vitamin B12 status (148-221 pmol/L). Elevated tHcy (> 6.5 µmol/L) and MMA (> 0.26 µmol/L) were found in 62% and 69% of the infants, respectively. Compared to weaned, exclusively or partially breastfed infants were younger and had 46% higher tHcy concentrations (P < 0.001), in addition to 47% and 39% lower cobalamin concentrations (P < 0.001), respectively. However, the observed biomarker concentrations appeared to be independent of infant age. In conclusion, low vitamin B12 status was prevalent and appeared to be more common in the younger exclusively breastfed compared to older weaned infants. The implications of low vitamin B12 status in infancy are unknown and require further investigation.

Targeted delivery of rosuvastatin enhances treatment of hyperhomocysteinemia-induced atherosclerosis using macrophage membrane-coated nanoparticles.

Rosuvastatin (RVS) is an excellent drug with anti-inflammatory and lipid-lowering properties in the academic and medical fields. However, this drug faces a series of challenges when used to treat atherosclerosis caused by hyperhomocysteinemia (HHcy), including high oral dosage, poor targeting, and long-term toxic side effects. In this study, we applied nanotechnology to construct a biomimetic nano-delivery system, macrophage membrane (Møm)-coated RVS-loaded Prussian blue (PB) nanoparticles (MPR NPs), for improving the bioavailability and targeting capacity of RVS, specifically to the plaque lesions associated with HHcy-induced atherosclerosis. In vitro assays demonstrated that MPR NPs effectively inhibited the Toll-like receptor 4 (TLR4)/hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathways, reducing pyroptosis and inflammatory response in macrophages. Additionally, MPR NPs reversed the abnormal distribution of adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)/ATP binding cassette transporter G1 (ABCA1)/ATP binding cassette transporter G1 (ABCG1) caused by HIF-1α, promoting cholesterol efflux and reducing lipid deposition. In vivo studies using apolipoprotein E knockout (ApoE -/-) mice confirmed the strong efficacy of MPR NPs in treating atherosclerosis with favorable biosecurity, and the mechanism behind this efficacy is believed to involve the regulation of serum metabolism and the remodeling of gut microbes. These findings suggest that the synthesis of MPR NPs provides a promising nanosystem for the targeted therapy of HHcy-induced atherosclerosis.

Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review.

Background: Folic acid (FA), which in its chemical form is pteroylglutamic acid, is the fully oxidised, water-soluble, monoglutamic form of vitamin B9. This compound is part of the folate group but with higher bioavailability, and it is found in vitamin supplements and fortified foods and drugs. Folate metabolism is complex and associated with various metabolic pathways, all of which confer protection on the cell and allow its survival. Methods: We conducted a non-systematic search of articles published in English and Spanish including controlled trials, cohort studies, systematic re-views, and meta-analyses were included, as well as key studies in animal models related to pharmacokinetic studies. Search terms encompassed: "folic acid", "folates", "5-metyltetrahydrofolate", "5-MTHF", "neural tube defects", "supplementation", "fortification", AND "homocysteine" Results: A crucial role demonstrated for FA is to help prevent neural tube defects (NTDs). However, more studies are definitely still needed to establish 5-MTHF as a safe and effective therapeutic approach comparable with FA. Moreover, there is a lack of clinical studies that evaluate the efficacy of 5-MTHF supplementation in the prevention of NTDs. The present evidence-based narrative review discusses differences between FA and 5-MTHF in terms of structure, metabolism, bioavailability, clinical efficacy, and safety. Conclusions: Despite the potential value of 5-MTHF as an alternative to FA, clinical studies would be urgently needed to support the efficacy, dosage, timing, and/or safety of its use as a supplement.

Neuroprotective effect of vitamin B12 supplementation on cognitive functions and neuronal morphology at different time intervals after traumatic brain injury in male Swiss albino mice.

Traumatic brain injury is a highly irreversible process that consists of primary as well as secondary injury which develops and progresses over months to years, leading to cognitive dysfunctions. Vitamin B12 received considerable interest due to its potential therapeutic properties. The pathways of vitamin B12 are closely related to neuronal survival but its effects on the pathophysiology of injury with respect to cognition is a relatively unexplored area of research. In this study, we investigated, the effect of vitamin B12 and its involvement in neuroprotection on TBI-induced pathophysiology in male Swiss albino mice. Our findings suggested that vitamin B12 supplementation improves TBI-mediated neurological impairments, spatial and recognition memory, and anxiety-like behavior. Furthermore, the oxidative stress was reduced by declined homocysteine level with vitamin B12 supplementation validating declined expression of astrocytes and TBI biomarkers. The studies on neuronal morphology revealed that vitamin B12 supplementation increases the dendritic arborization and density of mushroom and filopodia-shaped spines and further increases the expression of synaptic plasticity-related genes and proteins. Taken together, our findings reveal that, supplementation of vitamin B12 restored the TBI-induced downregulation of dendritic arborization, and spine density which ultimately increases synaptic plasticity, cell survival, and recovery of cognitive dysfunctions.