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Biochimica Et Biophysica Acta. Proteins... May 2024Methionine gamma lyase (MGL) is a bacterial and plant enzyme that catalyzes the conversion of methionine in methanthiol, 2-oxobutanoate and ammonia. The enzyme belongs... (Review)
Review
Methionine gamma lyase (MGL) is a bacterial and plant enzyme that catalyzes the conversion of methionine in methanthiol, 2-oxobutanoate and ammonia. The enzyme belongs to fold type I of the pyridoxal 5'-dependent family. The catalytic mechanism and the structure of wild type MGL and variants were determined in the presence of the natural substrate as well as of many sulfur-containing derivatives. Structure-function relationship studies were pivotal for MGL exploitation in the treatment of cancer, bacterial infections, and other diseases. MGL administration to cancer cells leads to methionine starvation, thus decreasing cells viability and increasing their vulnerability towards other drugs. In antibiotic therapy, MGL acts by transforming prodrugs in powerful drugs. Numerous strategies have been pursued for the delivering of MGL in vivo to prolong its bioavailability and decrease its immunogenicity. These include conjugation with polyethylene glycol and encapsulation in synthetic or natural vesicles, eventually decorated with tumor targeting molecules, such as the natural phytoestrogens daidzein and genistein. The scientific achievements in studying MGL structure, function and perspective therapeutic applications came from the efforts of many talented scientists, among which late Tatyana Demidkina to whom we dedicate this review.
Topics: Structure-Activity Relationship; Methionine; Racemethionine; Catalysis; Cell Survival
PubMed: 38147934
DOI: 10.1016/j.bbapap.2023.140991 -
BMB Reports May 2024The gut microbiota, an intricate community of bacteria residing in the gastrointestinal system, assumes a pivotal role in various physiological processes. Beyond its... (Review)
Review
The gut microbiota, an intricate community of bacteria residing in the gastrointestinal system, assumes a pivotal role in various physiological processes. Beyond its function in food breakdown and nutrient absorption, gut microbiota exerts a profound influence on immune and metabolic modulation by producing diverse gut microbiota-generated metabolites (GMGMs). These small molecules hold potential to impact host health via multiple pathways, which exhibit remarkable diversity, and have gained increasing attention in recent studies. Here, we elucidate the intricate implications and significant impacts of four specific metabolites, Urolithin A (UA), equol, Trimethylamine N-oxide (TMAO), and imidazole propionate, in shaping human health. Meanwhile, we also look into the advanced research on GMGMs, which demonstrate promising curative effects and hold great potential for further clinical therapies. Notably, the emergence of positive outcomes from clinical trials involving GMGMs, typified by UA, emphasizes their promising prospects in the pursuit of improved health and longevity. Collectively, the multifaceted impacts of GMGMs present intriguing avenues for future research and therapeutic interventions. [BMB Reports 2024; 57(5): 207-215].
Topics: Gastrointestinal Microbiome; Humans; Aging; Methylamines; Equol; Coumarins; Imidazoles; Propionates; Animals
PubMed: 38627947
DOI: 10.5483/BMBRep.2024-0022 -
Gynecological Endocrinology : the... Dec 2023Effective management of vasomotor symptoms (VMS) in patients undergoing treatment for breast cancer (BC) represents a critical but frequent unmet need. This review... (Review)
Review
Vasomotor symptoms and management of women undergoing treatment for breast cancer: literature review with focus on the therapeutic potential of cytoplasmic pollen extract.
OBJECTIVE
Effective management of vasomotor symptoms (VMS) in patients undergoing treatment for breast cancer (BC) represents a critical but frequent unmet need. This review summarizes the epidemiology, pathophysiology, and clinical features of VMS in patients with BC and provides a synopsis of the complementary and alternative medicine (CAM) approaches in relieving VMS with a focus on purified cytoplasm of pollen (PCP).
METHODS
The literature on VMS epidemiology, pathophysiology, clinical burden, and CAM treatment in healthy women and patients with BC was reviewed.
RESULTS
VMS are common in patients with BC undergoing hormonal treatment and negatively impact quality of life, leading to treatment discontinuation in up to 25% of patients with detrimental impact on risk of BC recurrence and overall survival. CAM approaches to treat VMS in patients with BC include vitamin E, phytoestrogens, and black cohosh, even if there is a lack of solid evidence to guide clinicians in the choice of treatment. PCP, obtained according to standards of good manufacturing practice, has a definite pharmacological mechanism of action, is devoid of estrogen activity, and has shown clinical efficacy on menopause-associated symptoms with a favorable safety profile and high compliance. As such, it appears to represent a valid management option to improve quality of life in patients with pre- and postmenopausal BC.
CONCLUSIONS
Physicians should actively investigate the presence and impact of VMS in patients receiving therapy for BC. Additional and appropriately sized randomized clinical trials are needed to provide clear evidence on how to best meet the needs of patients with BC suffering from menopause-associated symptoms.
Topics: Female; Humans; Breast Neoplasms; Hot Flashes; Quality of Life; Neoplasm Recurrence, Local; Menopause; Cytoplasm; Pollen
PubMed: 36591791
DOI: 10.1080/09513590.2022.2162035 -
JNCI Cancer Spectrum Jan 2024Phytonutrient intakes may improve outcomes following breast cancer, but the impact of postdiagnosis introduction vs established prediagnostic exposure as well as optimum... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phytonutrient intakes may improve outcomes following breast cancer, but the impact of postdiagnosis introduction vs established prediagnostic exposure as well as optimum doses has not been established. Evidence from observational studies for key exposures was evaluated, including dosage and intake time frames.
METHODS
MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and the ISRCTN registry were searched for prospective and retrospective observational studies investigating the impact of soybean, lignans, cruciferous (cabbage-family) vegetables, green tea, or their phytonutrients on breast cancer survival outcomes. A random-effects model was used to calculate summary hazard ratios (HRs) and 95% confidence intervals (CIs). Nonlinear dose-response analyses were conducted using restricted cubic splines.
RESULTS
Thirty-two articles were included. Soy isoflavones were associated with a 26% reduced risk of recurrence (HR = 0.74, 95% CI = 0.60 to 0.92), particularly among postmenopausal (HR = 0.72, 95% CI = 0.55 to 0.94) and estrogen receptor-positive survivors (HR = 0.82, 95% CI = 0.70 to 0.97), with the greatest risk reduction at 60 mg/day. In mortality outcomes, the reduction was mostly at 20 to 40 mg/day. Soy protein and products were inversely associated with cancer-specific mortality for estrogen receptor-positive disease (HR = 0.75, 95% CI = 0.60 to 0.92). An inverse association was observed for serum or plasma enterolactone, measured prediagnosis and early postdiagnosis, with cancer-specific mortality (HR = 0.72, 95% CI = 0.58 to 0.90) and all-cause mortality (HR = 0.69, 95% CI = 0.57 to 0.83). No effects were observed for cruciferous vegetables. There was a 44% reduced risk of recurrence with prediagnostic green tea for stage I and II breast cancer (HR = 0.56, 95% CI = 0.38 to 0.83).
CONCLUSIONS
Soy, enterolactone, and green tea demonstrated significant risk reductions in outcomes following breast cancer. Evidence is needed regarding the impact of postdiagnostic introduction or substantial increase of these exposures.
Topics: Humans; Female; Prospective Studies; Retrospective Studies; Breast Neoplasms; Receptors, Estrogen; Tea
PubMed: 38070485
DOI: 10.1093/jncics/pkad104 -
Journal of Translational Medicine Jan 2024The main challenge in personalized treatment of breast cancer (BC) is how to integrate massive amounts of computing resources and data. This study aimed to identify a...
BACKGROUND
The main challenge in personalized treatment of breast cancer (BC) is how to integrate massive amounts of computing resources and data. This study aimed to identify a novel molecular target that might be effective for BC prognosis and for targeted therapy by using network-based multidisciplinary approaches.
METHODS
Differentially expressed genes (DEGs) were first identified based on ESTIMATE analysis. A risk model in the TCGA-BRCA cohort was constructed using the risk score of six DEGs and validated in external and clinical in-house cohorts. Subsequently, independent prognostic factors in the internal and external cohorts were evaluated. Cell viability CCK-8 and wound healing assays were performed after PTGES3 siRNA was transiently transfected into the BC cell lines. Drug prediction and molecular docking between PTGES3 and drugs were further analyzed. Cell viability and PTGES3 expression in two BC cell lines after drug treatment were also investigated.
RESULTS
A novel six-gene signature (including APOOL, BNIP3, F2RL2, HINT3, PTGES3 and RTN3) was used to establish a prognostic risk stratification model. The risk score was an independent prognostic factor that was more accurate than clinicopathological risk factors alone in predicting overall survival (OS) in BC patients. A high risk score favored tumor stage/grade but not OS. PTGES3 had the highest hazard ratio among the six genes in the signature, and its mRNA and protein levels significantly increased in BC cell lines. PTGES3 knockdown significantly inhibited BC cell proliferation and migration. Three drugs (gedunin, genistein and diethylstilbestrol) were confirmed to target PTGES3, and genistein and diethylstilbestrol demonstrated stronger binding affinities than did gedunin. Genistein and diethylstilbestrol significantly inhibited BC cell proliferation and reduced the protein and mRNA levels of PTGES3.
CONCLUSIONS
PTGES3 was found to be a novel drug target in a robust six-gene prognostic signature that may serve as a potential therapeutic strategy for BC.
Topics: Female; Humans; Breast Neoplasms; Diethylstilbestrol; Genistein; Limonins; Molecular Docking Simulation; Prognosis; RNA, Messenger
PubMed: 38245717
DOI: 10.1186/s12967-024-04899-0 -
Autophagy May 2024Huntington disease (HD) is a neurodegenerative disorder caused by a mutation in the gene. The expansion of CAG triplets leads to the appearance of misfolded HTT...
Huntington disease (HD) is a neurodegenerative disorder caused by a mutation in the gene. The expansion of CAG triplets leads to the appearance of misfolded HTT (huntingtin) forming aggregates and leading to impairment of neuronal functions. Here we demonstrate that stimulation of macroautophagy/autophagy by genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4 H-1-benzopyran-4-one) caused a reduction of levels of mutated HTT in brains of HD mice and correction of their behavior as assessed in a battery of cognitive, anxiety and motor tests, even if the compound was administered after symptoms had developed in the animals. Biochemical and immunological parameters were also improved in HD mice. Studies on molecular mechanisms of genistein-mediated stimulation of autophagy in HD cells indicated the involvement of the FOXO3-related pathway. In conclusion, treatment with genistein stimulates the autophagy process in the brains of HD mice, leading to correction of symptoms of HD, suggesting that it might be considered as a potential drug for this disease. Combined with a very recently published report indicating that impaired autophagy may be a major cause of neurodegenerative changes, these results may indicate the way to the development of effective therapeutic approaches for different neurodegenerative diseases by testing compounds (or possibly combinations of compounds) capable of stimulating autophagy and/or unblocking this process.: CNS: central nervous system; EPM: elevated plus-maze; GOT1/ASPAT: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALAT/ALT: glutamic pyruvic transaminase, soluble; HD: Huntington disease; HTT: huntingtin; IL: interleukin; mHTT: mutant huntingtin; NOR: novel object recognition; MWM: Morris water maze; OF: open field; ROS: reactive oxygen species; TNF: tumor necrosis factor.
Topics: Genistein; Animals; Huntington Disease; Autophagy; Forkhead Box Protein O3; Mice; Huntingtin Protein; Humans; Brain; Mice, Transgenic; Behavior, Animal; Disease Models, Animal
PubMed: 37992314
DOI: 10.1080/15548627.2023.2286116 -
Heliyon Nov 2023A powerful steroid hormone precursor, 1,25 dihydroxycholecalciferols (1,25(OH)D), and dietary phytoestrogen (genistein) are essential compounds that act by binding to...
A powerful steroid hormone precursor, 1,25 dihydroxycholecalciferols (1,25(OH)D), and dietary phytoestrogen (genistein) are essential compounds that act by binding to nuclear receptors and altering gene expression. They have many biological benefits, some of which have anticancer properties. We studied the impact of 1,25(OH)D and genistein on the proliferation, progression, and metastasis of MCF-7 and MDA-MB-231 cells when they were used alone or in combination and investigated whether there was a synergistic effect between genistein and 1,25(OH)D. To achieve these goals, a variety of assays, including flow cytometry, cell invasion assays, cell adhesion assays, Western blotting, and RT‒PCR, were used. Our findings showed that genistein, 1,25(OH)D, and the two combined all effectively declined the growth of MCF-7 and MDA-MB-231 cells by arresting the cells in the G0/G1 phase and inducing an apoptotic pathway. Stimulation of apoptosis was achieved by upregulating the expression of BAX and CASP3 genes and downregulating the expression levels of BCL-2 gene. Furthermore, both compounds suppress metastasis by reducing cell adhesion and cell migration/invasion by elevating the expression level of E-cadherin and reducing the expression level of P-cadherin and N-cadherin. Additionally, both genistein and 1,25(OH)D increased the expression level of ERK1 and reduced the expression levels of JNK, p38, Ras, and MEK proteins, which reduced metastasis, enhanced the response to cancer treatment, and improved overall survival. Thus, genistein and 1,25(OH)D can both be considered key candidates in the search for new breast cancer treatments.
PubMed: 38034665
DOI: 10.1016/j.heliyon.2023.e21975 -
Redox Report : Communications in Free... Dec 2023Gastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein...
OBJECTIVES
Gastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein is a legume flavonoid with antioxidants, anti-inflammatory and antibacterial activities. Therefore, we aimed to investigate the ability of genistein to reduce experimentally induced GU in rats by affecting gastric tissue fibrosis Wnt/β-catenin/TGF-β/SMAD4 pathway.
METHODS
Thirty rats were used. Ten rats served as control, and GU was induced in twenty rats using a single dose of indomethacin (80 mg/kg) orally. Following induction of GU, ten were treated with genistein 25 mg/kg orally. The gastric tissues were isolated to investigate markers of gastric fibrosis, Wnt, β-catenin, transforming growth factor (TGF)-β, SMAD4, and Protein kinase B (PKB). In addition, gastric sections were stained with PAS and anti-TGF-β antibodies.
RESULTS
Investigation GU micro-images revealed degeneration in both surface cells and glandular epithelial cells, which was improved by genistein. In addition, treatment with genistein significantly reduced the expression of Wnt, β-catenin, TGF-β, SMAD4, and PKB.
CONCLUSION
Besides antioxidant activity, genistein improves experimentally induced GU in rats, at least in part, via reduction of gastric tissue fibrosis as indicated by reduction in expression of Wnt, β-catenin, TGF-β, SMAD4, and PKB.
Topics: Animals; Rats; beta Catenin; Catenins; Fibrosis; Genistein; Stomach Ulcer; Transforming Growth Factor beta
PubMed: 37260037
DOI: 10.1080/13510002.2023.2218679 -
Journal of the Science of Food and... Dec 2023The main aim of this 2-year non-randomized parallel controlled clinical pilot trial was to evaluate the long-term effect of a moderate daily intake of beer (with and...
BACKGROUND
The main aim of this 2-year non-randomized parallel controlled clinical pilot trial was to evaluate the long-term effect of a moderate daily intake of beer (with and without alcohol) on cardiovascular health in postmenopausal women. A total of 34 participants were grouped into three study arms: 16 were administered alcoholic beer, 6 consumed non-alcoholic beer, and 12 were in the control group. Changes in glucose metabolism, lipid profile, liver enzymes, anthropometric measurements, body composition, and blood pressure variables were monitored. Data on medical history, diet, and exercise were collected, and gustatory capacities were determined.
RESULTS
Moderate consumption of beer, both alcoholic and non-alcoholic, seemed to have positive effects on biochemical indicators of cardiovascular health in postmenopausal women, with 660 mL day of non-alcoholic beer reducing low-density lipoprotein cholesterol blood levels, and 330 mL day of alcoholic beer increasing high-density lipoprotein cholesterol. The evolution of changes in android and gynoid fat percentage and their ratio differed significantly between study groups, which was attributable to either the interventions or the disparity between groups regarding the time elapsed since menopause onset. Iso-α-acids recognition threshold could be involved in intervention group election, whereas the sensory phenotypes studied were not associated with alcohol drinking frequency.
CONCLUSIONS
Moderate beer consumption was found to improve the lipid profile of postmenopausal women, although their effects in preventing cardiometabolic alterations deserve further research (trial registration number: ISRCTN13825020; https://doi.org/10.1186/ISRCTN13825020). © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Topics: Female; Humans; Alcohol Drinking; Beer; Cholesterol, HDL; Ethanol; Postmenopause
PubMed: 37402233
DOI: 10.1002/jsfa.12826 -
Toxicology and Applied Pharmacology Aug 2023Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis...
Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis stress. We aim here at pharmacological discovering of formononetin (FMN) action, to which anti-inflammatory signaling spans across immune membrane receptors and second messenger metabolites. In ANA-1 macrophage stimulated by LPS, and simultaneous treatment with FMN, results show the Toll-like receptor 4 (TLR4) and estrogen receptor (ER) signals, in concert with reactive oxygen species (ROS) and cyclic adenosine monophosphate (cAMP), respectively. LPS stimulates inactivation of the ROS-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) by upregulating TLR4, but it does not affect cAMP. However, FMN treatment not only activates Nrf2 signaling by TLR4 inhibition, but also it activates cAMP-dependent protein kinase activities by upregulating ER. The cAMP activity gives rise to phosphorylation (p-) of protein kinase A, liver kinase B1 and 5'-AMP activated protein kinase (AMPK). Moreover, bidirectional signal crosstalk is amplified between p-AMPK and ROS, as FMN combinational validation with AMPK activator/inhibitor/target small-interfering RNA or ROS scavenger. The signal crosstalk is well positioned serving as the 'plug-in' knot for rather long signaling axis, and the immune-to-metabolic circuit via ER/TLR4 signal transduction. Collectively, convergence of the FMN-activated signals drives significant reduction of cyclooxygenase-2, interleukin-6 and NLR family pyrin domain-containing protein 3, in LPS-stimulated cell. Although anti-inflammatory signaling is specifically related to the immune-type macrophage, the p-AMPK antagonizing effect arises from FMN combination with ROS scavenger H-bond donors. Information of our work assists in predictive traits against macrophage inflammatory challenges, using phytoestrogen discoveries.
Topics: Humans; Reactive Oxygen Species; Toll-Like Receptor 4; AMP-Activated Protein Kinases; Lipopolysaccharides; NF-E2-Related Factor 2; Signal Transduction; Macrophages; Inflammation; Anti-Inflammatory Agents
PubMed: 37269934
DOI: 10.1016/j.taap.2023.116571