Developing structurally well-defined targeted drugs is an effective way to enhance the chemotherapy efficacy. Herein, a target mitochondrial complex I (complex I) inhibitor was developed for the key methylation site ARG-85 in the key subunit NDUFS2. Based on the unique :NH═C- group of guanidyl and the surrounding environment of ARG-85, the macrocyclic and bulky manganese porphyrin complex [MnIII(TTPPC2-)]+ was selected to insert into the gap of NDUFS2. Experimental and computational analyses revealed that the planar π system of the TTPPC2- ligand and the rotatable benzene ring stably bind between the :NH═C- group of ARG-85 and the manganese metal center, a medium-strong Lewis acid. The Mn-specific recognition of guanidine drives the selective inhibition of complex I activity. Further, MnIII(TTPPC2-)]+ was modified into targeted nanoformulation Mn NPs. In vitro and in vivo experiments confirmed the efficient and mechanism inhibition of complex I activity, offering a novel strategy for targeted drug development.

Metformin is a well-tolerated drug frequently prescribed for managing type 2 diabetes. Extended metformin use has been linked to a significant decrease in cancer incidence across both diabetic and non-diabetic populations. Here we investigate the anti-proliferative effects of metformin on fission yeast S. pombe. Our findings demonstrate that metformin's inhibitory impact on cell proliferation is effective in the absence of AMP-activated protein kinase (AMPK). Using an unbiased genetic screen we identified the plasma membrane signalling scaffold Efr3, critical for phosphatidylinositol signalling and the generation of PI4Ps, as a key determinant of resistance to the anti-proliferative effect of metformin. Deletion of efr3 resulted in both AMPK-dependent and AMPK-independent resistance to metformin. We show that Efr3 does not influence cell proliferation by controlling Ras1 activity or its cellular localization in yeast. We observe that dnm1 (DRP1) mutants with elongated mitochondria are also resistant to the anti-proliferative effect of metformin and that metformin treatment promotes mitochondrial fusion. Metabolic measurements after prolonged metformin exposure demonstrated a reduction in respiration in both wild type and the efr3 deletion, however, that reduction is less pronounced in the efr3 deletion, which also contained elongated mitochondria. It is likely that mitochondrial fusion enhances yeast fitness in response to metformin exposure. Together we provide a new perspective on the cellular response to metformin.

AMP-activated protein kinase (AMPK) is a central mediator of cellular metabolism and is activated in direct response to low ATP levels. Activated AMPK inhibits anabolic pathways and promotes catabolic activities that generate ATP through the phosphorylation of multiple target substrates. AMPK is a therapeutic target for activation in several chronic metabolic diseases, and there is increasing interest in targeting AMPK activity in cancer where it can act as a tumor suppressor or conversely it can support cancer cell survival. Small molecule AMPK activators and inhibitors have demonstrated some success in suppressing cancer growth, survival, and drug resistance in preclinical cancer models. In this perspective, we summarize the role of AMPK in cancer and drug resistance, the influence of the tumor microenvironment on AMPK activity, and AMPK activator and inhibitor development. In addition, we discuss the potential importance of isoform-selective targeting of AMPK and approaches for selective AMPK targeting in cancer.

Metformin has been shown to possess immune-modulating and anti-inflammatory effects in various animal and clinical studies. It is believed to be effective in treating some immune-mediated inflammatory diseases (IMIDs). However, there remains ongoing debate regarding the extent to which metformin can reduce the risk of developing IMIDs. We used the data from genome-wide association studies to explore the causal relationship between metformin treatment and some IMIDs through the Mendelian randomization (MR) analysis. Additionally, sensitivity analyses were performed using the Cochran Q-test, MR-PRESSO and "leave-one-out" to confirm the robustness of our conclusions. The MR analysis indicated that metformin treatment could reduce the risk of rheumatoid arthritis (RA) (OR = 0.018, 95% CI: 1.33 × 10-3-0.233, P = .002), multiple sclerosis (MS) (OR = 0.966, 95% CI: 0.936-0.997, P = .030) and primary sclerosing cholangitis (PSC) (OR = 6.82 × 10-4, 95% CI: 7.83 × 10-6-5.93 × 10-2, P = .001). But metformin treatment is not significantly associated with the risk of Crohn disease (OR = 0.994, 95% CI: 0.979-1.009, P = .431), ulcerative colitis (UC) (OR = 0.987, 95% CI: 0.965-1.009, P = .234), systemic lupus erythematosus (SLE) (OR = 164.373, 95% CI: 0.158-1.71 × 105, P = .150), autoimmune hepatitis (AIH) (OR = 2.909, 95% CI: 4.58 × 10-3-1.85 × 103, P = .746) and primary biliary cholangitis (PBC) (OR = 0.055, 95% CI: 1.44 × 10-3-2.112, P = .119). Due to the heterogeneity of the data from UC, SLE, MS, and PBC, we adjusted them. After adjustment, there is no change in the results for UC, SLE, MS, and PBC. The findings of this study support metformin treatment may reduce the risk of RA, MS, and PSC.

Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, HrasG12V cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and HrasG12V mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the HrasG12Vmodel. Using 13C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and HrasG12V mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.

Metformin is a first line treatment for type II diabetes. Cases of metformin-associated lactic acidosis are regularly reported. A direct causal link between metformin overdose and lactic acidosis is not clearly established. The aim of this study is to describe cases of metformin-associated lactic acidosis, to assess their vital et renal prognosis, and to analyze the correlations between metforminemia, lactacidemia, pH and death.

Cases of metformin-associated lactic acidosis from a single hospital center in Saint-Denis, France, between 2010 and 2022 were analyzed. Inclusion criteria were patients aged 18 or older, treated with metformin, metabolic acidosis with a pH inferior to 7.35 and lactacidemia superior to 5mmol/l.

Twenty-eight patients were included. Median age was 65 years old. Voluntary intoxication was present in 17% of cases. Metformin was contraindicated in 39% of cases. All patients presented with acute kidney injury at admission. Mortality rate was 7%. No factor was associated with death in the univariate analysis. Correlation between pH, lactacidemia, creatininemia and glycated hemoglobin was found. There was no correlation between metforminemia and lactacidemia.

Metformin-associated lactic acidosis is a rare complication. Its prognosis is inconstant, varying with the presence or absence of a severe disease causing the overdose. No association was found between clinical data, biological data and death.

Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M).

Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death.

Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.

The balance of redox states is crucial for maintaining physiological homeostasis. For decades, the focus has been mainly on the concept of oxidative stress, which is involved in the mechanism of almost all diseases. However, robust evidence has highlighted that reductive stress, the other side of the redox spectrum, plays a pivotal role in the development of various diseases, particularly those related to metabolism and cardiovascular health.

In this review, we present an extensive array of evidence for the occurrence of reductive stress and its significant implications mainly in metabolic and cardiovascular diseases.

Reductive stress is defined as a shift in the cellular redox balance towards a more reduced state, characterized by an excess of endogenous reductants (such as NADH, NADPH, and GSH) over their oxidized counterparts (NAD+, NADP+, and GSSG). While oxidative stress has been the predominant mechanism studied in obesity, metabolic disorders, and cardiovascular diseases, growing evidence underscores the critical role of reductive stress. This review discusses how reductive stress contributes to metabolic and cardiovascular pathologies, emphasizing its effects on key cellular processes. For example, excessive NADH accumulation can disrupt mitochondrial function by impairing the electron transport chain, leading to decreased ATP production and increased production of reactive oxygen species. In the endoplasmic reticulum (ER), an excess of reductive equivalents hampers protein folding, triggering ER stress and activating the unfolded protein response, which can lead to insulin resistance and compromised cellular homeostasis. Furthermore, we explore how excessive antioxidant supplementation can exacerbate reductive stress by further shifting the redox balance, potentially undermining the beneficial effects of exercise, impairing cardiovascular health, and aggravating metabolic disorders, particularly in obese individuals. This growing body of evidence calls for a reevaluation of the role of reductive stress in disease pathogenesis and therapeutic interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the "Drug of Miracles and Wonders," as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight.

Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.

Among women, breast cancer is one of the most prevalent cancers. The disease has a complex etiology, with multiple biological pathways contributing to its development. As insulin signaling has mitogenic effects, glucose is a necessary cellular metabolic substrate, and the growth and metastasis of breast cancer are closely related to cellular glucose metabolism. Anti-diabetic medications have drawn increased attention as a potential treatment for breast cancer. Metformin lowers cancer incidence and death rates in patients with type 2 diabetes, according to epidemiologic studies. Preclinical studies conducted in vivo and in vitro offer fascinating new insights into the cellular mechanisms underlying metformin oncostatic action. We present an overview of the mechanisms of anticancer effects of metformin and discuss its potential function as an adjuvant in the treatment of breast cancer.

Metformin has shown benefits in treating metabolic dysfunction-associated steatotic liver disease (MASLD), but its mechanisms remain unclear. This study investigates miR-200a-5p's role in the AMPK/SERCA2b pathway to reduce liver fat accumulation and ER stress in MASLD.

A PA cell model induced by palmitic and oleic acids (2:1) was used to assess lipid accumulation via Oil Red O and Nile Red staining. mRNA levels of miR-200a-5p and lipid metabolism genes were measured with RT-PCR, and AMPK, p-AMPK, and SERCA2b protein levels were analyzed by Western blotting. The interaction between miR-200a-5p and AMPK was studied using a luciferase reporter assay. A high-fat diet-induced MASLD mouse model was used to evaluate metformin's effects on liver steatosis and lipid profiles. Serum miR-200a-5p levels were also analyzed in MASLD patients.

In the PA cell model, elevated miR-200a-5p and lipid metabolism gene mRNA levels were observed, with decreased AMPK and SERCA2b protein levels. miR-200a-5p mimic reduced AMPK and SERCA2b expression. Metformin treatment reduced liver steatosis and lipid deposition in mice, normalizing miR-200a-5p, lipid metabolism gene mRNA, and AMPK/SERCA2b protein levels. Elevated serum miR-200a-5p was detected in MASLD patients.

These findings suggest that metformin alleviates lipid deposition and ER stress in MASLD through the modulation of the AMPK/SERCA2b pathway via miR-200a-5p.

Background/Objectives: Glycolysis and mitochondrial oxidative phosphorylation are the two major metabolic pathways for cellular ATP production. The metabolic plasticity displayed by cancer cells allows them to effectively shift between each of these pathways as a means of adapting to various growth conditions, thus ensuring their survival, proliferation and disease progression. Metabolic plasticity also provides cancer cells with the ability to circumvent many traditional monotherapies aimed at only one or the other of the major ATP-producing pathways. The purpose of this study was to determine the effectiveness of a dual treatment strategy aimed simultaneously at both pathways of ATP production in human breast cancer cells. It was hypothesized that concurrent exposure of these cells to the mitochondria-targeting chemotherapeutic agent, elesclomol, in combination with either of two glycolytic inhibitors, 2-deoxy-D-glucose or 3-bromopyruvate, would yield greater in vitro anticancer effects than those observed for any of the compounds used as a single agent. Methods: Cytotoxicity and clonogenic assays were employed to assess the survival and proliferation of MCF7 and MDA-MB-231 human breast adenocarcinoma cells exposed to the compounds alone and in combination. Results: The data obtained show that the cancer-cell-killing and antiproliferative effects of the dual treatment were significantly enhanced compared to those observed for any of the compounds alone. Conclusions: The results of this study are important in that they suggest the possibility of a novel and effective chemotherapeutic strategy for breast cancer cell killing.

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

Pathogen reduction technology (PRT)-treated apheresis platelets (APs) were returned without platelet swirl and with pH22°C < 6.2. The platelet donor was taking prescription levothyroxine and metformin plus over-the-counter medications and supplements. We hypothesized that either PRT or medication was causative.

One AP from a double AP collection from this donor was PRT-treated, the other unit untreated. Units were assessed over 7-day storage with a standard panel of platelet assays and metabolomics using high resolution mass spectrometry. The dose effect of metformin on platelets over storage was evaluated in vitro using APs obtained from non-medicated donors.

This donor's PRT- and non-PRT treated paired units had pH values <6.2 by the end of day 2. Lactate generation rates in the PRT- and non-PRT units were very high compared to previously reported values and approached that reported for anaerobic storage. Metabolomic analysis revealed impairments in a number of energy metabolic pathways between PRT- and non-PRT platelets; however, this did not support a major causative role of PRT in the significant upregulation of lactic acid production. Metformin caused a dose-dependent upregulation of glycolysis, resulting in pH decline.

We conclude that metformin is the most likely cause for this donor's stored platelet pH failures. Metformin is commonly used to treat type 2 diabetes and is not a donor deferral medication. Further investigation is indicated into the potential impact of metformin on platelet storage characteristics, the potential implications for medication deferral, and the need for additional screening tools in the laboratory.

This study focuses on the synthesis of Biguanide-PROTACs, formed by conjugating the biguanide motif with a spacer and a ligand for recognition subunits of two E3 ubiquitin ligases. Evaluation of their activity on pancreatic cancer cell (KP4) proliferation established a correlation between membrane permeability and median effective concentration. Mechanistic insights revealed that only two compounds exhibited biguanide-like AMPK activation, while only one hydrophobic compound uniquely altered mitochondrial protein levels. The prospect of developing and expanding the Biguanide-PROTAC library holds several promises, offering potential insights into biguanide mechanisms and the creation of more potent anticancer agents. This study contributes to understanding the intricate interplay between compound structure, permeability, and anticancer activity, paving the way for targeted drug development in pancreatic cancer treatment.

Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration-using glyceollin I, metformin, or phenformin-induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)-associated DNA repair genes. These serial events created so-called "BRCAness," in which cells exhibit an HR deficiency phenotype despite lacking germline mutations in HR genes such as BRCA1 and BRCA2, and, thus, sensitized the cancer cells to clinically available poly(ADP-ribose) polymerase inhibitors. The increase in lactate repressed HR-associated gene expression by decreasing histone acetylation. These effects were selective to breast cancer cells; normal epithelial cells retained HR proficiency and cell viability. These mechanistic insights into the BRCAness-prone properties of breast cancer cells support the therapeutic utility and cancer cell-specific potential of mitochondria-targeting drugs.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits.

This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors.

This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways.

In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Metformin (MTF) is a widely used oral antidiabetic medication. Regardless the reason, high doses of MTF cause lactic acidosis as a result of its effects on mitochondrial ATP production and no-mediated vascular smooth muscle relaxation. Metformin-associated lactic acidosis can be life-threatening despite all treatments. Methylene blue (MB) has the potential to reverse the toxic effects of MTF through its effects on both the mitochondrial respiratory chain and nitric oxide production. The use of MB in MTF intoxication has only been reported in a limited number of cases. Herein, we present a 16-year-old female patient who attempted suicide by ingesting high doses of MTF. Supportive treatments, such as vasopressor, inotropic treatments, and sodium bicarbonate, were started in the patient who developed fluid-resistant hypotension after pediatric intensive care unit admission. Because of rising lactate levels, Continuous renal replacement therapy (CRRT) was started immediately. Despite all treatments, hypotension and hyperlactatemia persisted; MB was given as a rescue therapy. Noticeable hemodynamic improvement was observed within 30 minutes of initiating MB infusion, allowing a gradual decrease in the doses of inotropic infusions within the first hour of therapy. Patient's cardiovascular support was discontinued on the second day, and she was discharged on the fifth day. We speculate that, considering the mechanisms of MTF toxicity and the mechanisms of action of MB, it is suggested that early administration of MB, not only as a rescue treatment but as the initial approach to MTF poisoning in combination with other treatments, may result in improved outcomes.

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Metformin, a safe biguanide derivative with antiproliferative properties, has shown antiparasitic efficacy against the Echinococcus larval stage. Hence, we assessed the efficacy of a dose of 250 mg kg-1 day-1 in experimental models of advanced CE, at 6 and 12 months post-infection with oral and intraperitoneal administration, respectively. At this high dose, metformin reached intracystic concentrations between 0.7 and 1.7 mM and triggered Eg-TOR inhibition through AMPK activation by AMP-independent and -dependent mechanisms, which are dependent on drug dose. Cystic metformin uptake was controlled by increased expression of organic cation transporters in the presence of the drug. In both experimental models, metformin reduced the weight of parasite cysts, altered the ultrastructural integrity of their germinal layers, and reduced the intracystic availability of glucose, limiting the cellular carbon and energy charge and the proliferative capacity of metacestodes. This glucose depletion in the parasite was associated with a slight increase in cystic uptake of 2-deoxiglucose and the transcriptional induction of GLUT genes in metacestodes. In this context, drastic glycogen consumption led to increased lactate production and altered intermediary metabolism in treated metacestodes. Specifically, the fraction of reducing soluble sugars decreased twofold, and the levels of non-reducing soluble sugars, such as sucrose and trehalose, were modified in both cystic fluid and germinal cells. Taken together, our findings highlight the relevance of metformin as a promising candidate for CE treatment and warrant further research to improve the therapeutic conditions of this chronic zoonosis in humans.

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.

The prevalence of type 2 diabetes (T2D) is increasing relentlessly all over the world, in parallel with a similar increase in obesity, and is striking ever younger patients. Only a minority of patients with T2D attain glycemic targets, indicating a clear need for novel antidiabetic drugs that not only control glycemia but also halt or slow the progressive loss of β-cells. Two entirely novel classes of antidiabetic agents-glucokinase activators and imeglimin-have recently been approved and will be the subject of this review.Allosteric activators of glucokinase, an enzyme stimulating insulin secretion in β-cells and suppressing hepatic glucose production, are oral low-molecular-weight drugs. One of these, dorzagliatin, is approved in China for use in adult patients with T2D, either as monotherapy or as an add-on to metformin. It remains to be seen whether the drug will produce sustained antidiabetic effects over many years and whether the side effects that led to the discontinuation of early drug candidates will limit the usefulness of dorzagliatin.Imeglimin-which shares structural similarities with metformin-targets mitochondrial dysfunction and was approved in Japan against T2D. In preclinical studies, the drug has also shown promising β-cell protective and preservative effects that may translate into disease-modifying effects.Hopefully, these two newcomers will contribute to filling the great medical need for new treatment modalities, preferably with disease-modifying potential. It remains to be seen where they will fit in contemporary treatment algorithms, which combinations of drugs are effective and which should be avoided. Time will tell to what extent these new antidiabetic agents will add value to the current treatment options against T2D in terms of sustained antidiabetic effect, acceptable safety, utility in combination therapy, and impact on hard end-points such as cardiovascular disease.

Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.

Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.

We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.

Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

AUTAC-Biguanide is a hybrid compound designed to target mitochondria, inducing their degradation by mitophagy. This study unveils the potential of biguanides as cancer cell-targeting agents, emphasizing AUTAC-Biguanide's superior antiproliferative properties compared to metformin and its selectivity for cancer cells. The mechanism behind this heightened effect includes the ability of AUTAC-Biguanide to trigger mitophagy. By providing a comprehensive analysis of these findings, this study adds valuable insights to the field of mitochondrial-targeting anticancer agents.

Cerebellar ataxia is a heterogeneous group of neural disorders clinically characterized by cerebellar dysfunction. The diagnosis of patients with progressive cerebellar ataxia is complex due to the direct correlation with other neuron diseases. Although there is still no cure for this pathological condition, some metabolic, hereditary, inflammatory, and immunological factors affecting cerebellar ataxia are being studied and may become therapeutic targets. Advances in studying the neuroanatomy, pathophysiology, and molecular biology of the cerebellum (CE) contribute to a better understanding of the mechanisms behind the development of this disorder. In this study, Wistar rats aged 30 to 35 days were injected intraperitoneally with 3-acetylpyridine (3-AP) and/or metformin (for AMP-activated protein kinase (AMPK) enzyme activation) and euthanized in 24 hours and 4 days after injection. We analyzed the neuromodulatory role of the AMPK on cerebellar ataxia induced by the neurotoxin 3-AP in the brain stem (BS) and CE, after pre-treatment for 7 and 15 days with metformin, a pharmacological indirect activator of AMPK. The results shown here suggest that AMPK activation in the BS and CE leads to a significant reduction in neuroinflammation in these regions. AMPK was able to restore the changes in fatty acid composition and pro-inflammatory cytokines caused by 3-AP, suggesting that the action of AMPK seems to result in a possible neuroprotection on the cerebellar ataxia model.

Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. In this article, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immunomodulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.

Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.

Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3β, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.

Mitochondria are semi-autonomous organelles present in several copies within most cells in the human body that are controlled by the precise collaboration of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoding mitochondrial proteins. They play important roles in numerous metabolic pathways, such as the synthesis of adenosine triphosphate (ATP), the predominant energy substrate of the cell generated through oxidative phosphorylation (OXPHOS), intracellular calcium homeostasis, metabolite biosynthesis, aging, cell cycles, and so forth. Previous studies revealed that dysfunction of these multi-functional organelles, which may arise due to mutations in either the nuclear or mitochondrial genome, leads to a diverse group of clinically and genetically heterogeneous disorders. These diseases include neurodegenerative and metabolic disorders as well as cardiac and skeletal myopathies in both adults and newborns. The plethora of phenotypes and defects displayed leads to challenges in the diagnosis and treatment of mitochondrial diseases. In this regard, the related literature proposed several diagnostic options, such as high throughput mitochondrial genomics and omics technologies, as well as numerous therapeutic options, such as pharmacological approaches, manipulating the mitochondrial genome, increasing the mitochondria content of the affected cells, and recently mitochondrial diseases transmission prevention. Therefore, the present article attempted to review the latest advances and challenges in diagnostic and therapeutic options for mitochondrial diseases.

Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4+T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.