SAMe (S-Adenosylmethionine)

BACKGROUND: Mild depression lacks a consistent definition across diagnostic criteria and rating scales, posing challenges to standardizing treatment strategies. International guidelines predominantly recommend psychotherapy as the first-line treatment for mild depression, while the use of antidepressants remains contentious. Supplements such as omega-3 fatty acids, St. John's Wort, and magnesium have garnered attention as alternative therapeutic options for depression. This systematic review aims to assess the efficacy of pharmacological interventions, including supplements, in the treatment of mild depression. METHODS: Comprehensive searches were performed in PubMed and Embase through November 2024 to identify randomized controlled trials (RCTs) investigating pharmacotherapy or supplements for mild depression diagnosed using standardized criteria. Eligible studies underwent screening and risk of bias assessment utilizing the ROB2 tool. Data on remission rates, symptom improvement, dropout rates, and adverse events were extracted, with meta-analyses conducted where applicable. RESULTS: Eight RCTs comprising 1049 participants met inclusion criteria. Among the agents studied, St. John's Wort was analyzed in two trials, both comparing it to fluoxetine. A meta-analysis found no significant difference in response rates between the two treatments (risk ratio [RR] = 0.96, 95% CI: 0.78-1.18) or dropout rates (RR = 1.08, 95% CI: 0.62-1.88). For other agents, single studies evaluated their effects. Eicosapentaenoic acid and Rhodiola rosea demonstrated significant improvements in depressive symptoms compared to placebo. In non-blinded trials, magnesium chloride showed efficacy in alleviating depressive symptoms. Other interventions, such as lavender, lemon balm, and transcranial electroacupuncture stimulation, were as effective as antidepressants. Conversely, S-adenosylmethionine did not produce significant improvements relative to placebo. CONCLUSION: This review demonstrates that certain supplements, such as eicosapentaenoic acids and Rhodiola rosea, are therapeutic options for mild depression. However, no RCTs compared antidepressants directly to placebo for mild depres

BACKGROUND: There is increasing evidence that supplementation of S-adenosylmethionine (SAM) can improve cognitive function in animals and humans, although the outcomes are not always inconsistent. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the correlation between SAM supplementation and improved cognitive function. METHODS: We searched studies in the PubMed, Cochrane Library, Embase, Web of Science, and Clinical Trials databases from January 1, 2002 to January 1, 2022. Risk of bias was assessed using the Cochrane risk of bias 2.0 (human studies) and the Systematic Review Center for Laboratory Animal Experimentation risk of bias (animal studies) tools; and evidence quality was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation. STATA software was employed to perform meta-analysis, and the random-effects models was used to evaluate the standardized mean difference with 95% confidence intervals. RESULTS: Out of the 2,375 studies screened, 30 studies met the inclusion criteria. Meta-analyses of animal (p = 0.213) and human (p = 0.047) studies showed that there were no significant differences between the SAM supplementation and control groups. The results of the subgroup analyses showed that the animals aged ≤8 weeks (p = 0.027) and the intervention duration >8 weeks (p = 0.009) were significantly different compared to the controls. Additionally, the Morris water maze test (p = 0.005) used to assess the cognitive level of the animals revealed that SAM could enhance spatial learning and memory in animals. CONCLUSION: SAM supplementation showed no significant improvement in cognition. Therefore, further studies are needed to assess the effectiveness of SAM supplementation.

CONTEXT: Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. OBJECTIVES: To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. DATA SOURCES: Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. DATA EXTRACTION: The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. DATA SYNTHESIS: A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. RESULTS: From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography-mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. CONCLUSION: This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42018091898. © The Author(s) 2020. Published by Oxford University Press on

OBJECTIVE: There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants. The adjunctive use of standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several neurochemical pathways implicated in depression. While many studies have been conducted in this area, to date no specialized systematic review (or meta-analysis) has been conducted. METHOD: A systematic search of PubMed, CINAHL, Cochrane Library, and Web of Science was conducted up to December 2015 for clinical trials using adjunctive nutrients for depression. Where sufficient data were available, a random-effects model analyzed the standard mean difference between treatment and placebo in the change from baseline to endpoint, combining the effect size data. Funnel plot and heterogeneity analyses were also performed. RESULTS: Primarily positive results were found for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethyl-EPA), and vitamin D, with positive isolated studies for creatine, folinic acid, and an amino acid combination. Mixed results were found for zinc, folic acid, vitamin C, and tryptophan, with nonsignificant results for inositol. No major adverse effects were noted in the studies (aside from minor digestive disturbance). A meta-analysis of adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3. Conversely, a meta-analysis of folic acid revealed a nonsignificant difference from placebo. Marked study heterogeneity was found in a Higgins test for both omega-3 and folic acid studies; funnel plots also revealed asymmetry (reflecting potential study bias). CONCLUSIONS: Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.

It has been well established that S-adenosyl-L-methionine (SAMe) is the principal methyl donor in methyltransferase reactions and that SAMe supplementation restores hepatic glutathione (GSH) deposits and attenuates liver injury. However, the effectiveness of SAMe therapy in chronic liver disease has not been adequately addressed. We searched globally recognized electronic databases, including PubMed, the Cochrane Database and EMBASE, to retrieve relevant randomized controlled trials (RCTs) of chronic liver disease published in the past 20 years. We then performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria.The results showed that twelve RCTs from 11 studies, which examined 705 patients, were included in this research. For liver function, certain results obtained from data synthesis and independent comparisons demonstrated significant differences between the levels of total bilirubin (TBIL) and aspartate transaminase (AST). However, no studies identified significant differences regarding alanine transaminase (ALT) levels. An analysis of the adverse events and long-term prognosis also indicated no significant differences between the SAMe and the placebo groups. In a subgroup analysis of gravidas and children, several of the included data indicated that there was a significant difference in the pruritus score. Furthermore, the results regarding ursodeoxycholic acid (UDCA) and stronger neo-minophagen C (SNMC) indicated that both treatments were more effective than SAMe was in certain chronic liver diseases. These findings suggest that SAMe could be used as the basis of a medication regimen for liver function improvement because of its safety. However, SAMe also demonstrated limited clinical value in the treatment of certain chronic liver diseases.

BACKGROUND: Alzheimer's disease (AD) is the most frequently diagnosed form of dementia resulting in cognitive impairment. Many AD mouse studies, using the methyl donor S-adenosylmethionine (SAM), report improved cognitive ability, but conflicting results between and within studies currently exist. To address this, we conducted a meta-analysis to evaluate the effect of SAM on cognitive ability as measured by Y maze performance. As supporting evidence, we include further discussion of improvements in cognitive ability, by SAM, as measured by the Morris water maze (MWM). METHODS: We conducted a comprehensive literature review up to April 2014 based on searches querying MEDLINE, EMBASE, Web of Science, the Cochrane Library and Proquest Theses and Dissertation databases. We identified three studies containing a total of 12 experiments that met our inclusion criteria and one study for qualitative review. The data from these studies were used to evaluate the effect of SAM on cognitive performance according to two scenarios: 1. SAM supplemented folate deficient (SFD) diet compared to a folate deficient (FD) diet and 2. SFD diet compared to a nutrient complete (NC) diet. Hedge's g was used to calculate effect sizes and mixed effects model meta-regression was used to evaluate moderating factors. RESULTS: Our findings showed that the SFD diet was associated with improvements in cognitive performance. SFD diet mice also had superior cognitive performance compared to mice on an NC diet. Further to this, meta-regression analyses indicated a significant positive effect of study quality score and treatment duration on the effect size estimate for both the FD vs SFD analysis and the SFD vs NC analysis. CONCLUSION: The findings of this meta-analysis demonstrate efficacy of SAM in acting as a cognitive performance-enhancing agent. As a corollary, SAM may be useful in improving spatial memory in patients suffering from many dementia forms including AD.

OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the Unites States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA). STUDY DESIGN: This was a meta-analysis of randomized controlled trials. DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists. OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects. RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] =.31; 95% confidence interval [CI],.099-.520), but not in reducing pain (ES =.22; 95% CI, -.247 to.693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES =.12; 95% CI, -.029 to.273; functional limitation: ES =.025; 95% CI, -.127 to.176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs. CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.

INTRODUCTION: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple neuronal pathways, including tau dephosphorylation. Reduced SAMe availability has been reported in the Alzheimer's disease (AD) brain, prompting interest in supplementation as a potential therapeutic strategy. METHODS: This multicenter, randomized, double-blind, placebo-controlled phase 2 study recruited people (n = 63) with a clinical AD diagnosis. Participants received 180 days of SAMe (400 mg daily) or placebo. Primary outcome was change in plasma phosphorylated tau (p-tau)217 concentration. Secondary endpoints included safety, tolerability, and cognitive outcomes. RESULTS: Mean percentage change in plasma p-tau217 in the SAMe group was an increase of 53.22 (standard deviation [SD] 159.19) compared to 25.34 (SD 94.83) in the placebo group (standardized mean difference 37.58, 95% confidence interval -32.61, 107.76; p = 0.288). No significant differences were observed in safety or other secondary endpoints. DISCUSSION: SAMe did not demonstrate disease-modifying efficacy at the dose and duration studied; however it was safe and well tolerated. TRIAL REGISTRATION: ACTRN12620000506998. Registered on the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). © 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

BACKGROUND AND AIMS: Elevated plasma levels of total homocysteine (Hcy) and S-Adenosylhomocysteine (SAH) are associated with increased risks of neurological and cardiovascular diseases (CVD). Whilst elevated plasma levels of Hcy can be managed through supplementation with B-group vitamins, there are no effective therapies for managing SAH in patients with elevated SAH and normal Hcy. SAH, a by-product of cellular methylation reactions, is considered a more sensitive biomarker for CVD than homocysteine (Hcy). The aim of this study was to determine if a test product containing ashwagandha extract, alpha-glycerylphosphorylcholine and creatine monohydrate, could lower plasma SAH levels in adults with elevated SAH and normal Hcy. METHODS AND RESULTS: In this prospective, randomized, single-blind, placebo-controlled clinical trial, 40 participants with elevated SAH (≥20 nmol/L) and normal Hcy (≤13 μmol/L) were randomized into two groups: 15 participants received the placebo, and 25 participants received the test product. The test product significantly lowered plasma SAH levels by approximately 12% and increased S-Adenosylmethionine (SAM): SAH ratio by approximately 26% after 12 weeks of supplementation compared to baseline. The test product was safe and well-tolerated, with no serious adverse events. No clinically relevant changes in vital signs and safety laboratory parameters were detected. CONCLUSION: This is the first demonstration of a nutritional product's effectiveness in decreasing plasma levels of SAH in otherwise healthy individuals with elevated SAH and normal Hcy. Hence, this test product offers a unique opportunity for investigating the impact of lowering plasma SAH on the risk of developing CVD and other diseases. Clincaltrial.gov registration: NCT05994794, 2023-08-16.

Arsenic exposure remains a leading public health concern. Folic acid (FA) supplementation enhances one-carbon metabolism (OCM), thus promoting arsenic methylation and facilitating urinary arsenic elimination. Here, we investigate the metabolic profiles linked to arsenic exposure and metabolism based on a FA clinical trial. Arsenic exposure was assessed by the concentrations of blood arsenic (bAs) species: arsenite [InAsIII], arsenate [InAsV], monomethyl- [MMA], and dimethyl- [DMA] arsenicals. Arsenic metabolism was assessed by the relative distribution (%) of these arsenicals in urine. Nontargeted metabolomic profiling was analyzed by LC-HRMS. OCM-related metabolites were analyzed by HPLC/MS/MS. Metabolomic profiling identified 8 unique metabolites and 812 metabolomic features (FDR < 0.05) associated with bAs (predominantly AsV), and 66 metabolites and 285 metabolomic features with %uAs (predominantly %uInAs). Metabolic pathways enriched for bAs and %uAs were similar, highlighting phenylalanine, tyrosine, and tryptophan biosynthesis. A FA-induced %uInAs change was associated with four metabolites, three of which share links to acetyl-CoA metabolism. Of 11 measured OCM metabolites, cystathionine was positively associated with all bAs species. Methionine, S-adenosylmethionine, S-adenosylhomocysteine, cysteine, choline, betaine, and dimethylglycine were associated with increased As methylation profiles in urine (FDR < 0.05). Collectively, these findings may aid in the discovery of mechanisms underlying arsenic-induced health outcomes and potential targeted interventions. This trial was registered with clinicaltrials.gov: NCT01050556.

BACKGROUND: Children with sickle cell disease (SCD) in Canada are routinely supplemented with folic acid to provide sufficient folate for the increased demands of erythropoiesis. However, with the mandatory folic acid fortification of refined grains and pharmacotherapies that extend the lifespan of sickled red blood cells (RBC), this clinical practice is in question. OBJECTIVES: This study aims to determine the efficacy of folic acid supplementation by measuring the effect of 12 ± 1 wk of 1 mg/d folic acid, compared with placebo, on concentrations of RBC folate (primary outcome), serum folate, and 1-carbon-related metabolites, and clinical outcomes in children with SCD. METHODS: In this double-blind randomized controlled noninferiority cross-over trial, 31 children with SCD, aged 2-19 y, were enrolled and randomly assigned (1:1 with blocks of 4) to 1 mg/d folic acid, the current standard of care, or a placebo for 12 ± 1 wk. After a 12 ± 1 wk washout period, treatments were reversed. RESULTS: The mean [95% confidence interval (CI)] difference in endline RBC folate concentrations across treatments was -179 (-260, -99) nmol/L, with the lower boundary of the CI exceeding noninferiority but the upper boundary not (P = 0.0001; modified intention-to-treat). There was no significant difference in the number of participants who had RBC folate deficiency after each treatment (P = 0.059). No participants presented with serum folate deficiency (<7 nmol/L). There were no significant differences observed in 1-carbon metabolite concentrations (total homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, vitamin B12, or methylmalonic acid), hematological measures, nor clinical outcomes (specifically acute pain episodes or megaloblastic changes) when individuals were supplemented with folic acid in comparison with placebo. CONCLUSIONS: Despite mandatory food fortification and advances in the medical treatment of SCD, it appears that some children with this condition may still benefit from daily folic acid supplementation. Whether this translates to improved clinical outcomes remains uncertain. This trial was registered at clinicaltrials.gov as NCT04011345 (https://clinicalt

Depression is one of the most serious chronic psychiatric disorders affecting people worldwide. Subthreshold depression (SD) is a form of subclinical depression with increased risk of major depressive disorder (MDD). Patients diagnosed with SD may not be eligible for antidepressant drugs and, particularly in the case of MDD, these antidepressants may have adverse effects which outweigh their therapeutic effects, leading to discontinuation of therapy. Food supplements could provide an alternative strategy. The aim of this study is to demonstrate the efficacy of a food supplement based on a combination of S-adenosyl methionine (SAMe, 200 mg/day) and probiotics (Lactobacillus helveticus Rosell®-52, Bifidobacterium longum Rosell®-175, 3 ×109 CFU/day) in reducing depression symptoms in a monocentric, randomised, double-blind, placebo-controlled, cross-over clinical trial. 80 Subjects were recruited and offered the food supplement or placebo daily for three months, according to a cross-over clinical trial design, followed by a six-week follow-up period. The efficacy of the food supplement was measured by means of the "Hamilton Depression Rating Scale" (HAM-D) and "Patient Health Questionnaire-9" (PHQ-9), using a mixed analysis of variance model, with random intercept, for statistical analysis. The food supplement showed a significant decrease of PHQ-9 and HAM-D scores resulting in reduced SD and MDD symptoms as compared to placebo. In conclusion, the daily intake of the food supplement based on SAMe and probiotic strains for a period of three months is effective in improving the quality of life of SD subjects who are not eligible for antidepressant therapies, and patients suffering from mild-to-moderate depression who are not sensitive or cannot tolerate conventional drugs.

BACKGROUND: Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients. AIMS: We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients. METHODS: We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day. RESULTS: Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006). CONCLUSIONS: Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia. TRIAL REGISTRATION: Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov . © 2022. The Author(s).

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified. Publisher: Цель. Оценка безопасности и эффективности применения препарата Ремаксол раствор для ин

WHAT IS KNOWN AND OBJECTIVES: Ademetionine 1,4-Butanedisulfonate (SAMe) enteric-coated tablets are widely used for treatment of pre-cirrhotic and cirrhotic intrahepatic cholestasis, as well as intrahepatic cholestasis of pregnancy (ICP), but incomplete clinical data and interference from endogenous substances pose numerous challenges for clinical trial of ademetionine. The objective of this study was to evaluate the pharmacokinetic profile of SAMe enteric-coated tablets and to assess its food impact and safety in healthy Chinese subjects. METHODS: A randomized, open-label, single-dose study was carried out to determine the pharmacokinetics of SAMe enteric-coated tablets administered in both fasted and postprandial conditions. Baseline collection and data adjustment were required to reduce the effect of endogenous substances. Relevant pharmacokinetic data from subjects administered the reference formulation will be disclosed and utilized in this thesis. RESULTS: Twenty-four subjects with a body mass index (BMI) of 19-24 kg/m2 were enrolled in the study and all completed the trial. The impact of food on the drug was noticeable, with faster absorption in the fasting group (Tmax , 4.50 ± 1.07 and 7.50 ± 1.58 for the fasting and postprandial groups, respectively) but higher exposure in the postprandial group (AUC0-inf , 4021.02 ± 3377.13 and 5087.28 ± 3539.26 for the fasting and postprandial groups, respectively). No serious adverse effects were observed in the fasted and postprandial conditions. WHAT IS NEW AND CONCLUSIONS: The pharmacokinetic profile of SAMe enteric-coated tablets in healthy Chinese subjects was partially complemented in this study. SAMe enteric-coated tablets showed promising safety in fasted and postprandial conditions. However, the impact of food on the drug was significant and might access to the absorption site and affect biochemical reactions. © 2022 John Wiley & Sons Ltd.

OBJECTIVE: To compare the effect of ursodesoxycholic acid (UDCA) with S-adenosyl-L-methionine (SAMe) plus UDCA in handling of cholestasis in neonates, and their influences on serum endotoxin, matrix metalloproteinase-9 (MMP-9) and interleukin 18 (IL-18). STUDY DESIGN: Randomised controlled trial. PLACE AND DURATION OF STUDY: Luzhou People's Hospital, China, from April 2019 to December 2020. METHODOLOGY: A total of 102 neonates with cholestasis were evenly divided into control group and observation group with random double-blind. The former treated with UDCA tablets, and the latter was treated with SAMe plus UDCA. Serum endotoxin, MMP-9 and IL-18 were compared between the two groups. RESULTS: Total effective rate of treatment in observation group was 92.16% (47 cases), which was higher than that in control group 70.59% (36 cases) (p=0.005). Levels of serum endotoxin, MMP-9 and IL-18 in observation group were respectively 11.12 ± 1.07 pg/mL, 646.72 ± 42.56 ng/mL and 2.51 ± 0.19 pg/mL, which was lower than those in control group (p<0.001, p =0.007 and p<0.001, respectively) after 10 days of treatment. CONCLUSION: Compared with UDCA alone, SAMe plus UDCA can more effectively improve the curative effect of neonatal cholestasis, and reduce serum endotoxin, MMP-9 and IL-18 levels. Key Words: Ursodesoxycholic acid (UDCA), Neonates, Cholestasis, Endotoxin, Matrix metalloproteinase-9 (MMP-9), Interleukin 18 (IL-18).

Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive kind of prostate cancer (PCa). Because the traditional taxane-based therapy is ineffective, cabazitaxel (CBZ), a second-generation, semisynthetic taxane, has been developed. Despite it demonstrating efficacy in patients resistant to docetaxel and paclitaxel, two commonly used taxanes, and representing one of the second-line therapeutic options for patients with mCRPC, CBZ has limitations, including considerable side issues and reduced drug susceptibility that gradually emerge and constitute the primary cause of therapeutic failure. For the purposes of this study, the application of nature-derived adjuvants in chemotherapy is emerging as a promising area of research. S-Adenosyl-L-methionine (AdoMet) is a naturally occurring sulfur-containing nucleoside that serves as the major methyl donor for numerous methyltransferases, which is a key metabolite in the cell, participating in a broad range of essential biochemical processes. In the current research, we bring attention to the effectiveness of the combination of AdoMet and CBZ during treatment of mCRPC cells. Using mCRPC cell lines DU 145 and PC-3, we found that the combination of CBZ and AdoMet worked better than either agent alone in suppressing cancer cell growth. This synergistic effect may be mediated by increased production of reactive oxygen species (ROS) and a weakening of the cancer cells' antioxidant defenses, including reductions in glutathione, GPX4, and catalase. The resulting oxidative stress caused DNA damage and interference with mitotic spindle assembly, which induces cell cycle arrest and programmed cell death. These data indicate that AdoMet is capable of intensifying CBZ responsiveness in mCRPC cells, making the treatment more effective. © 2026 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.

BACKGROUND/AIM: Methionine addiction is a fundamental and general hallmark of cancer termed the Hoffman effect. Methionine restriction using recombinant methioninase (rMETase) has shown synergistic efficacy with numerous types of chemotherapeutic agents against cancer cells and not normal cells. Methionine adenosyltransferase 2A (MAT2A) is a crucial enzyme converting methionine to S-adenosylmethionine (SAM). A MAT2A inhibitor, AG-270, has been proposed as a potential anti-cancer drug. The present study evaluated whether AG-270 is a cancer-specific agent by comparing its efficacy in combination with rMETase on cancer and normal cells. MATERIALS AND METHODS: The half-maximal inhibitory concentrations (IC50) of rMETase and AG-270 were determined on HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts in vitro. The efficacy of rMETase combined with AG-270, at their respective IC50 values, on HCT116 and Hs-27 was also determined. Cell viability was evaluated using the WST-8 reagent. RESULTS: The IC50 values of rMETase were 0.35 U/ml for HCT116 and 1.14 U/ml for Hs-27. The IC50 values of AG-270 were 4.38 μM for HCT116 and 6.55 μM for Hs-27. The combination of rMETase and AG-270, at their respective IC50, had synergistic efficacy on both cancer and normal cells, reducing viability to approximately 20% in both cell lines (p<0.05). CONCLUSION: AG-270 showed lack of cancer specificity in combination with rMETase when tested on both cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy.

Background: Epigenetic dysregulation is a common feature of cancer. Promoter demethylation of tumor-promoting genes and global DNA hypomethylation may trigger tumor progression. Epigenetic changes are unstable; thus, research has focused on detecting remedies that target epigenetic regulators. Previous studies have suggested that concordantly targeting hypomethylation and hypermethylation is beneficial for suppressing both the oncogenic and pro-metastatic functions of cancer cells. Therefore, we aimed to investigate the effect of a combination of S-adenosylmethionine (SAM) and the demethylating agent decitabine on prostate cancer cells. Materials and Methods: Prostate cancer cells (PC-3) were treated with SAM, decitabine, or a combination of both. Proliferation, migration, invasion, and methylation assays were also performed. A transcriptome study was conducted to detect different gene clusters between the treatment groups, followed by analyses using the Kyoto Encyclopedia of Genes and Genomes pathway and ingenuity pathway analysis. Finally, to gain information on differential gene expression, promoter methylation studies were performed. Results: Groups treated with decitabine, SAM, or their combination showed reduced proliferative capacity. The decitabine-treated group showed a marginal increase in cell migration and invasion, whereas the SAM-treated and combination treatment groups showed reduced invasion and migration potential. Methylation assays demonstrated the restoration of decitabine-induced demethylation in prostate cancer samples, whereas the transcriptome study revealed the upregulation of different gene clusters between the treatment groups. Methylation studies confirmed that SAM could restore the decitabine-induced demethylation of proto-oncogenes, but it did not induce the re-methylation of tumor-suppressor genes. Conclusions: Combination treatment with SAM and decitabine had an additive effect and did not nullify each other.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial. © 2024. The Author(s).

Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies. © 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP-/- cancers, however the MTAP-/- genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP+/+ cancers. Methylthio-DADMe-immucillin-A (MTDIA) is a picomolar transition state analog inhibitor of MTAP that renders cells enzymatically MTAP-deficient to induce the MTAP-/- phenotype. Here, we demonstrate that MTDIA and MAT2a inhibitor AG-270 combination therapy mimics synthetic lethality in MTAP+/+ CRC cell lines with similar effects in mouse xenografts and without adverse histology on normal tissues. Combination treatment is synergistic with a 104-fold increase in drug potency for inhibition of CRC cell growth in culture. Combined MTDIA and AG-270 decreases S-adenosyl-L-methionine and increases 5'-methylthioadenosine in cells. The increased intracellular methylthioadenosine:S-adenosyl-L-methionine ratio inhibits PRMT5 activity, leading to cellular arrest and apoptotic cell death by causing MDM4 alternative splicing and p53 activation. Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP+/+ cancers, especially the remaining 98% of CRCs without the MTAP-/- genotype.

Environmental risks of manufactured nanomaterials (MNMs) have been widely investigated while the understanding for joint toxicity mechanism of MNMs with other contaminants is still limited. This limitation may be attributed to variations in the concentration ratios of MNMs and co-existing contaminants in the real environment. To better assess the joint toxicity and clarify its underlying mechanisms, this study exposed Phaeodactylum tricornutum to different concentration combinations of nano-sized titanium dioxide (nTiO2) and As(V) at toxic unit (TU) ratios of 1:4,1:1, and 4:1. The results demonstrated that the joint toxicity modes of nTiO2 and As(V) varied with the TU ratios exhibiting synergism for 1:4, partially addition for 1:1, and antagonism for 4:1. Specifically, at low TU ratio of 1:4, the adsorption of As(V) by nTiO2 together with the subsequent internalization of nTiO2 promoted a significant enrichment of As in algae. Simultaneously, the up-regulation of pst (phosphate transporter) genes in charge of the As(V) transport molecular further exacerbated the enrichment of inorganic As in algae, while the down-regulation of ArsM (arsenite S-adenosylmethionine methyltransferases) genes in charge of the As metabolism inhibited As biotransformation from toxic inorganic to nontoxic organic, causing the aggravated accumulation of toxic inorganic As in algae. At higher TU ratios of 1:1 and 4:1, the accumulation of As decreased in algae due to the higher sedimentation of nTiO2 and thus the lower internalization of As-adsorbed nTiO2, as well as the down-regulation of pst genes restricting the transportation of As(V) into algal cells, which jointly accelerated the As biotransformation from toxic inorganic to nontoxic organic. Our results suggest that more attention should be paid to exposure concentration ratios of MNMs and co-existing contaminants and biological responses including bioavailability, bioaccumulation, biotransformation, which would play a critical role in determining the joint toxicity to the organism.

Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N1-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM.

BACKGROUND: S-adenosylmethionine (SAMe) has antiinflammatory and analgesic effects and has been reported to ameliorate the pain and dysfunction of osteoarthritis (OA). The metabolism of SAMe can be affected by geographic or ethnic factors. However, its efficacy and tolerability versus NSAIDs have not been reported in an Asian population. OBJECTIVE: This study compared the efficacy and tolerability of SAMe 1200 mg/d and nabumetone 1000 mg/d in Korean patients with knee OA. METHODS: This study was an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV clinical trial. Eligible patients were aged >18 years and had knee OA according to the clinical and radiologic criteria of the American College of Rheumatology, with a symptom duration of > or =3 months and with a baseline pain rating of >40 mm on a visual analog scale (VAS) or a pain rating on the VAS that was increased by >10 mm or 20% during the washout period compared with the screening visit. After a washout period of 2 weeks, patients with OA were randomly assigned to receive SAMe 1200 mg/d (400 mg TID) or nabumetone 1000 mg once a day in the evening for 8 weeks. The primary end point was the patient's assessment of pain intensity using a VAS at week 8, and the secondary end points were functional class, patient's global assessment of disease status, physician's global assessment of response to therapy, and the Western Ontario and McMaster Universities (WOMAC) index. Adverse events were assessed based on spontaneous reports by patients during interviews and by laboratory tests. RESULTS: One hundred thirty-four patients, all Asians, were randomly allocated to 1 of 2 treatment groups: 67 patients (56 women, 11 men; mean [SD] age, 63.9 [8.2] years) received SAMe 400 mg TID, and 67 patients (60 women, 7 men; mean age, 62.1 [8.4] years) received nabumetone 1000 mg once daily for 8 weeks. An analysis of changes in pain intensity between weeks 0 and 8 found that both SAMe and nabumetone effectively reduced pain intensity from baseline in each group (mean [SD] change: SAMe, -13.0 [20.8] mm, P < 0.001; nabumetone, -15.7 [20.9] mm, P < 0.001), and the degree of decrease in pain intensity was not signifi

BACKGROUND: S-adenosylmethionine (SAMe) is an endogenous molecule that plays an important role in cellular metabolism. Despite being widely used as a dietary supplement with claimed benefits for numerous conditions, there is little information about the pharmacokinetic properties of exogenous SAMe. OBJECTIVES: One aim of this study was to characterize the pharmacokinetic properties of SAMe after administration of single and multiple doses of orally and intravenously administered SAMe tosylate disulfate (STD) in healthy male and female Chinese volunteers. Because men have higher erythrocyte levels of endogenous SAMe than do women, we also assessed the effects of sex on the disposition of SAMe. METHODS: A simple and sensitive assay for SAMe based on liquid chromatography-mass spectrometry using selected-ion monitoring of analyte and acyclovir as internal standard was developed and validated. The assay was used to study the pharmacokinetic properties of SAMe. STD was administered as single and multiple doses of enteric-coated tablets and IV infusion of STD to groups of healthy native Chinese volunteers. After an overnight fast, male and female Chinese volunteers were assigned to receive STD 1000 mg for 5 days, either in enteric-coated tablet formulation or as a 250-mL IV infusion. Blood samples were collected 24 hours after the first and last dose and used for determining plasma SAMe concentrations and pharmacokinetic parameters. For the oral formulation, SAMe concentrations were corrected for concentrations of endogenous SAMe. Pharmacokinetic parameters were calculated for men and women separately and for the total group of volunteers. Adverse events were monitored using a physician during blood collection and by spontaneous reporting. RESULTS: Twenty healthy volunteers were enrolled (oral formulation: 5 men, 5 women; mean [SD] age, 24.1 [4.7] years [range, 21-37 years]; mean [SD] weight, 59.9 [4.8] kg [range, 54-70 kg]; IV formulation: 5 men, 5 women; mean [SD] age, 22.6 [1.8] years [range, 21-27 years]; mean [SD] weight, 59.5 [5.4] kg [range, 53-67 kg]). None of the between-sex differences in SAMe pharmacokinetic properties were significant. The (mean [SD]) phar

The rapid aging of the global population necessitates addressing age-related conditions through innovative strategies. Nutritional supplements have emerged as potential interventions for preventing or slowing age-related changes, with betaine being a promising candidate. This systematic review aims to provide a comprehensive analysis of current literature on the impact of betaine on the aging process. Specifically, we summarize the mechanisms through which betaine is proposed to affect aging, we integrate existing findings, we identify gaps in the literature, and we discuss practical implications for promoting healthy aging. Evidence suggests that betaine may counteract aging-related changes in methylation potential by increasing concentration of S-adenosylmethionine, a key methyl donor. Additionally, betaine reduces homocysteine concentrations, potentially mitigating vascular, neurodegenerative, and oxidative damage. Betaine has also been shown to enhance mitochondrial function, to reduce oxidative stress, and to attenuate inflammation. It may serve as a preventive agent against sarcopenia by promoting anabolic signaling pathways and improving muscle strength in younger adults. Betaine may also exert an effect on bone remodeling and adipose tissue metabolism, with animal studies indicating enhanced fat oxidation and reduced fat synthesis. Although certain limited studies have suggested betaine's potential in mitigating age-related neurodegenerative diseases, the currently available evidence does not establish a clear link between dietary betaine intake and the incidence of cardiovascular diseases or type-2 diabetes. In conclusion, emerging evidence highlights the potential of betaine in attenuating age-related changes. However, further research is required to elucidate the efficacy and safety of betaine supplementation in older populations.

BACKGROUND/OBJECTIVES: S-adenosylmethionine (SAMe) is a natural compound implicated in the treatment of liver dysfunction. In this systematic review, our objective was to determine the efficacy, safety, and optimal dose of SAMe in liver diseases. METHODS: Using the PRISMA methodology, we searched PubMed, CINAHL, and Web of Science using key MeSH search terms. For title/abstract screening, full-text review, and data extraction, two independent researchers reviewed articles, and a third researcher resolved conflicts. Data extraction also included a quality assessment of included articles. RESULTS: Of the 1881 non-duplicated studies, 15 articles focusing on SAMe use in the liver were included. All included studies (n = 15) scored a 4 or 5 out of 5 points on the quality assessment, which indicated high study quality. Overall, SAMe was effective in improving liver-related parameters with few adverse events, which were primarily mild, transient gastrointestinal complaints. CONCLUSIONS: The most common doses were SAMe 1000 mg or 1200 mg per day with or without another treatment or natural supplement. Future studies are needed to assess long-term efficacy and safety data of SAMe and the optimal route of administration in liver diseases.