Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.

Metformin is a diabetes medication with anti-mitotic properties. A narrative review was performed to investigate people using metformin and the risk of developing pancreatic ductal adenocarcinoma (PDAC) as well as survival outcomes in established PDAC.

Relevant studies on metformin use and PDAC were retrieved from PubMed including observational studies on metformin and the risk of developing PDAC and survival outcomes in PDAC, and randomized controlled trials of metformin as a treatment in PDAC.

Of the 367 studies searched, 26 studies fulfilled the criteria for this review. Metformin was not consistently associated with a reduced risk of developing PDAC. However, metformin use, especially higher cumulative doses, in some studies was associated with longer survival in patients with established PDAC, especially in the subgroup with resectable PDAC. Metformin use was not associated with longer survival in more advanced (non-resectable metastatic) PDAC.

Metformin was not consistently associated with a reduced risk of developing PDAC. Metformin may be associated with overall survival benefits in patients with PDAC including the resectable PDAC subgroup but not in the metastatic PDAC subgroup. The evidence to date does not support the routine use of metformin as an adjuvant therapy for advanced PDAC.

The prevalence of colorectal cancer (CRC) is on the rise among the younger population, with an anticipated increase in new cases for individuals aged 20-49 years by 2030. The accessibility of community pharmacists and their strong community connections present unique opportunities to enhance patient engagement in a population-based CRC screening program.

This study seeks to assess the effectiveness of a community pharmacist-led point-of-care CRC screening program utilizing fecal immunochemical test (FIT) kits to identify CRC prevalence in high-risk individuals.

Over the course of a 10-month prospective intervention conducted in UAE community pharmacies, we evaluated the impact of a pharmacist-led point-of-care colorectal cancer screening program. Six pharmacies were selected based on their services and capabilities. Eligible participants were those identified during medication reviews as exhibiting colorectal cancer risk factors. Pharmacists provided communication materials, distributed FIT kits, and implemented reminders. Participants collected samples for hemoglobin analysis, which served as an indicator of colorectal bleeding. Collected data encompassed demographics, lifestyle, and health-related characteristics. Pharmacists performed medication reviews and offered recommendations.

A total of four hundred and one recruited int the study. The mean age of study cohort at baseline was 66.6 ± 11.3 years. In our study with 401 participants, 36.4 % had undiagnosed colorectal cancer (CRC). Univariate logistic regression identified older age, a history of Type 2 diabetes mellitus (DM), and inflammatory bowel disease (IBD) as significant factors associated with increased CRC prevalence, while aspirin users exhibited a lower likelihood of CRC. In the multivariate regression model, the history of Type 2 DM and IBD remained significant predictors for heightened CRC risk.

This study strengthens the plausibility of cause-and-effect relationships between colorectal cancer and demographic variables using epidemiological evidence. The significant relationships found between prevalence of CRC and age, type 2 diabetes, IBD and aspirin use support the effectiveness of using FIT kits in community pharmacist-led point-of-care CRC screening program to identify high-risk individuals. The finding highlights the significance of improving efforts on colorectal cancer prevention and control.

Despite the existence of promising outcomes from standard 2D culture systems, these data are not completely akin to in vivo tumor parenchyma. Therefore, the development and fabrication of various 3D culture systems can in part mimic intricate cell-to-cell interaction within the real tumor mass. Here, we aimed to evaluate the tumoricidal impacts of metformin (MTF) on colorectal cancer (CRC) tumoroids in an in vitro system via the modulation of autophagy.

CRC tumoroids were developed using human umbilical vein endothelial cells (HUVECs), adenocarcinoma HT29 cells, and fibroblasts (HFFF2) in a ratio of 1: 2: 1 and 2.5% methylcellulose. Tumoroids were exposed to different concentrations of MTF, ranging from 20 to 1000 mM, for 72 h. The survival rate was detected using an LDH release assay. The expression and protein levels of autophagy-related factors were measured using PCR array and western blotting, respectively. Using H & E, and immunofluorescence staining (Ki-67), the integrity and proliferation rate of CRC tumoroids were examined.

The current protocol yielded typical compact tumoroids with a dark central region. Despite slight changes in released LDH contents, no statistically significant differences were achieved in terms of cell toxicity in MTF-exposed groups compared to the control tumoroids, indicating the insufficiency of MTF in the induction of tumor cell death (p > 0.05). Western blotting indicated that the LC3II/I ratio was reduced in tumoroids exposed to 120 mM MTF (p < 0.05). These data coincided with the reduction of intracellular p62 content in MTF 120 mM-treated tumoroids compared to MTF 40 mM and control groups (p < 0.05). PCR array analysis confirmed the up-regulation, and down-regulation of several genes related to various signaling transduction pathways associated with autophagy machinery and shared effectors between autophagy and apoptosis in 40 and 120 mM MTF groups compared to the non-treated control group (p < 0.05). These changes were more prominent in tumoroids incubated with 120 mM MTF. Histological examination confirmed the loosening integrity of tumoroids in MTF-treated groups, especially 120 mM MTF, with the increase in cell death via the induction of apoptosis (chromatin marginalization) and necrotic (pyknotic nuclei) changes. In the 120 mM MTF group, spindle-shaped cells with the remnants of a fibrillar matrix were detected. Data indicated the reduction of proliferating Ki-67+ cells within the tumoroids by increasing the MTF concentration from 40 to 120 mM.

Different shared autophagy/apoptosis genes were modulated in CRC tumoroids after MTF treatment coinciding with both typical necrotic and apoptotic cells within the tumoroid structure. MTF can inhibit the integrity and proliferation of CRC tumoroids in dose-dependent manner.

Type 2 diabetes mellitus (T2DM) has been confirmed as an independent risk factor for colorectal cancer (CRC) in many studies. However, the mechanisms behind T2DM's role in the progression of CRC remain unclear. This study aims to explore the potential biomarkers and molecular mechanisms involved in T2DM-promoted CRC progression. The limma package was used to identify differentially expressed genes in tumor tissue from CRC patients with or without T2DM. The key biological processes were screened by gene ontology and gene set enrichment analysis. A diagnostic model for co-morbidities was constructed by logistic regression model with least absolute shrinkage and selection operator (Lasso) regularization method. The diagnostic performance was assessed by supplementing external datasets to draw ROC curves on the diagnostic model. The diagnostic model was further screened for key genes by prognostic analysis. The relationship of key genes with immune cells and other cells was evaluated by immune infiltration algorithm and single-cell transcription analysis. Drug prediction was performed by cMAP and the obtained drugs were molecularly docked with the key genes. The differentially expressed genes of T2DM-promoted CRC progression were mainly enriched to O-linked glycosylation-related processes. The diagnostic model constructed based on Lasso logistic regression had good diagnostic performance (AUC > 0.8). COX11 was the key gene for co-morbidities: in tumor tissues, COX11 expression was significantly higher than that in normal colon tissues. However, COX11 gene expression was significantly lower in patients with comorbidities than in patients without T2DM in tumor tissue. External datasets confirmed from both mRNA and protein expression levels that low COX11 expression was significantly associated with poor CRC prognosis. Immune infiltration analysis suggested that its expression related to the proportion of M2 macrophages. Single-cell transcriptome analysis revealed a close association of COX11 expression with endothelial cells and macrophages. The top4 drugs predicted bound well to COX11. Our study revealed that the pathogenesis of T2DM-promoted CRC progression related to O-linked glycosylation. We constructed a diagnostic model for T2DM-CRC co-morbidity. Meanwhile, we identified COX11 as a potential immune-related molecular marker closely associated with T2DM-promoted CRC progression. These mechanisms and molecular markers may provide new ideas for further studies of T2DM-promoted CRC progression and contribute to drug discovery for the treatment of co-morbidities.

The purpose of this study was to conduct a systematic review and meta-analysis to investigate the association between the utilization of metformin and the occurrence and survival rate of esophageal cancer (EC) in individuals with diabetes.

A systematic review and a meta-analysis were performed. Related literature was searched from databases, including PubMed, Embase, Web of Science, and Cochrane Library, covering the period from the inception of these databases until July 2023.

A total of 16 studies were eligible, including twelve reporting incidences of EC and four reporting OS of EC patients. The combined findings revealed a significant association between the use of metformin and a lower risk of EC (OR, 0.87, P = 0.04). Furthermore, metformin could significantly prolong the OS time (HR, 0.87, P = 0.002). In analyses stratified by treatment modalities, metformin combined with surgery and neoadjuvant chemoradiotherapy presented the strongest protective effect on EC patients with diabetes (HR, 0.38, P = 0.003).

Our meta-analysis indicated that the use of metformin might reduce the EC incidence and improve the OS in EC patients with diabetes.

Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust causal inference.

Mendelian randomization (MR) was used to evaluate the causal relationship between metformin and MTDS. Genetic variants associated with metformin's molecular targets were selected from GTEx, eQTLGen, and UK Biobank and validated using genetic colocalization to ensure instrument validity. GWAS summary statistics for MTDS, encompassing up to 314,193 controls and 6,847 colorectal cancer cases, were obtained from FinnGen and EBI. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode analyses. Bonferroni correction was applied to adjust for multiple testing across 14 cancer types.

Genetically proxied metformin use was associated with an increased risk of colorectal cancer (OR = 2.38, 95%CI = 1.38-4.09, P = 0.0018) and related subtypes. No causal relationship was found for hepatocellular carcinoma, gastric cancer, pancreatic cancer, or other digestive system cancers. The robustness of these findings was supported by sensitivity analyses, which indicated no significant pleiotropy, and leave-one-out tests.

This study provides robust genetic evidence that metformin use increases the risk of colorectal cancer, challenging its role as a preventive agent for digestive cancers. These findings emphasize the need for clinicians to carefully evaluate the risks and benefits of metformin, particularly in populations at higher risk for colorectal cancer. Future research should focus on delineating the mechanisms underlying this association to optimize the use of metformin in clinical practice.

Metformin, a widely used antihyperglycemic drug, has shown efficacy in treating type 2 diabetes mellitus (T2DM) and is associated with potential benefits beyond glycemic control. This study investigates the impact of metformin on mortality in T2DM patients using a prospective cohort design utilizing data from the National Health and Nutrition Examination Survey (NHANES).

In NHANES 1999-2014, a total of 5813 representative participants aged 20 and above with T2DM were included in the analysis. We utilized Kaplan-Meier survival curves and multivariate Cox regression analysis to investigate the impact of metformin on both all-cause mortality and cause-specific mortality among patients with T2DM.

Kaplan-Meier analysis showed a significant reduction in all-cause and cause-specific mortality in metformin users compared to non-users (p < 0.05). Multivariate Cox regression confirmed these findings, indicating that metformin use was associated with a 18% reduction in all-cause mortality (HR = 0.82, 95% CI = 0.73-0.92, p < 0.001) and 25% reduction in cardiovascular mortality (HR = 0.75, 95% CI = 0.60-0.94, p = 0.01).

Our results suggest that metformin significantly reduces all-cause and cardiovascular mortality in T2DM patients, highlighting its potential benefits beyond glycemic control. These results contribute to the existing literature by providing robust evidence from a large prospective cohort study. However, further research is needed to validate these findings and elucidate the underlying mechanisms controlling the effects of metformin on mortality outcomes in individuals with T2DM.

Pancreatic cancer has doubled over the previous two decades. Routine therapies are becoming incredibly resistant and failing to compensate for the burden caused by this aggressive neoplasm. As genetic susceptibility has always been a highlighted concern for this disease, identifying the molecular pathways involved in the survival and function of pancreatic cancer cells provides insight into its variant etiologies, one of which is the role of AMPK. This regulating factor of cell metabolism is crucial in the homeostasis and growth of the cell. Herein, we review the possible role of AMPK in pancreatic cancer while considering its leading effects on glycolysis and autophagy. Then, we assess the probable therapeutic agents that have resulted from the suggested pathways. Studying the underlying genetic changes in pancreatic cancer provides a chance to detect and treat patients suffering from advanced stages of the disease, and those who have given up their hope on conventional therapies can gain an opportunity to combat this cancer.

Prior research suggests metformin has anti-cancer effects, yet data are limited. We examined the association between diabetes treatment (metformin versus sulfonylurea) and risk of incident diabetes-related and non- diabetes-related cancers in US veterans. This retrospective cohort study included US veterans, without cancer, aged ≥ 55 years, who were new users of metformin or sulfonylureas for diabetes between 2001 to 2012. Cox proportional hazards models, with propensity score-matched inverse probability of treatment weighting (IPTW) were constructed. A total of 88,713 veterans (mean age 68.6 ± 7.8 years; 97.7% male; 84.1% White, 12.6% Black, 3.3% other race) were followed for 4.2 ± 3.0 years. Among metformin users (n = 60,476), there were 858 incident diabetes-related cancers (crude incidence rate [IR; per 1,000 person-years] = 3.4) and 3,533 non-diabetes-related cancers (IR = 14.1). Among sulfonylurea users (n = 28,237), there were 675 incident diabetes-related cancers (IR = 5.5) and 2,316 non-diabetes-related cancers (IR = 18.9). After IPTW adjustment, metformin use was associated with a lower risk of incident diabetes-related cancer (hazard ratio [HR] = 0.66, 95% CI 0.58-0.75) compared to sulfonylurea use. There was no association between treatment group (metformin versus sulfonylurea) and non-diabetes-related cancer (HR = 0.96, 95% CI 0.89-1.02). Of diabetes-related cancers, metformin users had lower incidence of liver (HR = 0.39, 95% CI 0.28-0.53), colorectal (HR = 0.75, 95% CI 0.62-0.92), and esophageal cancers (HR = 0.54, 95% CI 0.36-0.81). Among US veterans, metformin users had lower incidence of diabetes-related cancer, particularly liver, colorectal, and esophageal cancers, as compared to sulfonylurea users. Use of metformin was not associated with non-diabetes-related cancer. Further studies are needed to understand how metformin use impacts cancer incidence in different patient populations.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, primarily developing in the context of chronic liver disease. Traditional prevention has focused on liver-specific interventions like antiviral therapies and surveillance. However, extrahepatic factors also significantly contribute to HCC risk. This review explores comprehensive strategies for HCC prevention, including both hepatic and extrahepatic factors.

An extensive literature search of peer-reviewed articles up to October 2024 was conducted, focusing on studies addressing HCC prevention strategies. Studies that focused on both hepatic and extrahepatic factors were included. Data were extracted and synthesized to provide an overview of current prevention strategies and their effectiveness in reducing HCC incidence.

Hepatitis B vaccination and antiviral treatments for hepatitis B and C significantly reduce HCC incidence. Lifestyle modifications-such as reducing alcohol consumption, maintaining a healthy weight through diet and exercise, and smoking cessation-are crucial in lowering HCC risk. Environmental measures to limit exposure to aflatoxins and other hazards also contribute to prevention. Regular surveillance of high-risk groups enables early detection and improves survival rates. Emerging strategies like immunotherapy and gene therapy show potential for further reducing HCC risk.

A comprehensive approach combining medical interventions, lifestyle changes, and environmental controls is essential for effectively decreasing HCC incidence globally. Implementing these combined measures could significantly reduce the global burden of HCC.

Background Diabetes mellitus and cancer are two associated chronic diseases. Despite being a widely researched topic, the underlying mechanisms of this association remain unclear. One of the poorly explored topics regarding diabetes and cancer is the relation between the age of cancer onset and diabetes mellitus status; therefore, this research exposes the difference in the age of cancer diagnosis in both groups. Methods We conducted a retrospective study by reviewing the clinical files on a secondary care hospital's database. Files from first-time consultations of patients over 18 diagnosed using a histopathological report were included. The present study aimed to determine whether there is a difference in age at the onset of cancer in diabetic and non-diabetic individuals. Moreover, we calculated the average BMI at the onset for both populations. Results Our study included 8,741 patients; 1,551 (17.8%) were diabetic, and 7,190 (82.2%) were non-diabetic. From 28 types of cancer, 27 showed a difference in the age at the onset of cancer when diabetic and non-diabetic subjects were compared. This difference is significant as it suggests a potential link between diabetes and cancer, which could have implications for early detection and prevention strategies. Out of the 27 types, 17 showed statistical significance with p-values ranging from 0.048 to <0.0001 considering a 95% CI. Among those, the most significant types of cancer were breast, cervical, lung, ovarian, rectal, thyroid, and sarcoma, reporting p-values <0.0001. The mean age at onset of cancer in diabetic and non-diabetic populations was 62.7 years (SD ± 3.9) and 55.3 years (SD ± 7.9), respectively, showing a difference of 7.4 years in both groups. The BMI was statistically significant in patients with breast (p = 0.006), endometrial (p = 0.007), head and neck (p=0.014), and thyroid (p = 0.022) cancer types. Conclusion  The data offer a critical view of the relationship between cancer and diabetes. Since virtually no one has produced a similar report, there is a broad field for researching the causal factors implicated in the pathway of diabetic and non-diabetic individuals who develop cancer. Research regarding metformin, diabetic neuropathy, and other possible causes must be addressed to determine whether they are involved in this process.

Colorectal cancer (CRC) is one of the most common malignancies and the leading causes of cancer related deaths worldwide. The development of CRC is driven by a combination of genetic and environmental factors. There is growing evidence that changes in dietary nutrition may modulate the CRC risk, and protective effects on the risk of developing CRC have been advocated for specific nutrients such as glucose, amino acids, lipid, vitamins, micronutrients and prebiotics. Metabolic crosstalk between tumor cells, tumor microenvironment components and intestinal flora further promote proliferation, invasion and metastasis of CRC cells and leads to treatment resistance. This review summarizes the research progress on CRC prevention, pathogenesis, and treatment by dietary supplementation or deficiency of glucose, amino acids, lipids, vitamins, micronutri-ents, and prebiotics, respectively. The roles played by different nutrients and dietary crosstalk in the tumor microenvironment and metabolism are discussed, and nutritional modulation is inspired to be beneficial in the prevention and treatment of CRC.

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.

Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.

Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.

Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin's influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin's potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin's candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin's role in EC management, potentially improving patient care and outcomes.

Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021.

We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC.

Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control.

Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care.

This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to identify pertinent articles on metformin's use as an anti-cancer agent in HCC. Eleven studies were included, with five pre-clinical and six clinical studies. The mean overall survival (OS) and progression-free survival were both higher in the locoregional therapy (LRT) + metformin-treated groups. The outcome variables, including local tumor recurrence rate, reduction in HCC tumor growth and size, tumor growth, proliferation, migration and invasion of HCC cells, HCC cell apoptosis, DNA damage, and cell cycle arrest, showed favorable outcomes in the LRT + metformin-treated groups compared with LRT alone. This systemic review provides a strong signal that metformin use can improve the tumor response after locoregional therapy. Well-controlled prospective trials will be needed to elucidate the potential antitumor effects of metformin and other mTOR inhibitors.

Metformin users appear to have a substantially lower risk of cancer than nonusers in many observational studies. These inverse associations may be explained by common flaws in observational analyses that can be avoided by explicitly emulating a target trial.

We emulated target trials of metformin therapy and cancer risk using population-based linked electronic health records from the UK (2009-2016). We included individuals with diabetes, no history of cancer, no recent prescription for metformin or other glucose-lowering medication, and hemoglobin A1c (HbA1c) <64 mmol/mol (<8.0%). Outcomes included total cancer and 4 site-specific cancers (breast, colorectal, lung, and prostate). We estimated risks using pooled logistic regression with adjustment for risk factors via inverse-probability weighting. We emulated a second target trial among individuals regardless of diabetes status. We compared our estimates with those obtained using previously applied analytic approaches.

Among individuals with diabetes, the estimated 6-year risk differences (metformin - no metformin) were -0.2% (95% CI = -1.6%, 1.3%) in the intention-to-treat analysis and 0.0% (95% CI = -2.1%, 2.3%) in the per-protocol analysis. The corresponding estimates for all site-specific cancers were close to zero. Among individuals regardless of diabetes status, these estimates were also close to zero and more precise. By contrast, previous analytic approaches yielded estimates that appeared strongly protective.

Our findings are consistent with the hypothesis that metformin therapy does not meaningfully influence cancer incidence. The findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.

Humans age at different rates and families with exceptional longevity provide an opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of extended life span, compression of morbidity with resultant extension of health span, and longevity-associated biomarker profiles. These biomarkers, including low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels, are associated with functional genotypes that are enriched in centenarians, suggesting that they may be causative for longevity. While not all genetic discoveries from centenarians have been validated, in part due to exceptional life span being a rare phenotype in the general population, the APOE2 and FOXO3a genotypes have been confirmed in a number of populations with exceptional longevity. However, life span is now recognized as a complex trait and genetic research methods to study longevity are rapidly extending beyond classical Mendelian genetics to polygenic inheritance methodologies. Moreover, newer approaches are suggesting that pathways that have been recognized for decades to control life span in animals may also regulate life span in humans. These discoveries led to strategic development of therapeutics that may delay aging and prolong health span.

Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth.

To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients.

A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted.

A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31).

Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.

Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may not be long enough to capture the true effect of this medication on longevity.

We searched medical records for Wales, UK, using the Secure Anonymised Information Linkage dataset for type 2 diabetes patients treated with metformin (N = 129,140) and sulphonylurea (N = 68,563). Non-diabetic controls were matched on sex, age, smoking, and history of cancer and cardiovascular disease. Survival analysis was performed to examine survival time after first treatment, using a range of simulated study periods.

Using the full twenty-year period, we found that type 2 diabetes patients treated with metformin had shorter survival time than matched controls, as did sulphonylurea patients. Metformin patients had better survival than sulphonylurea patients, controlling for age. Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment.

While metformin does appear to confer benefits to longevity in the short term, these initial benefits are outweighed by the effects of type 2 diabetes when patients are observed over a period of up to twenty years. Longer study periods are therefore recommended for studying longevity and healthy lifespan.

Work examining the non-diabetes outcomes of metformin therapy has suggested that there metformin has a beneficial effect on longevity and healthy lifespan. Both clinical trials and observational studies broadly support this hypothesis, but tend to be limited in the length of time over which they can study patients or participants.

By using medical records we are able to study individuals with Type 2 diabetes over a period of two decades. We are also able to account for the effects of cancer, cardiovascular disease, hypertension, deprivation, and smoking on longevity and survival time following treatment.

We confirm that there is an initial benefit to longevity of metformin therapy, but this benefit does not outweigh the negative effect on longevity of diabetes. Therefore, we suggest that longer study periods are required for inference to be made about longevity in future research.

The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.

Colorectal cancer (CRC) is one of the deadliest forms of cancer worldwide. CRC development occurs mainly through the adenoma-carcinoma sequence, which can last decades, giving the opportunity for primary prevention and early detection. CRC prevention involves different approaches, ranging from fecal occult blood testing and colonoscopy screening to chemoprevention. In this review, we discuss the main findings gathered in the field of CRC chemoprevention, focusing on different target populations and on various precancerous lesions that can be used as efficacy evaluation endpoints for chemoprevention. The ideal chemopreventive agent should be well tolerated and easy to administer, with low side effects. Moreover, it should be readily available at a low cost. These properties are crucial because these compounds are meant to be used for a long time in populations with different CRC risk profiles. Several agents have been investigated so far, some of which are currently used in clinical practice. However, further investigation is needed to devise a comprehensive and effective chemoprevention strategy for CRC.

SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.

Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks.

To examine by an updated meta-analysis the association between these medications and HCC risk.

Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model.

Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2  = 0%).

Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.

We aim to evaluate the relationship between the use of metformin and the risk of pancreatic cancer in type 2 diabetes patients.

We systematically searched the observational studies on PubMed, Embase, Web of Science, Cochrane Library, clinicalrials.gov, and CNKI databases, extracted relevant data, combined the OR value and 95% CI using the random effect model, and conducted a sensitivity analysis, subgroup analysis, and meta-regression to evaluate the size and stability of this relationship.

Twenty-nine studies from twenty-four articles met our inclusion criteria, including more than 2 million subjects. Overall analysis showed that compared with no use of metformin, the use of metformin could reduce the risk of pancreatic cancer in patients with type 2 diabetes (OR = 0.82, 95% CI (0.69, 0.98)). Subgroup analysis showed that compared with the use of hypoglycemic drugs, the use of metformin could reduce the risk of pancreatic cancer in patients with type 2 diabetes (OR = 0.79, 95% CI (0.66, 0.94)). However, compared with no drugs or only diet therapy, metformin users might increase the risk of pancreatic cancer (OR = 2.19, 95% CI (1.08, 4.44)). Sensitivity analysis confirmed the stability of the study, and there was no significant publication bias.

Compared with the no-use of metformin, metformin users with diabetes can reduce the risk of pancreatic cancer. More research is needed to prove it works.

Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50-1.35, p = 0.436), OS (HR = 0.88, 95% CI: 0.74-1.04, p = 0.135), or DFS (HR = 1.03, 95% CI: 0.79-1.34, p = 0.829) between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use (HR = 0.65, 95% CI: 0.39-1.07, p = 0.089); notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration.

Cancer is one of the leading causes of death and the most important impediments to the efforts to increase life expectancy worldwide. Currently, chemotherapy is the main treatment for cancer, but it is often accompanied by side effects that affect normal tissues and organs. The search for new alternatives to chemotherapy has been a hot research topic in the field of antineoplastic medicine. Drugs targeting diseased tissues or cells can significantly improve the efficacy of drugs. Therefore, organelle-targeted antitumor drugs are being explored, such as mitochondria-targeted antitumor drugs. Mitochondria is the central site of cellular energy production and plays an important role in cell survival and death. Moreover, a large number of studies have shown a close association between mitochondrial metabolism and tumorigenesis and progression, making mitochondria a promising new target for cancer therapy. Combining mitochondrial targeting agents with drug molecules is an effective way of mitochondrial targeting. In addition, hyperpolarized tumor cell membranes and mitochondrial membrane potentially allow selective accumulation of mitochondria-targeted drugs. This enhances the direct killing of tumor cells by drug molecules while minimizing the potential toxicity to normal cells. In this review, we discuss the common pro-mitochondrial agents, the advantages of triphenylphosphine (TPP) in mitochondrial-targeted cancer therapy and systematically summarize various TPP-based mitochondria-targeting anticancer drugs.

Recently, attention has been paid to some medications and gastric cancer (GC) risk. This review aimed to evaluate associations between commonly used drugs and GC risk and to grade evidence from published systematic reviews and meta-analyses. This umbrella review was registered in PROSPERO (CRD42022320276). The systematic reviews and meta-analyses of observational studies were retrieved by searching Embase, PubMed, and Web of Science. The evidence strength of commonly used drugs and GC risk was categorized into four grades: weak, suggestive, highly suggestive, and strong. Of 19 associations between commonly used drugs and GC risk and its subtypes, none was supported by convincing or highly suggestive evidence. The risk of GC related to non-steroidal anti-inflammatory drugs (NSAIDs), non-aspirin NSAIDs, and acid-suppressive drugs, as well as the risk of non-cardia GC related to NSAIDs and aspirin, was supported by suggestive evidence. The results showed that a reduced GC risk was associated with two drug types (NSAIDs and non-aspirin NSAIDs), and an increased GC risk was associated with acid-suppressing drugs at the suggestive evidence level. Moreover, NSAIDs and aspirin reduced non-cardia GC risk as supported by suggestive evidence. However, the evidence supporting statins or metformin in reducing GC risk was weak, and thus future studies are required to clarify these associations.

The correlation of imbalanced gut microbiota with the onset and progression of colorectal cancer (CRC) has become clear. This work investigates the effect of metformin on gut microbiota and genesis of CRC in mice. Human fecal samples were collected from healthy control (HC) donors and CRC patients. Compared to HC donors, CRC patients had reduced abundance of gut microbiota; however, they had increased abundance of detrimental Bacteroidetes. Mice were injected with azomethane (AOM) to induce colorectal tumorigenesis models. Treatment of CRC patients-sourced fecal microbiota promoted tumorigenesis, and it increased the expression of Ki67, β-catenin, COX-2, and Cyclin D1 in mouse colon tissues. Further treatment of metformin blocked the colorectal tumorigenesis in mice. Fecal microbiota from the metformin-treated mice was collected, which showed decreased Bacteroidetes abundance and suppressed AOM-induced colorectal tumorigenesis in mice as well. Moreover, the metformin- modified microbiota promoted the M1 macrophage-related markers IL-6 and iNOS but suppressed the M2 macrophage-related markers IL-4R and Arg1 in mouse colon tissues. In conclusion, this study suggests that metformin-mediated gut microbiota alteration suppresses macrophage M2 polarization to block colorectal tumorigenesis.

Background: Epidemiologic studies have produced conflicting results on the effects of metformin on pancreatic cancer. This study aimed to observe and analyze whether metformin use is associated with better prognosis in pancreatic cancer. Materials and Methods: In this retrospective cohort study, all baseline data were retrieved from The Chinese Medicine Information Retrieval System (https://dc.wzhospital.cn/vpn/index.html) of The First Affiliated Hospital of Wenzhou Medical University. Survival data were collected by follow-up visits and medical records. Overall survival was the primary endpoint, while progression-free survival and disease-free survival were secondary endpoints. Progression or recurrence was assessed with radiologic images. Results: Seventy-six metformin users and 92 metformin nonusers diagnosed with pancreatic cancer from 2012 to 2020 in this hospital were enrolled. The adjusted hazard ratio for overall survival for metformin users was 0.50 (95% confidence interval = 0.33-0.76), where median overall survival was 16.0 months for metformin users versus 11.5 months for metformin nonusers. The protective effect was also found by analyzing progression-free survival (adjusted hazard ratio = 0.39, 95% confidence interval = 0.18-0.86) and disease-free survival (adjusted hazard ratio = 0.30, 95% confidence interval = 0.14-0.68). In the subgroup analysis, metformin use had a statistically significant association with prolongation of survival in stage I to II pancreatic cancer patients (hazard ratio = 0.47, 95% confidence interval = 0.25-0.91), but not for advanced tumor stage (hazard ratio for IV stage = 0.62, 95% confidence interval = 0.33-1.19), after adjustment for other risk factors. Conclusion: Metformin use is related to favorable survival outcomes of pancreatic cancer, especially in early tumor stage.

There have been conflicting reports concerning an increased risk of pancreatic cancer (PC) in new users of glucagon-like peptide-1 agonists (GLP-1As). We aimed to explore whether the use of GLP-1A is associated with an increased risk of PC.

A multicenter, retrospective cohort study was conducted using TriNetX. Adult patients with diabetes and/or overweight and obesity who were newly treated with GLP-1A or metformin for the first time between 2006 and 2021 were matched 1:1 using propensity score matching. The risk of PC was estimated using a Cox proportional hazards model.

A total of 492,760 patients were identified in the GLP-1A and 918,711 patients in the metformin group. After propensity score matching, both cohorts (370,490 each) were well matched. During follow-up, 351 patients in the GLP-1A and 956 on metformin developed PC after an exposure lag of 1 year. Glucagon-like peptide-1 agonists was associated with a significantly lower risk of PC (hazard ratio, 0.47; 95% confidence interval, 0.42-0.52).

The use of GLP-1A in patients with obesity/diabetes is associated with a lower risk of PC compared with a similar cohort of patients using metformin. Our study findings reassure clinicians and patients with apprehensions about any possible association between GLP-1A and PC.

Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.

Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.

Public attention and interest for longevity interventions are growing. These can include dietary interventions such as intermittent fasting, physical interventions such as various exercise regimens, or through supplementation of nutraceuticals or administration of pharmaceutics. However, it is unlikely that most interventions identified in model organisms will translate to humans, or that every intervention will benefit each person equally. In the worst case, even detrimental health effects may occur. Therefore, identifying longevity interventions using human data and tracking the aging process in people is of paramount importance as we look towards longevity interventions for the public. In this work, we illustrate how to identify candidate longevity interventions using population data in humans, an approach we have recently employed. We consider metformin as a case-study for potential confounders that influence effectiveness of a longevity intervention, such as lifestyle, sex, genetics, age of administration and the microbiome. Indeed, metformin, like most other longevity interventions, may end up only benefitting a subgroup of individuals. Fortunately, technologies have emerged for tracking the rate of 'biological' aging in individuals, which greatly aids in assessing effectiveness. Recently, we have demonstrated that even wearable devices, accessible to everyone, can be used for this purpose. We therefore propose how to use such approaches to test interventions in the general population. In summary, we advocate that 1) not all interventions will be beneficial for each individual and therefore 2) it is imperative that individuals track their own aging rates to assess healthy aging interventions.

Studies have demonstrated that metformin has antitumor effects in addition to therapeutic effects on hyperglycemia; however, few studies have explored the effects of metformin in chemotherapy. Therefore, we hypothesized that the administration of metformin would enhance the therapeutic effects of 5-fluorouracil and oxaliplatin (FuOx) to inhibit the growth of colorectal cancer (CRC) cells in vitro and in vivo. The results of our in vitro experiments demonstrated that metformin significantly increased the effects of FuOx with respect to cell proliferation (p < 0.05), colony formation (p < 0.05), and migration (p < 0.01) and induced cell cycle arrest in the G0/G1 phase in HT29 cells and the S phase in SW480 and SW620 cells (p < 0.05). Flow cytometry analysis revealed that metformin combined with FuOx induced late apoptosis (p < 0.05) by mediating mitochondria-related Mcl-1 and Bim protein expression. Furthermore, in vivo, metformin combined with FuOx more notably reduced tumor volume than FuOx or metformin alone did in BALB/c mice (p < 0.05). These findings demonstrate that metformin may act as an adjunctive agent to enhance the chemosensitivity of CRC cells to FuOx. However, further clinical trials are warranted to validate the clinical implications of the findings.

Diabetes Mellitus (DM) is both, correlated and a known risk factor for colorectal cancer (CRC). Besides favoring the incidence of CRC, DM also accelerates its progression, worsening its prognosis. Previously, hyperglycemia, the DM hallmark, has been shown to lead to aberrant glycosylation of CRC cells, heightening their malignancy both in vivo and in vitro. Here we use mass spectrometry to elucidate the composition and putative structures of N-glycans expressed by MC38 cultured in normoglycemic (LG) and hyperglycemic-like conditions (HG). N-glycans, 67, were identified in MC38 cells cultured in LG and HG. The cells grown in HG showed a greater abundance of N-glycans when compared to LNG cells, without changes in the proportion of sialylated, fucosylated and mannosylated N-glycans. Among the identified N-glycans, 16 were differentially expressed, mostly mannosylated and fucosylated, with a minority of them being sialylated. Metabolomics analysis indicates that the alterations observed in the N-glycosylation may be mostly due to increase of the activated monosaccharides pool, through an increased glucose entrance into the cells. The alterations found here corroborate data from the literature regarding the progression of CRC, advocating for development or repositioning of effective treatments against CRC in diabetic patients.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.

Hepatocellular carcinoma is one of the most common malignant tumors in the world. Although there are many options for the treatment of hepatocellular carcinoma, such as surgical resection, interventional therapy, radiotherapy, chemotherapy, targeted therapy and liver transplantation, the poor therapeutic effect seriously reduces the quality of life for patients and also increases the social and economic burden. Metformin is originally used as the first-line drug for type 2 diabetes, but it has been found to play a certain effect in the prevention and treatment of malignant tumor. The potential roles of metformin against hepatocellular carcinoma, such as regulation of the microenvironment, proliferation signal pathway, metabolism, invasion and metastasis, apoptosis, autophagy, and epigenetics of hepatoma cells. It provides a new choice for the prevention and treatment of hepatocellular carcinoma.

Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.