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1.
J Ethnopharmacol ; 300: 115716, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36122792

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Mey (PG) is famous for "Qi-tonifying" effect, which has a medicinal history of more than 2 millennia. Modern pharmacology has confirmed that the "Qi-tonifying" effect of PG may be closely related to its pharmacological properties such as anti-oxidation, antineoplastic and treatment of cardiovascular disease. As one of the earliest cells affected by oxidative stress, RBCs are widely used in the diagnosis of diseases. Ginseng polysaccharide (GPS), is one of the major active components of PG, which plays an important role in resisting oxidative stress, affecting energy metabolism and other effects. However, the molecular mechanism explaining the "Qi-tonifying" effect of GPS from the perspective of RBCs oxidative damage has not been reported. AIM OF THE STUDY: This study aimed to investigate the protective effect of GPS on oxidatively damaged RBCs using in vitro and in vivo models and explore the molecular mechanisms from the perspective of glycolysis and gluconeogenesis pathways. To provides a theoretical basis for the future research of antioxidant drugs. MATERIALS AND METHODS: Established three different in vitro and in vivo research models: an in vitro model of RBCs exposed to hydrogen peroxide (H2O2) (40 mM), an in vivo model of RBCs from rats subjected to exhaustive swimming, and an in vitro model of BRL-3A cells exposed to H2O2 (25 µM). All three models were also tested in the presence of different concentrations of GPS. RESULTS: The findings showed that GPS was the most potent antagonist of H2O2-induced hemolysis and redox inbalance in RBCs. In exhaustive exercise rats, GPS ameliorated RBVs hemolysis, including reducing whole-blood viscosity (WBV), improving deformability, oxygen-carrying and -releasing capacities, which was related to the enhancing of antioxidant capacity. Moreover, GPS promoted RBCs glycolysis in rats with exhaustive exercise by recovering the activities of glycolysis-related enzymes and increasing band 3 protein expression, thereby regulating the imbalance of energy metabolism caused by oxidative stress. Furthermore, we demonstrated that GPS improved antioxidant defense system, enhanced energy metabolism, and regulated gluconeogenesis via activating PPAR gamma co-activator 1 alpha (PGC-1α) pathway in H2O2-exposed BRL-3A cells. Mechanistically, GPS promoted glycolysis and protected RBCs from oxidative injury was partly dependent on the regulation of gluconeogenesis, as inhibition of gluconeogenesis by metformin (Met) attenuates the regulation of antioxidant enzymes and key enzymes of glycolytic by GPS in exhaustive exercise rats. CONCLUSION: This study demonstrates that GPS protects RBCs from oxidative stress damage by promoting RBCs glycolysis and liver gluconeogenesis pathways. These results may contribute to the study of new RBCs treatments to boost antioxidant capacity and protect RBCs against oxidative stress.


Assuntos
Metformina , Panax , Animais , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Proteína 1 de Troca de Ânion do Eritrócito/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Eritrócitos , Gluconeogênese , Glicólise , Hemólise , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Metformina/farmacologia , Estresse Oxidativo , Oxigênio/metabolismo , PPAR gama/metabolismo , Polissacarídeos/farmacologia , Ratos
2.
J Ethnopharmacol ; 301: 115791, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36240976

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-zhenzhu-tiaozhi formula (FTZ) is a patented preparation of traditional Chinese medicine that has been used to treat hyperglycemia and hyperlipidemia in the clinic for almost 10 years. Our previous study had demonstrated that FTZ can protect islet ß cell injury in vitro. However, the efficacy of FTZ on ß cell regeneration in vivo and the involved anti-diabetic mechanism remains unknown. AIM OF THE STUDY: We aim to investigate the effects of FTZ as a good remedy for islet protection and ß cell regeneration, and to reveal the underlying mechanism. MATERIALS AND METHODS: C57BL/6 mice were fed with high-fat diet for 3 weeks and then intraperitoneally injected with streptozotocin (90 mg/kg/d × 1 d) to establish type 2 diabetes (T2D) models. Mice in each group were divided into three batches that sacrificed after 3, 7 and 28 days of FTZ administration. Body weight, blood glucose, and oral glucose tolerance test were measured at indicated time points. Fasting insulin was determined by enzyme-linked immunosorbent assay (ELISA) kit. Neonatal ß cell was assessed by insulin & PCNA double immunofluorescence staining, and the underlying mechanisms related to ß cell regeneration were further performed by hematoxylin-eosin staining, insulin & glucagon double immunofluorescence staining and Western blot. RESULTS: FTZ and metformin can significantly help with the symptoms of DM, such as alleviating weight loss, reducing blood glucose, improving the level of insulin in vivo, and relieving insulin resistance, suggesting FTZ and metformin treatment maintained the normal morphological function of islet. Notably, ß cell regeneration, which is indicated by insulin and PCNA double-positive cells, was promoted by FTZ, whereas few neonatal ß cells were observed in metformin group. Hematoxylin-eosin staining, and its quantification results showed that FTZ effectively prevented the invasion of inflammatory cells into the islets in diabetic mice. Most ß cells in the islets of diabetic model mice were devoid, and the islets were almost all α cells, while the diabetic mice administered FTZ could still maintain about half of the ß cells in the islet. Furthermore, FTZ upregulated the expression of critical transcription factors during ß cell development and maturation (such as PDX-1, MAFA and NGN3) in diabetic mice. CONCLUSIONS: FTZ can alleviate diabetes symptoms and promote ß cell regeneration in diabetic mice. Moreover, FTZ promotes ß cell regeneration by preserving islet (resisting inflammatory cells invading islets), maintaining the number of ß cells in islets, and increasing the expression of PDX-1, MAFA and NGN3.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Metformina , Camundongos , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Camundongos Endogâmicos C57BL , Insulina , Regeneração , Metformina/farmacologia
3.
Oncol Rep ; 49(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36367180

RESUMO

Lung cancer is the most common type of cancer and the leading cause of cancer­associated death worldwide. Despite the availability of various treatments such as surgery, chemoradiotherapy, targeted drugs and immunotherapy, treatment is expensive and the prognosis remains poor. At present, lung cancer drugs and treatment programs remain in a state of continuous exploration and research to improve the prognosis, and to reduce the pain and economic burden for the patients. Type 2 diabetes is a common chronic disease in middle­aged and elderly patients, leading to significantly increased complications of cardiovascular and cerebrovascular diseases. Epidemiology shows that type 2 diabetes also increases the incidence of malignant tumors, including lung, liver, colorectal and pancreatic cancer. Metformin is a biguanide, widely used as a first­line oral drug in treating type 2 diabetes. Metformin has a hypoglycemic effect and a biological antitumor impact, reducing the incidence of various tumors, including lung cancer, and improving the prognosis of patients with tumors. The anti­lung cancer effect of metformin involves a variety of mechanisms that can improve the therapeutic effect and prognosis of lung cancer, as a single drug or in combination with other therapies. The present study aims to review the associated literature and the therapeutic effects of metformin on lung cancer.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Pulmonares , Metformina , Neoplasias Pancreáticas , Idoso , Humanos , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/induzido quimicamente , Metformina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico
4.
Probl Endokrinol (Mosk) ; 68(5): 45-55, 2022 Jul 14.
Artigo em Russo | MEDLINE | ID: mdl-36337018

RESUMO

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


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Neoplasias , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neoplasias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Microambiente Tumoral
5.
Int J Oral Sci ; 14(1): 54, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36376276

RESUMO

As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase (PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling pathway. Collectively, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.


Assuntos
Metformina , Camundongos , Animais , Metformina/farmacologia , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Gluconeogênese/genética , Camundongos Knockout
6.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36361682

RESUMO

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide, showing a high fatality rate and recurrence due to diagnosis at an advanced stage of the disease and the occurrence of chemoresistance, which weakens the therapeutic effects of the chemotherapeutic treatments. In fact, although paclitaxel and platinum-based drugs (carboplatin or cisplatin) are widely used alone or in combination to treat ovarian cancer, the occurrence of chemoresistance significantly reduces the effects of these drugs. Metformin is a hypoglycemic agent that is commonly used for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease. However, this drug also shows anti-tumor activity, reducing cancer risk and chemoresistance. This review analyzes the current literature regarding the role of metformin in ovarian cancer and investigates what is currently known about its effects in reducing paclitaxel and platinum resistance to restore sensitivity to these drugs.


Assuntos
Antineoplásicos , Diabetes Mellitus Tipo 2 , Metformina , Neoplasias Ovarianas , Feminino , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Cisplatino/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
7.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36361684

RESUMO

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [18F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting KV1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Células T de Memória , Microambiente Tumoral , Neoplasias/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico
8.
Molecules ; 27(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36364022

RESUMO

Herb-drug interactions are vital in effectively managing type-2-diabetes complications. Puerarin is a natural isoflavonoid in the Pueraria genus, and its pharmacological activities, including antidiabetic activity, are well established. The similar modes of action of puerarin and metformin in diabetic models suggest their positive pharmacodynamic interactions. This study investigated this in streptozotocin/nicotinamide-induced type-2 diabetic rats. Puerarin at doses of 80 mg/kg, 120 mg/kg and 160 mg/kg improved the activity of metformin in reversing hyperglycaemia, dysregulated lipid profiles, dysfunction of the liver, kidney, and pancreas, and inflammation. The treatment with either puerarin (high dose, 160 mg/kg intraperitoneally) or metformin (100 mg/kg intraperitoneally) did not bring the dysregulated biomarkers to normal levels in 4 weeks. By contrast, the combination of puerarin (160 mg/kg) and metformin (100 mg/kg) did. This study is the first to report scientific evidence for the positive pharmacodynamic interactions between puerarin and metformin.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Isoflavonas , Metformina , Ratos , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações
9.
J Immunother Cancer ; 10(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36328378

RESUMO

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692). METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses. RESULTS: Increased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1. CONCLUSIONS: Our data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Metformina , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Células Matadoras Naturais , Citocinas/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/farmacologia
10.
J Adv Res ; 41: 205-218, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36328749

RESUMO

INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined. OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated ß-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.


Assuntos
Metformina , Músculo Liso Vascular , Animais , Músculo Liso Vascular/metabolismo , Senescência Celular/fisiologia , Metformina/farmacologia , Metformina/metabolismo , Proteômica , Proteína Supressora de Tumor p53/metabolismo , Estresse Oxidativo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Autofagia
11.
Biol Pharm Bull ; 45(11): 1716-1719, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36328507

RESUMO

We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels of free buformin and free metformin were not affected by mixtures of DFs, i.e., cellulose, chitosan, pectin (PE), and glucomannan (GM), in fluids of pH 1.2 and 6.8 (similar to the pH of the stomach and intestines, respectively). However, the free biguanide level was significantly reduced by mixing with PE or sodium alginate (AL), in water. The free glimepiride level was reduced in the mixture of AL, PE, and GM (in a solution with a pH of 6.8). The changes in aqueous AL solution pH seemed to reflect the free metformin levels. Therefore, the effects of DFs on free drug levels were dependent on drug type, hypoglycemic agent, and mixing solution. In this study, the oral regimen concentrations of the drug and DFs were used. Based on these results, it is important to consider the interactions between hypoglycemic agents and DFs.


Assuntos
Hipoglicemiantes , Metformina , Hipoglicemiantes/farmacologia , Buformina/farmacologia , Metformina/farmacologia , Fibras na Dieta/farmacologia
12.
Medicine (Baltimore) ; 101(45): e31635, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397350

RESUMO

Bladder cancer (BC) is a common type of cancer worldwide. Currently, the gold standard treatment is transurethral resection of bladder tumor (TUR-Bt) accompanied by intravesical Bacillus Calmette-Guérin (BCG) instillation for patients with middle-to-high-risk non-muscle-invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in almost 50% of high risk cases, leading to NMIBC persistence or early recurrence. In these patients, the gold standard remains radical cystectomy; however, it can seriously affect the patients' quality of life. Moreover, for patients with muscle-invasive bladder cancer (MIBC), the 5-year survival rate after radical cystectomy with neoadjuvant chemotherapy remains low. Recent discoveries have paved the way for a new era in BC treatment. Metformin is the most widely used oral hypoglycemic drug in clinical practice, being mostly used in the treatment of type 2 diabetes. Epidemiological studies have demonstrated that metformin exerts a potentially positive effect on reducing the incidence and mortality of cancer; therefore, a increasing number of studies have investigated the potential anticancer effects of metformin and its mechanisms of action. This review aims to summarize the evidence for the role of metformin in bladder cancer therapy, including how metformin mediates bladder cancer cell apoptosis.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias da Bexiga Urinária , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Metformina/farmacologia , Metformina/uso terapêutico , Qualidade de Vida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
13.
Ecotoxicol Environ Saf ; 247: 114233, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36334342

RESUMO

Nickel compounds, an international carcinogen in the industrial environment, increased the risk of lung inflammation even lung cancer in Ni refinery workers. Metformin has displayed the intense anti-inflammation and anti-cancer properties through regulating pyroptosis. This study was designed to explore whether Nickel-refining fumes (NiRF) can induce cell pyroptosis and how AMPK/CREB/Nrf2 mediated the protection afforded by metformin against Ni particles-induced lung impairment. Our results represented that Ni fumes exposure evoked pyroptosis via GOLPH3 and induced oxidative stress, while, metformin treatment alleviated Ni particles-mediated above changes. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) involved in the protection of metformin, and the deficiency of Nrf2 attenuated the beneficial protection. We also determined that Nrf2 was a downstream molecule of AMPK/CREB pathway. Furthermore, male C57BL/6 mice were administered with Ni at a dose of 2 mg/kg by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The results indicated that NiRF promoted GOLPH3 and pyroptosis by stimulating NLRP3, caspase-1, N-GSDMD, IL-18 and IL-1ß expression. However, various doses of metformin reduced GOLPH3 and the above protein levels of pyroptosis, also improved AMPK/CREB/Nrf2 expression. In summary, we found that metformin suppressed NiRF-connected GOLPH3-prompted pyroptosis via AMPK/CREB/Nrf2 signaling pathway to confer pulmonary protection.


Assuntos
Neoplasias Pulmonares , Metformina , Masculino , Camundongos , Animais , Camundongos Endogâmicos C57BL , Piroptose , Fator 2 Relacionado a NF-E2/genética , Metformina/farmacologia , Níquel/toxicidade , Proteínas Quinases Ativadas por AMP , Gases
14.
Eur Rev Med Pharmacol Sci ; 26(21): 8039-8056, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36394755

RESUMO

OBJECTIVE: Metformin, a medicine used for the treatment of type 2 diabetes, was previously reported to suppress age-dependent hyperproliferation of intestinal stem cells in Drosophila. Here, we aimed to investigate its anti-aging effects on other tissues, such as adult muscle and elucidate the mechanisms underlying the anti-ageing effect. MATERIALS AND METHODS: To evaluate the anti-muscle ageing effect of Metformin, we visualized ubiquitinated protein aggregates accumulated in adult muscle as the flies age by immunostaining and measured the total pixel size of the aggregates. We altered gene expression in the muscle by induction of dsRNA against the relevant mRNAs or mRNAs encoding the constitutively active mutant proteins using the Gal4/UAS system. We determined the mRNA levels by quantitative Real Time-Polymerase Chain Reaction (QRT-PCR). RESULTS: Continuous metformin feeding significantly extended the lifespan of Drosophila adults. Furthermore, the feeding suppressed the aging-dependent accumulation of ubiquitinated aggregates in adult muscle. To delineate the mechanism through which metformin influences the muscle aging phenotype, we induced the constitutively active AMPK specifically in the muscles and found that the activation of the AMPK-mediated pathway was sufficient for the anti-aging effect of Metformin. Furthermore, the AMPK-mediated downregulation of Tor-mediated pathways, subsequent induction of an eIF-4E inhibitor were involved in the effect. These genetic data suggested that the metformin effect is related to the partial suppression of protein synthesis in ribosomes. Furthermore, metformin stimulated autophagy induction in adult muscles. CONCLUSIONS: Our results suggest that metformin can be regarded as an anti-aging compound in Drosophila muscle. The stimulation of autophagy was also involved in the anti-aging effect, which delayed the progression of muscle aging in Drosophila adults.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Animais , Metformina/farmacologia , Drosophila/metabolismo , Adenilato Quinase , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento
15.
Cell Mol Biol Lett ; 27(1): 100, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401206

RESUMO

BACKGROUND: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. METHODS: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. RESULTS: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial-mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. CONCLUSIONS: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.


Assuntos
Antineoplásicos , Citostáticos , Metformina , Neoplasias da Próstata , Humanos , Masculino , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Taxoides/farmacologia , Taxoides/uso terapêutico , Citostáticos/farmacologia , Citostáticos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias da Próstata/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Estresse Fisiológico
16.
Front Endocrinol (Lausanne) ; 13: 927959, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187136

RESUMO

To assess and analyse the effectiveness and safety of combined Chinese herbal formula (CHF) and metformin treatment in the modulation of the gut microbiota in the amelioration of type 2 diabetes mellitus(T2DM), all publications addressing the effect of this combination treatment on the quantitative alterations in the gut microbiota and glucose parameters were collected. Rob tool in the Cochrane handbook was performed to evaluate the methodological quality of all included studies. Relevant information and statistics were abstracted and synthesized in Review Manager 5.4 to evaluate the efficacy of combination treatment. Sensitivity analyses and subgroup analyses were used to analyse the sources of heterogeneity. Publication bias analyses were performed by Stata software to assess the robustness and quality of the outcomes. As a result, a total of 12 eligible RCTs with 1307 T2DM participants from 7 electronic databases were included. Combined CHF with metformin treatment showed better efficacies than metformin monotherapy in regulating the structure of the gut microbiota, characterized by increased Bifidobacterium, Lactobacillus and Bacteroidetes and decreased Enterobacteriaceae, Enterococcus, and Saccharomyces along with better decreases in glycated haemoglobin, fasting plasma glucose, 2-hour postprandial blood glucose, fasting insulin and homeostasis model assessment of insulin resistance. Subgroup analyses further analysed the effect of metformin doses and CHF classifications on controlling hyperglycaemia and altering the gut microbiota. In conclusion, our meta-analysis suggested that combined CHF with metformin treatment is promising for the modulation of the gut microbiota along with ameliorating hyperglycemia in T2DM patients. Importantly, more well-designed RCTs are needed to validate the outcomes and verify the treatment value for clinical purposes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021291524, identifier CRD42021291524.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hiperglicemia , Metformina , Glicemia , China , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada , Humanos , Hiperglicemia/tratamento farmacológico , Insulina/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico
17.
J Mater Chem B ; 10(43): 8852-8855, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36278271

RESUMO

Herein, a viscosity-sensitive and hepatic-targeted NIR fluorescent probe has been developed for early diagnosis of hepatic fibrosis. Importantly, we observed increased liver viscosity upon CCl4-induced hepatotoxicity and decreased liver viscosity after metformin treatment, which confirmed its high clinical application prospects.


Assuntos
Cirrose Hepática , Metformina , Humanos , Viscosidade , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/diagnóstico por imagem , Corantes Fluorescentes/uso terapêutico , Metformina/farmacologia
18.
Mech Ageing Dev ; 208: 111743, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36279989

RESUMO

The strong evidence of metformin use in subjects affected by type 2 diabetes (T2DM) on health outcomes, together with data from pre-clinical studies, has led the gerontological research to study the therapeutic potential of such a drug as a slow-aging strategy. However, despite clinical use for over fifty years as an anti-diabetic drug, the mechanisms of action beyond glycemic control remain unclear. In this review, we have deeply examined the literature, doing a narrative review from the metformin story, through mechanisms of action to slow down aging potential, from lower organisms to humans. Based on the available evidence, we conclude that metformin, as shown in lower organisms and mice, may be effective in humans' longevity. A complete analysis and follow-up of ongoing clinical trials may provide more definitive answers as to whether metformin should be promoted beyond its use to treat T2DM as a drug that enhances both healthspan and lifespan.


Assuntos
Diabetes Mellitus Tipo 2 , Geriatria , Metformina , Humanos , Camundongos , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Longevidade , Envelhecimento , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico
19.
Sci Rep ; 12(1): 17084, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224264

RESUMO

Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1-control group, which received saline solution, 2-D-galactose (D-gal) group, which received D-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3-D-galactose + Metformin (D-gal + Met) treated group, which received D-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.


Assuntos
Galactose , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Galactose/farmacologia , Masculino , Metformina/farmacologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Solução Salina/farmacologia , Sinaptofisina/metabolismo
20.
Cell Commun Signal ; 20(1): 165, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284303

RESUMO

BACKGROUND: Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. RESULTS: In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. CONCLUSION: In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss. Video abstract.


Assuntos
Reabsorção Óssea , Metformina , Osteoporose Pós-Menopausa , Humanos , Camundongos , Feminino , Animais , Osteoclastos , Osteoporose Pós-Menopausa/metabolismo , Metformina/farmacologia , Reabsorção Óssea/tratamento farmacológico , Autofagia , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Diferenciação Celular , Ligante RANK/metabolismo , Fator de Transcrição E2F1/metabolismo
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