ARTICLE | doi:10.20944/preprints202212.0244.v2
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: breast cancer; diabetes; metformin
Online: 13 January 2023 (07:29:32 CET)
Background: Metformin is a drug used to treat patients with type 2 diabetes, especially those who suffer from obesity. It is also used in the treatment of women with polycystic ovary syndrome (PCOS). This disease has been shown to be related to insulin resistance and multiplied blood sugar ranges. Further, it has been found that the use of metformin improves the menstrual cycles and ovulation rates of these women. Methods: A structured questionnaire will be conducted to determine the prevalence of breast cancer among women using metformin in the Ha’il region. Result: Incidence of breast cancer among women using metformin in the Ha’il region is very low. Conclusions: According to previous findings, metformin has been linked to lower breast cancer risk in women with type 2 diabetes. Furthermore, the findings of this study have corroborated the literature for the same by indicating that there is a substantial connection between metformin use and a lower risk of breast cancer in women with type 2 diabetes
ARTICLE | doi:10.20944/preprints202009.0660.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: metformin cocrystal; mechanochemical synthesis; dicationic metformin; water channels; pi-interactions; mesoporous anhydrate
Online: 27 September 2020 (04:12:17 CEST)
A new cocrystal salt of metformin, an antidiabetic drug, and N,N’-(1,4-phenylene)dioxalamic acid, was synthesized by mechanochemical synthesis, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type cocrystal composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption-desorption analyses were performed to elucidate the structure of the molecular and supramolecurar structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar between them. To the best of our knowledge, the selective formation of the monoanion HpOXA⁻, as well as its structure in the solid, is herein reported for the first time. Regular O(-)∙∙∙C(), O(-)∙∙∙N+ and bifacial O(-)∙∙∙C()∙∙∙O(-) of n→* charge-assisted interactions are herein described in H2MfA cocrystal salts which could be responsible of the interactions of metformin in biologic systems. The results, support the participation of n→* charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.
ARTICLE | doi:10.20944/preprints202311.0687.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: Metformin; tendon injury; scar tissue
Online: 10 November 2023 (11:06:59 CET)
Tendon injuries, while prevalent, present a significant challenge in fully restoring their structural and functional integrity. Utilizing alpha-smooth muscle actin (α-SMA)-Ai9-scleraxis (Scx)-green fluorescent protein (GFP) transgenic mice, which exhibit both Scx (a tendon cell marker) and α-SMA (a myofibroblast marker), we explored Met's effects on tendon healing and repair and its mechanisms of action. Our findings revealed that intraperitoneal (IP) injections of Met -administered before or after injury, as well as both - effectively prevent the release of HMGB1 into the tendon matrix and reduce circulating levels of HMGB1. Additionally, Met treatment increased and activated AMPK and suppressed TGF-β1 levels within the healing tendon. These interventions also improved tendon healing by blocking the migration of α-SMA+ myofibroblasts, reducing the prevalence of disorganized collagen fibers and collagen type III, and enhancing the presence of collagen type I. These outcomes highlight Met's anti-fibrotic properties on acutely injured tendons and suggest its potential for repurposing as a therapeutic agent to minimize scar tissue formation in tendon injuries, which could have profound implications in clinical practice.
REVIEW | doi:10.20944/preprints202111.0531.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: brain tumors; glioblastoma; angiogenesis; metformin
Online: 29 November 2021 (12:30:08 CET)
Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.
ARTICLE | doi:10.20944/preprints202211.0068.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic cancer; metabolism; metformin; NAD; NAMPT
Online: 3 November 2022 (03:38:59 CET)
Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirm that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio turned PDAC cells resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cells xenografts but not in mice with PANC1 xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress providing new insights about the mechanisms leading to cancer cell death.
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Metformin; cerebralischemia-reperfusion; inflammation; PI3K/Akt.
Online: 12 March 2021 (08:43:06 CET)
Metformin（Met） is a commonly used drug in the treatment of type 2 diabetes. Currently, it has been found that Met can effectively reduce the incidence of stroke and exert anti-inflammatory effects. However, its role in ischemia-reperfusion (I/R) induced nerve injury remains unclear. This study aims to investigate the neuroprotective effects of Met in I/R-induced neuron injury as well as the underlying mechanism.A middle cerebral artery occlusion (MCAO) model was established in SD rats, which were then treated with different doses of Met.Neurological deficits of rats were measured at different times post-surgery. TTC staining to observe the volume of cerebral infarction.HE staining was performed to observe pathological changes of brain tissues .Immunohistochemistry was performed to observe the expression of inflammatory factors in the cerebral tissues .qRT-PCR method was used to detect the relative expression of PI3K、Akt mRNA in cells after 24 h of drug action.Western blot method was used to detect the expression of PI3K、p-PI3K、Akt and p-Akt in hippocampus.What’s more, in vitro experiments were performed on BV2 microglia to verify the role of Met against oxygen-glucose deprivation (OGD). As a result, Met dose-dependently attenuated neurological deficits and neuronal apoptosis. Besides, Met administration also significantly reduced BV2 cells apoptosis and inflammatory response. Mechanistically, Met inactivated PI3K/Akt pathway induced by I/R and OGD, while upregulated PI3K. In conclusion, Met protected rats from cerebral I/R injury via reducing neuronal apoptosis and microglial inflammation through PI3K/Akt pathway.
COMMUNICATION | doi:10.20944/preprints202304.1127.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: COVID-19; gut microbiota; diversity; diabetes; metformin
Online: 28 April 2023 (07:06:36 CEST)
The gut microbiota plays a crucial role in maintaining host health and has a significant impact on human health and disease. In this study, we investigated the alpha diversity of gut microbiota in COVID-19 patients and analyzed the impact of COVID-19 variants, antibiotic treatment, type 2 diabetes (T2D), and metformin therapy on gut microbiota composition and diversity. We used a culture-based method to analyze the gut microbiota and calculated alpha-diversity using the Shannon H' and Simpson 1/D indices. We collected clinical data, such as length of hospital stay (LoS), C-reactive protein (CRP) levels, and neutrophil-to-lymphocyte ratio (NLR). We found that patients with T2D had significantly lower alpha-diversity than those without T2D. Antibiotic use was associated with a reduction in alpha-diversity, while metformin therapy was associated with an increase. We did not find significant differences in alpha-diversity between the Delta and Omicron groups. Length of hospital stay, CRP levels, and NLR showed weak to moderate correlations with alpha diversity. Our findings suggest that maintaining a diverse gut microbiota may benefit COVID-19 patients with T2D. Interventions aimed at preserving or restoring gut microbiota diversity, such as avoiding unnecessary antibiotic use and promoting metformin therapy, may improve patient outcomes.
REVIEW | doi:10.20944/preprints202202.0353.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Diabetic; Chronic Kidney Disease; Metformin; Acidosis Lactate
Online: 28 February 2022 (09:28:33 CET)
Background: Diabetes Mellitus is a metabolite disorder with parameters of high blood sugar levels. In the management of diabetes can be used the drug metformin is the gold of choice to achieve a therapeutic effect and rarely causes side effects of the drug, but it still has debate view. However, if used in excessive doses for patients with kidney disease, it will be contraindicated with side effects such as lactic acidosis. Objective: This study aims to evaluate the side effect of Metformin for diabetic kidney diseases (DKD) patients. Method: This study used the Narrative Review Method that was obtained from 2011 to 2021, in the English language from PubMed, Google Scholar, and Cochrane Library. Results: Metformin is at the forefront of the treatment of type 2 diabetes mellitus (DM2). Metformin is likely to have lactic acidosis-related adverse effects in chronic kidney disease (CKD) patients, such as increased arterial lactate. Lactic acidosis is defined as an increase in arterial lactate with an indicator of more than five mmol/L and an arterial blood pH of less than 7.35. Metformin-induced lactate levels are considered to be below the parameters. DKD risk factors can be conceptually classified as several susceptibility factors, initiation factors, and developmental factors. The two most prominent risk factors are hyperglycemia and hypertension. Conclusion: Metformin can increase lactate levels in CKD patients but is still below the parameters of lactic acidosis. This study may have some weaknesses and requires further prospective research to validate the results.
ARTICLE | doi:10.20944/preprints202011.0373.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Magnesium supplementation; Metformin; INSR; GLU4; glucose tolerance
Online: 13 November 2020 (12:32:43 CET)
Magnesium supplementation has recently attracted attention as effective in the management of diabetes and its related complications though its mechanisms of action is yet to be fully unraveled. This study was carried out to determine the effects of magnesium supplementation on body weight, fasting blood sugar, Oral glucose tolerance (OGTT 2 and OGTT 4), glucose transporter isoform 2 (GLUT2), GLUT4 and insulin receptor (INSR) mRNA expressions in streptozotocin-nicotinamide induced diabetic Sprague dawley rats. A total of 24 Sprague dawley rats (Four groups of six rats each) were used for this study, and the treatment was for 28 days. Group 1: Normal control rats were given distilled water; Group 2: Metformin treated rats were given 100 mg/kg body weight; Group 3: Metformin + Magnesium treated rats were given 100 mg/kg and 1000 mg/kg body weight respectively; Group 4: Diabetic untreated rats given distilled water. Data were analyzed statistically using Analysis of Variance (ANOVA) and graphically by Graph pad prism. The GLUT4 and INSR gene expressions of Group 3 were significantly (p<0.05) upregulated when compared with Group 4. There was significant (p<0.05) decrease fasting blood sugar and GLUT2 mRNA level in the treated diabetic rats but the metformin-magnesium supplement treated group showed more decrease (p<0.05) when compared with the group treated with metformin only. This study demonstrates that magnesium may mediate effective metabolic control by stimulating insulin sensitivity, and upregulating mRNA levels of GLUT4, INSR as well as improving glucose tolerance in diabetic rats. Therefore, magnesium supplementation appears to have a beneficial role and improves glucose uptake by cells in those at high risks of diabetes. Magnesium supplementation, Metformin, INSR, GLU4, glucose tolerance.
ARTICLE | doi:10.20944/preprints201803.0184.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: colorectal cancer cells; metformin; apoptosis; oxidative stress
Online: 21 March 2018 (03:30:49 CET)
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anticancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM, for 24/48 hours. We performed immunofluorescence experiments by means of confocal microscopy and Western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by flow cytometry assay to detect the cell apoptosis rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of nuclear factor E2–related factor 2 (NRF-2) and nuclear factor–kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing, since metformin is emerging as a multifaceted drug: it has a good safety profile and is associated with low cost, and it might be a promising candidate for the prevention or treatment of colorectal cancer.
ARTICLE | doi:10.20944/preprints201611.0071.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: diabetes mellitus; metformin; glibenclamide and lipid profile
Online: 14 November 2016 (07:14:00 CET)
Diabetes mellitus (DM) has been defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. This study includes (84) subjects, their age ranged from (40 to 54) years. (20) subjects were healthy chosen as control group and (64) patients with type 2 diabetes mellitus were divided into three groups according to their type of anti diabetic therapy: (23) newly diagnosed group without therapy (Group1), (20) with metformin therapy (Group2) and (21) with metformin plus glibenclamide therapies (Group3). In the study lipid profile level were quantitatively determine by enzymatic methods, in addition to that fasting plasma glucose (FPG), Glycated hemoglobin (HbA1c%) and body mass index (BMI) were identified in the patients. There is significant increase in the level of lipid profile in patients group. Metformin alone produce a non-significant favorable effect on all lipids profile parameters while metformin plus glibenclamide showed a significant reduction in TC and LDL-C.
ARTICLE | doi:10.20944/preprints202310.1746.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: sensitization; adenosine monophosphate-activated protein kinase; metformin; cocaine
Online: 26 October 2023 (18:55:47 CEST)
Repeated cocaine produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsiv-ity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine. AMPK maintains cellular energy homeostasis at the organismal and cellular level. Here we first quanti-fied changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Rats were given cocaine (15 mg/kg, IP) or saline for six days with a challenge injection on day seven resulting in four groups: saline-saline, saline-cocaine, cocaine-saline, and cocaine-cocaine. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Other rats were pretreated with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensi-tization. Sex differences largely obscured protein level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated co-caine. These data inform our understanding of AMPK activation dynamics in subcellular com-partments and provide additional support for repurposing metformin for cocaine use disorder.
ARTICLE | doi:10.20944/preprints202307.1868.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: SLC22A1; OCT1; rs622342; rs72552763; METFORMIN; HbA1c; Glycaemic control
Online: 27 July 2023 (09:39:43 CEST)
This study reports on allelic and genotypic frequencies of OCT1, OCT2, OCT3 polymorphisms among metformin-treated DMT2 patients. It also reports the association with HbA1c control on 59 DMT2 patients. They were genotyped through real-time PCR (TaqMan assays). Metformin plasmatic levels were determined through mass spectrometry. Neither the analysis of HbA1c control by SNPs in SLC22A1, SLC22A2, and SLC22A3, nor the dominant genotypic model analysis yielded statistical significance across genotypes in polymorphisms rs72552763 (p=0.4678), rs622342 (p= 0.2215), rs316019 (p=0.2209), and rs2076828 (p=0.215). HbA1c levels were different in rs72552763 (p= 0.0220) and rs622342 (p=0.0093) genotypes. The dominant genotypic model found the lowest HbA1c levels by GAT/GAT (p= 0.0058) and A/A (p=0.0108), in rs72552763 and rs622342 respectively. We may conclude that rs72552763 and rs622342 polymorphisms in SLC22A1, exercise a relevant effect in metformin response determined by HbA1c levels among Mexican-Mestizo DMT2 patients.
ARTICLE | doi:10.20944/preprints202309.0773.v1
Subject: Biology And Life Sciences, Other Keywords: chitosan hydrogels; bladder cancer; metformin; intravesical administration; orthotopic model
Online: 12 September 2023 (11:47:59 CEST)
Our previous study found that intravesical perfusion metformin has excellent inhibitory effects against bladder cancer (BC). However, this administration route allows the drug to be diluted and excreted in urine. Therefore, increasing the adhesion of metformin to the bladder mucosal layer may prolong the retention time and increase the pharmacological activity. It is well known that chitosan (Cs) has a strong adhesion to the bladder mucosal layer. Thus, this study established a novel for-mulation of metformin to enhance its antitumor activity by extending its retention time. In this research, we prepared Cs freeze-dried powder and investigated the effect of metformin-loaded chitosan hydrogels (MLCH) in vitro and in vivo. The results showed that MLCH had a strong in-hibitory effect against proliferation and colony formation in vitro. The reduction in BC weight and expression of tumour biomarkers in orthotopic mice showed the robust antitumor activity of MLCH via intravesical administration in vivo. The non-toxic profile of MLCH was observed as well, using histological examinations. Mechanistically, MLCH showed stronger functional activation of the AMPK/mTOR signalling pathway compared with metformin alone. These findings highlighted the potential of this novel formulation as an efficient candidate for managing BC via intravesical ad-ministration.
ARTICLE | doi:10.20944/preprints202102.0577.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: carotid atherosclerosis; pre-diabetes mellitus; microRNAs; inflammation; metformin therapy
Online: 25 February 2021 (11:43:02 CET)
BACKGROUND AND PURPOSE—Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation of atherosclerotic plaque, favoring its conversion to unstable phenotype with rupture and MACE. Notably, the metformin therapy reducing the metabolic distress and the inflammatory burden, could lead to reduction of MACE in ACAS patients with pre-diabetes. In this setting, microRNAs (miRs) could be used as molecular biomarkers of atherosclerosis progression, plaque rupture and worse prognosis in normoglycemics (NG) vs. pre-diabetics metformin users (PDMU) vs. pre-diabetics non metformin users (PDNMU). However, the aim of our study was to investigate a wide miRNA panel in peripheral blood exosomes from patients with ACAS divided in NG vs. PDMU vs. PDNMU, and to associate the circulating miRNA expression profiles with MACE at 2 years of follow-up after endarterectomy. METHODS—The study included 234 patients with ACAS divided in NG (n 125), PDNMU (n 73) and PDMU (n 36). The miRs’ expression profiles of circulating exosomes were determined at baseline and at 2 years of follow-up by Affymetrix microarrays from plasma samples of the patients from any study cohort. Then we collected and analyzed MACE at 2 years of follow-up in NG vs. PDMU vs. PDNMU. RESULTS—prediabetics vs. NG had over-inflammation (p<0.05) and over expressed miR 24 and miR 27 at baseline. At 2 years of follow-up PDNMU vs. NG, PDMU vs. NG and PDNMU vs. PDMU over-expressed inflammatory markers and miR 24, miR 27, miR 100, miR 126 and miR 133 (p<0.05). Finally, at follow-up end we observed a significant difference about MACE comparing PDNMU vs. NG (n 27 (36.9%) vs. n 8 (6.4%); p<0.05), PDNMU vs. PDMU (n 27 (36.9%) vs. n 6 (16.6%); p <0.05), and PDMU vs. NG (n 6 (16.6%) vs. n 8 (6.4%); p<0.05). Admission glucose values (HR 1.020, CI 95% [1.001-1.038], p 0.029), atheromatous carotid plaque (HR 5.373, CI 95% [1.251-11.079], p 0.024), and miR 24 (HR 3.842, CI 95% [1.768-19.222], p 0.011) predicted MACE at 2 years of follow-up. CONCLUSIONS—Specific circulating miRs could be over-expressed in pre-diabetics and specifically in PDNMU vs. PDMU after endarterectomy. MiR24, hyperglycemia and atheromatous plaque could predict MACE at 2 years of follow-up.
ARTICLE | doi:10.20944/preprints202005.0016.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: COVID-19; elderly; proton pump inhibitors; antipsychotics; metformin; oral antidiabetics
Online: 2 May 2020 (15:48:33 CEST)
Background: COVID-19 is a disease of the elderly as 95% of deaths related to COVID-19 occur in people over 60 years of age. Despite the urgent need for a preventive treatment there are currently no serious leads, other than the vaccination. Objective: To find a preventive treatment of COVID-19 in elderly patients. Design: Retrospective case-control study. Setting: Robertsau Geriatric Hospital of the University Hospitals of Strasbourg, France. Patients: 179 elderly patients who had been in contact with the SARS-CoV-2, of whom 89 had tested RT-PCR-positive (COVID-pos) for the virus and 90 had tested RT-PCR-negative (COVID-neg). Measurements: Treatments within 15 days prior to RT-PCR (including antihypertensive drugs, antipsychotics, antibiotics, nonsteroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), paracetamol, anticoagulant, oral antidiabetics (OADs), corticosteroids, immunosuppressants), comorbidities, symptoms, laboratory values, and clinical outcome were all collected using the electronic patient record. Results: COVID-pos patients more frequently had a history of diabetes (P=.016) and alcoholism (P=.023), a lower leukocyte count (P=.014) and a higher mortality rate– 29.2% versus 14.4% – (P=.014) when compared to COVID-neg patients. Patients on PPIs were 2.3 times less likely (odds ratio [OR] = 0.4381, 95% confidence interval [CI] [0.2331, 0.8175], P=.0053) to develop COVID-19 infection, compared to those not on PPIs. No other treatment decreased or increased this risk. COVID-19 patients on antipsychotics (P=.0013) and OADs (P=.0166) were less likely to die. Limitations: retrospective study. Conclusion: PPIs treatment lowered the risk of development of COVID-19 infection, and antipsychotics and OADs decreased the risk of mortality in geriatric patients. If further studies confirm this finding, PPIs could be used preventatively in the elderly in this pandemic context. Moreover, OADS and antipsychotics should be tested in clinical trials.
ARTICLE | doi:10.20944/preprints202002.0124.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: glycemic variability; continuous glucose monitoring; dipeptidyl Peptidase-4 inhibitor; metformin
Online: 10 February 2020 (10:06:31 CET)
To cope the high glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) in diabetes. We compared the effect of low dose metformin 750mg/d adding vildagliptin 100mg/d (DPP4+LMET) or the high dose metformin 1500mg/d (HMET), in type 2 diabetes (T2D) with MDI, evaluating GV by continuous glucose monitoring (CGM). Single center, open-label, 12 weeks - 2 period crossover design. Twenty T2D with inadequately controlled (7.0% <HbA1c ≦9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM performed after each 12 weeks treatment periods. There was no significant difference in HbA1c, body weight changes, total daily dose of insulin. DPP4+LMET compared to the HMET, significantly reduced the calculated GV value, mean (7.15±1.3 vs 7.82±1.6, p<0.05), standard deviation (1.78±0.55 vs 2.27±1.11, p=0.03), continuous overlapping net glycemic action (6.44±1.28 vs 7.12±1.69, p<0.05), J-Index (26.7±11.0 vs 34.9±19.8, p<0.05), high blood glucose index (3.01±1.96 vs. 6.73±4.85, p=0.02), and mean amplitude of glycemic excursions (4.53±1.35 vs 5.50±2.34, p=0.03). The GV metrics with hypoglycemia and nocturnal hypoglycemia were not significantly different. DPP4+LMET decreased GV associated with hyperglycemia. Adding DPP4 inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI.
ARTICLE | doi:10.20944/preprints201807.0367.v1
Subject: Medicine And Pharmacology, Dentistry And Oral Surgery Keywords: nanoparticles; poly lactic-co-glycolic acid; metformin; periodontal disease; inflammation
Online: 20 July 2018 (03:40:29 CEST)
The aim of this study was synthesize and evaluate the effects of Poly (D, L-Lactide-co-glycolide) (PLGA) Nanoparticles (NPs) of metformin (PLGA+ Met) on inflammation, and bone loss in a ligature-induced periodontitis rat model. The prepared NPs were characterized by mean diameter, size particle, polydispensity index and encapsulation efficiency by Atomic force microscopy (AFM). Male albino Wistar rats were randomly divided into four groups of 20 rats in each group, and given the following treatments for 10 days to evaluate in vivo activity: (1) Sham: no ligature + water; (2) Positive control: ligature + water (with Periodontal disease and Diabetes); (3) ligature + PLGA+ 10 mg/kg Met (With Periodontal disease and Diabetes); and (4) ligature + PLGA+ 100 mg/kg Met (with Periodontal disease and Diabetes). Water or PLGA + Met was administered orally by gavage. Maxillae were fixed and scanned using Micro-computed Tomography (μCT) to quantify linear of bone loss. Histopathological characteristics were assessed through immunohistochemical staining for Osteocalcin, Cathepsyn K, RANKL/RANK/OPG pathway. IL-1β and TNF-α from gingival tissues were analysed by Elisa immunoassay. Quantitative RT-PCR reaction was used to evaluate gene expression of AMPK, NF-κB p-65, Hmgb1 and TAK-1 from gingival tissues. Statistical analysis was performed using one-way ANOVA at 5% significance. The mean diameter of MET-loaded PLGA nanoparticles was in a range of 457.1 ± 48.9 nm with a polydispersity index of 0.285, zeta potential: 8.16 ± 1.1 mV and entrapment efficiency (EE) was 70%. The results suggest that the addition of MET in the core slightly affected the particle sizes. Treatment with PLGA+ 10 mg/kg Met showed low inflammatory cells, decreased bone loss and integrity cement and levels of IL-1β, and TNF-α (p < 0.05) were significantly reduced. Additionally, weak staining was shown by RANKL, Cathepsyn K, OPG, and osteocalcin. Radiographically, linear measurements showed a statistically significant reduction in bone loss after treatment with PLGA+ 10 mg/kg Met compared to the positive control (p < 0.05). RT-PCR showed increased AMPK expression (p < 0.05) and decreased expression of NF-κB P65, HMGB1 and TAK-1 after PLGA+ 10 mg/kg Met (p < 0.05). The PLGA nanoparticle + 10 mg/kg Met decreased glucose levels and also decreased the inflammatory response, and bone loss in ligature-induced periodontitis in rats.
ARTICLE | doi:10.20944/preprints202310.1571.v2
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Transketolase; malonylation; acetylation; sirtuin 5; oxythiamine; metformin; amprolium; thiamine; posttranslational modifications
Online: 10 November 2023 (12:03:31 CET)
Transketolase (TKT) is an essential thiamine diphosphate (ThDP)-dependent enzyme of the non-oxidative branch of pentose phosphate pathway, with the glucose-6P flux through the pathway regulated in various medically important conditions. Here, we characterize the brain TKT regulation by acylation in rats with perturbed thiamine-dependent metabolism, known to occur in neurodegenerative diseases. The perturbations are modelled by administration of oxythiamine inhibiting ThDP-dependent enzymes in vivo, or by reduced thiamine availability in the presence of metformin and amprolium, inhibiting intracellular thiamine transporters. Compared to control rats, chronic administration of oxythiamine does not significantly change the modification level of the two detected TKT acetylation sites (K6 and K102), but doubles malonylation of TKT K499, concomitantly decreasing 1.7-fold the level of demalonylase sirtuin 5. The inhibitors of thiamine transporters do not change average levels of TKT acylation or sirtuin 5. TKT structures indicate that the acylated residues are distant from the active sites. The acylations-perturbed electrostatic interactions may be involved in conformational shifts and/or formation of TKT complexes with other proteins or nucleic acids. Acetylation of K102 may affect the active site entrance/exit and subunit interactions. Correlation analysis reveals that the action of oxythiamine is characterized by significant negative correlations of K499 malonylation or K6 acetylation with TKT activity, not observed upon the action of the inhibitors of thiamine transport. However, the transport inhibitors induce significant negative correlations between the TKT activity and K102 acetylation or TKT expression, absent in the oxythiamine group. Thus, perturbations in the ThDP-dependent catalysis or thiamine transport manifest in the insult-specific patterns of the brain TKT malonylation and acetylations.
ARTICLE | doi:10.20944/preprints202310.0508.v1
Subject: Biology And Life Sciences, Aging Keywords: C15:0; pentadecanoic acid; rapamycin; metformin; acarbose; longevity; essential fatty acid
Online: 9 October 2023 (10:53:44 CEST)
Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty acid with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK and inhibits mTOR, both of which are core components of the human longevity pathway. To assess the potential for C15:0 to enhance processes associated with longevity and healthspan, we used human cell-based molecular phenotyping assays to compare C15:0 with three longevity-enhancing candidates: acarbose, metformin, and rapamycin. C15:0 (n=36 activities in 10 of 12 cell systems) and rapamycin (n=32 activities in 12 of 12 systems) had the most clinically relevant, dose-dependent activities. At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFɑ, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.
ARTICLE | doi:10.20944/preprints201806.0091.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: metformin; pregnancy; gestational diabetes; polycystic ovarian syndrome; type 2 diabetes; obesity
Online: 6 June 2018 (12:09:00 CEST)
Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin for women with Polycystic Ovarian Syndrome and for non-diabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials.
ARTICLE | doi:10.20944/preprints202304.0607.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Metformin; HIV transcription and replication; transactivation; gene expression; CREB phosphorylation; HIV LTR promoter
Online: 20 April 2023 (05:24:55 CEST)
Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production though increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV.
ARTICLE | doi:10.20944/preprints202106.0624.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Esophageal squamous cell carcinoma; Metformin; Long noncoding RNAs; CCAT1; SPRY4-IT1; c-Myc
Online: 25 June 2021 (12:41:51 CEST)
Evidence indicates that the long noncoding RNAs are involved in the metformin-mediated anti-cancer processes. However, the potential effects of the long noncoding RNAs in metformin-mediated anti-tumor processes in esophageal squamous cell carcinomas (ESCC) are still elusive. This study uncovered that metformin decreases the level of long noncoding RNAs CCAT1 and SPRY4-IT1 thereby contributing to the down-regulation of c-Myc and vimentin. Also, the RNA level test of human ESCC tissue confirmed the positive correlation between CCAT1 and c-Myc. These findings demonstrated that metformin facilitated anti-cancer effects by targeting the 2 long noncoding RNAs (CCAT1 and SPRY4-IT1) and their consequential targets c-Myc and vimentin. Therefore, the CCAT1 and SPRY4-IT1 might act as novel molecular targets that mediate the anti-tumor effects in esophageal squamous cell carcinoma. This helps in predicting the treatment response of metformin in patients diagnosed with esophageal squamous cell carcinoma.
ARTICLE | doi:10.20944/preprints202102.0443.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: critical sized bone defect; bone tissue regeneration; nano-gelatin/ hydroxyapatite fiber (NGF); metformin.
Online: 19 February 2021 (14:35:11 CET)
Tissue engineering and regenerative medicine has gradually evolved as a promising therapeutic strategy to the modern healthcare of the aging and diseased population. In this study, we developed a novel nano-fibrous scaffold and verified its application in the critical bone defect regeneration. The metformin-incorporated nano-gelatin/hydroxyapatite fibers (NGF) was produced by electrospinning, cross-linked, and then characterized by XRD and FTIR. Cytotoxicity, cells adhesion, cell differentiation, and quantitative osteogenic gene and protein expression were analyzed by bone marrow stem cells from rat. Rat forearm critical bone defect model was performed for the in vivo study. The nano-gelatin/hydroxyapatite fibers (NGF) were characterized by their porous structures with proper interconnectivity without significant cytotoxic effects; the adhesion of bone marrow stem cells on the nano-gelatin/hydroxyapatite fibers (NGF) could be enhanced. The osteogenic gene and protein expression were upregulated. Post implantation, the new regenerated bone in bone defect was well demonstrated in the NGF samples. We demonstrated that the metformin-incorporated nano-gelatin-hydroxyapatite fibers greatly improved healing potential on the critical sized bone defect. Although metformin-incorporated nano-gelatin/hydroxyapatite fibers had advantageous effectiveness during bone regeneration, further validation is required before it can be applied to clinical applications.
REVIEW | doi:10.20944/preprints201809.0360.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: p-21 activated kinase; pioglitazone, metformin, type 2 diabetes mellitus, cancer, chemoprevention, and inflammation.
Online: 19 September 2018 (00:50:05 CEST)
Hypothesis: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here we performed a mini-meta analysis to explore if anti-diabetic drugs modify PAK signaling pathways, and provide insight regarding modulation of these pathways to potentially reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. Mini meta analysis correlated multiple clinical studies and revealed the overall clinical response rate and percentage of adverse events in piogliazone (n=53) and metformin (n=91) treated patients with PAK-associated diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance) which were highly associated with Wnt, and G-protein signaling. Anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall clinical response upon pioglitazone treatment was 53%. 79% of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM likely involves Wnt and G-protein signaling which may be altered by anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone may be promising in chemoprevention, however long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.
REVIEW | doi:10.20944/preprints201808.0403.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: p-21 activated kinase; pioglitazone, metformin, type 2 diabetes mellitus, cancer, chemoprevention, and inflammation.
Online: 23 August 2018 (05:10:55 CEST)
Hypothesis: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here we explored whether PAK signaling should be targeted via chemoprevention to reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using online STRING database. Systematic literature review provided the effect of anti-diabetic drugs on PAK signaling. Review of clinical studies revealed the overall clinical response rate and percentage of adverse events in piogliazone (n=53) and metformin (n=91) treated patients with PAK-dependent diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance) which were highly associated with Wnt, and G-protein signaling. Anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall clinical response upon pioglitazone treatment was 53%. 79% of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM involves Wnt and G-protein signaling which is altered by anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone is promising in chemoprevention, however long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.
ARTICLE | doi:10.20944/preprints202304.0914.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Metformin; Quorum sensing; Quorum quenching; Pseudomonas aeruginosa; Virulence; Drug repurposing; Anti-virulence therapy; Biofilm inhibition
Online: 25 April 2023 (09:54:20 CEST)
Metformin (MeT) is an FDA-approved drug with a myriad of health benefits. Besides being used as an anti-diabetic drug, MeT is also effective against various cancers, liver-, cardiovascular-, and renal diseases. It has also been proven to demonstrate anti-ageing and neuroprotective effects. This study was undertaken to examine its unique potential as an anti-virulence drug against an opportunistic bacterial pathogen, Pseudomonas aeruginosa. Due to the menace of multidrug resistance in pathogenic microorganisms, many novel or repurposed drugs with anti-virulence prospects are emerging as next-generation therapies with the aim to overshadow the application of existing antimicrobial regimens. The quorum sensing (QS) mechanisms of P. aeruginosa are an attractive drug target for attenuating bacterial virulence. In this context, the anti-QS potential of MeT was scrutinized using biosensor assays. MeT was comprehensively evaluated for its effects on different motility phenotypes, virulence factor production (phenotypic and genotypic expression) along with biofilm development in P. aeruginosa in vitro. At sub-lethal concentrations, MeT displayed prolific quorum quenching (QQ) ability and remarkably inhibited AHL biosynthesis in P. aeruginosa. Moreover, MeT (1/8 MIC) effectively downregulated the expression levels of various QS- and virulence genes in P. aeruginosa, which coincided with a notable reduction in the levels of alginate, hemolysin, pyocyanin, pyochelin, elastase, and protease production. In silico analysis through molecular docking also predicted strong associations between the QS receptors of P. aeruginosa and MeT. MeT also compromised the motility phenotypes and successfully abrogated biofilm formation by inhibiting EPS production in P. aeruginosa. Hence, the QQ, anti-virulence, and anti-fouling potential of MeT was elucidated for the first time against P. aeruginosa.
REVIEW | doi:10.20944/preprints202310.0576.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: methylglyoxal; glyoxalase; advanced glycation end products; MG-H1, metabolic syndrome; insulin resistance, diabetes mellitus; cardiovascular disease; metformin; methylglyoxal scavengers
Online: 10 October 2023 (12:31:23 CEST)
Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation followed by deleterious effects at the cellular and systemic level is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders including metabolic syndrome, diabetes mellitus and cardiovascular diseases. In this review an interplay between pathways leading to MGO generation and scavenging is addressed, in regard to this system’s impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.
REVIEW | doi:10.20944/preprints202307.1299.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: guanidene,metformin, diabetes mellitus type 2, vomit, diarrhea acidosis loss of body weight laxatives, malabsorption,anemia, dehydration,kidney injury
Online: 19 July 2023 (08:39:14 CEST)
After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany and the retraction of phenformin (N-Phenethylbiguanide) because of the letal complication of acidosiss,metformin (1-1-dimethylbiguanide) was first released in France in 1959 and then in the USA in 1995 for oral treatment of diabetes type 2. Acute gastrointestinal side effects often lead to dose reduction and strongly limit adherence to therapy.Main long-term consequences are deficency of vitamin B12 and of iron and sometimes also acidosis development. Intravenously injected F18-labelled glucose in metformin-treated type 2 diabetics accumulates in the the small and even more in the large intestine.The densitometry picture observed in metformin-treated diabetics is similar to that observed in patients after bowel-cleansing or chronically taking different types of laxatives where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to „attraction“ of glucose from the hepatocyte to the intestine,possibly through its secretion into the bile.Metformin is not different from the other biguanides ,synthalin B and phenformin.The mechanism of action,and the side effects are comparable to those of laxatives.
ARTICLE | doi:10.20944/preprints202107.0484.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: metformin; Natural Killer cells; Cytotoxic T lymphocytes; intercellular adhesion molecule-1 (ICAM-1); Natural Killer G2-D (NKG2D) ligands (NKG2DL); lymphocyte function-associated antigen 1 (LFA-1)
Online: 21 July 2021 (10:54:14 CEST)
Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.
REVIEW | doi:10.20944/preprints202101.0626.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: BTB and CNC homology 1 BACH1; mitochondrial metabolism; glycolysis; heme oxygenase 1 (HMOX1); mitochondrial electron transport chain (ETC); Nrf2 (encoded by Nfe2l2); metformin; hemin; breast cancer; lung cancer
Online: 29 January 2021 (13:57:41 CET)
BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.