The potential role for metformin in the prevention and treatment of tuberculosis.
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ABSTRACT:
SUBMITTER: Sutter A
PROVIDER: S-EPMC9264069 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
The potential role for metformin in the prevention and treatment of tuberculosis.
Sutter Alex A Landis Dylan D Nugent Kenneth K
Journal of thoracic disease 20220601 6
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Project description:Metformin is one of the most commonly used drugs worldwide. It is currently considered first-line pharmacological agent for management of diabetes mellitus type 2. Recent studies have suggested that metformin may have further benefits, especially in the field of urologic oncology. Use of metformin has been shown to be associated with decreased incidence and improved outcomes of prostate, bladder, and kidney cancer. These studies suggest that metformin does have a future role in the prevention and management of urologic malignancies. In this review, we will discuss the latest findings in this field and its implications on the management of urologic oncology patients.
| S-EPMC4869570 | biostudies-other
Project description:There is increasing interest in metformin's effects on the development, treatment and/or progression of breast cancer. This emerges from observational studies that diabetic women treated with metformin in comparison to other antidiabetic compounds had lower breast cancer incidence and/or mortality rates. The mechanism of action is considered to be activation of hepatic AMPK resulting in reduced gluconeogenesis. Calorie restriction, which consistently reduces mammary tumorigenesis in rodents, is also thought to act through this pathway leading to the hypothesis that metformin's anticancer effects are mediated in a similar fashion. Here we review the literature evaluating metformin's anticancer effects in relation to breast/mammary tumorigenesis. We include clinical observations, as well as studies utilizing rodent models and mammary cell lines. In addition to the anticancer effect of metformin mediated through the AMPK pathway, additional mechanisms of action that directly target tissues have been identified including effects on stem cells, apoptosis, STAT3 and HER2.
| S-EPMC4577062 | biostudies-literature
Project description:Tamoxifen (TAM) is a selective estrogen receptor modulator that is widely used in the prevention and treatment of estrogen receptor-positive (ER(+)) breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with TAM for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up and occurrence of contralateral breast cancer. However, in patients treated with TAM there is substantial interindividual variability in the development of resistance to TAM therapy, and in the incidence of TAM-induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. This article will focus on the UDP glucuronosyltransferases, a family of metabolizing enzymes that are responsible for the deactivation and clearance of TAM and TAM metabolites, and how interindividual differences in these enzymes may play a role in patient response to TAM.
| S-EPMC2694135 | biostudies-literature
Project description:PurposeFrailty is a syndrome of vulnerability and physical decline with aging that increases risk for disability, hospitalizations, and death. To date, interventions for frailty have primarily focused on exercise and/or nutritional interventions, many of which show improvement in frailty-related characteristics, such as gait speed and lower extremity strength and function. The goal of this article was to review prior research studies investigating interventions for frailty and review the literature with regard to the role of insulin resistance and inflammation in the development of frailty. Also included is a discussion of potential therapeutic interventions for frailty.MethodsA literature search was conducted by using PubMed and the search terms frailty, interventions, and older adults. This review focused on larger studies (N ≥ 100 participants) that examined the effect of specific interventions on frailty as a primary outcome or on measures that are closely related to frailty, such as gait speed, muscle strength, and/or sarcopenia.FindingsThe results of prior studies of exercise interventions for the frailty syndrome as the primary outcome are mixed, with some but not all showing benefit. However, many exercise interventions have demonstrated improvement in components of frailty, such as strength, gait speed, and physical activity. The evidence shows that regular physical activity is beneficial for frail older adults or those at high risk of frailty and that the adverse effects related to exercise are minimal compared with the potential gains. However, questions remain as to the optimal type and duration of exercise and whether results of clinical trials are easily and feasibly implemented in a clinical setting in individuals whose motivation for exercise may be low. There is now increasing interest in pharmacologic agents that could potentially be useful in the prevention or treatment of frailty, in part based on advances in basic biology of aging research demonstrating that pharmacological agents extend lifespan in rodents. Several studies now show that obesity, insulin resistance, inflammation, and diabetes are associated with and predict frailty. Because metformin targets insulin resistance and inflammation, it is a plausible pharmacologic agent to prevent frailty. A clinical trial is underway to examine metformin's usefulness in frailty prevention.ImplicationsAlthough the benefits of exercise are known, adherence to these regimens may be difficult for individual older adults due to lack of motivation, access, or limitations due to chronic medical conditions. Studies are currently underway to examine novel agents for the prevention of frailty in older adults.
| S-EPMC10279480 | biostudies-literature
Project description: Not available
| S-EPMC7491390 | biostudies-literature
Project description:Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies.
| S-EPMC3652561 | biostudies-literature
Project description:BackgroundThe global type 2 diabetes mellitus (DM) epidemic threatens progress made in reducing tuberculosis (TB)-related mortality worldwide. Previous clinical studies have not fully evaluated potential confounding variables in addressing the impact of DM on TB treatment outcomes. The antidiabetic agent metformin regulates autophagy and may play a role as a host-directed therapeutic adjuvant to antitubercular treatment.MethodsWe conducted a retrospective cohort study comprising patients aged ≥13 years undergoing treatment for culture-confirmed, drug-susceptible pulmonary TB. We assessed the effect of DM on mortality during TB treatment and 2-month TB sputum-culture conversion. We also evaluated the effect of metformin use on survival during TB treatment.ResultsAmong 2416 patients undergoing TB treatment, after adjusting for age, sex, chronic kidney disease, cancer, hepatitis C, tobacco use, cavitary disease, and treatment adherence, patients with DM had 1.91 times higher odds (95% confidence interval [CI], 1.51-2.40) of death during TB treatment than patients without DM, and 1.72 (95% CI, 1.25-2.38) times higher odds of remaining culture-positive at 2 months. Metformin use in patients with DM was significantly associated with decreased mortality during TB treatment (hazard ratio, 0.56 [95% CI, .39-.82]), and metformin users had similar mortality as patients without DM.ConclusionsThis study suggests that despite multiple potential confounding variables, DM poses an increased risk of adverse TB treatment outcomes. There was a significant association between metformin use and decreased mortality during TB treatment, suggesting a potential role for this agent as adjunctive, host-directed therapy.
| S-EPMC5848303 | biostudies-literature
Project description:ObjectiveGastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations.MethodsThe seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo.ResultsWe screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway.ConclusionThis study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.
| S-EPMC11294171 | biostudies-literature
Project description:Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the most devastating bacterial diseases to affect humans. M. tuberculosis is a robust pathogen that has evolved the capacity to survive and grow inside macrophage phagosomes. A cocktail of antibiotics has long been successfully used against M. tuberculosis but is becoming less effective owing to the emergence of multidrug resistance. The only available preventive vaccine, using Mycobacterium bovis bacille Calmette-Guérin, is considered to be ineffective against adult pulmonary TB, the most prevalent form of the disease. Here, we review the potential use of biodegradable nanoparticle-based anti-TB drug delivery systems that have been shown to be more effective against M. tuberculosis in animal models than conventional antibiotic treatment regimens. This technology also has substantial potential for vaccination and other therapeutic strategies against TB and other infectious diseases.
| S-EPMC8826847 | biostudies-literature
Project description:ContextAlthough intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied.ObjectiveThe objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program.DesignThis was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT.ParticipantsSelected individuals with IGT randomized in the Diabetes Prevention Program participated in the study.InterventionsInterventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity.Main outcome measuresLipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured.ResultsILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance.ConclusionILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.
| S-EPMC3790618 | biostudies-literature