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Clinical & Translational Immunology 2024Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their...
OBJECTIVE
Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory-like differentiation in bacterial infections remains elusive.
METHODS
Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory-like NK cell formation and function in response to the Gram-negative intracellular bacteria (BP), the causative agent of melioidosis.
RESULTS
We demonstrate that CD160 memory-like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3-month post-hospital admission. Using an assay, human BP-specific CD160 memory-like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re-stimulation. Antigen-specific and cytokine-induced IFN-γ production of this memory-like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160 memory-like NK cells is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.
CONCLUSION
This study reveals the link between metabolism and cellular function of memory-like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram-negative bacterial infection.
PubMed: 38957437
DOI: 10.1002/cti2.1513 -
Endocrine, Metabolic & Immune Disorders... Jul 2024Type 2 Diabetes Mellitus (T2DM) represents a significant and pressing worldwide health concern, necessitating the quest for enhanced antidiabetic pharmaceuticals....
BACKGROUND
Type 2 Diabetes Mellitus (T2DM) represents a significant and pressing worldwide health concern, necessitating the quest for enhanced antidiabetic pharmaceuticals. Guanidine derivatives, notably metformin and buformin, have emerged as pivotal therapeutic agents for T2DM management.
AIMS
The present study introduces an efficient one-pot synthesis method for the production of symmetrical guanidine compounds.
METHODS
This synthesis involves the reaction of isothiocyanates with secondary amines, employing an environmentally friendly and recyclable reagent, tetrabutylphosphonium tribromide (TBPTB).
RESULTS
A comprehensive assessment of the biological activity of the synthesized guanidine compounds, specifically in the context of T2DM, has been rigorously conducted.
CONCLUSION
Additionally, computational analyses have unveiled their substantial potential as promising antidiabetic agents. Results highlight the relevance of these compounds in the ongoing pursuit of novel therapeutic solutions for T2DM.
.PubMed: 38956919
DOI: 10.2174/0118715303287962240621053459 -
Journal of Ovarian Research Jul 2024This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR)...
INTRODUCTION
This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR) before and after metformin treatment, and aimed to identify bacterial taxa within EVs that were biologically and statistically significant for diagnosis and treatment.
METHODS
The case-control study was conducted at Xiamen Chang Gung Hospital, Hua Qiao University. Plasma samples were collected from five PCOS-IR patients of childbearing age before and after 3 months of metformin treatment, and the samples were sequenced. The diversity and taxonomic composition of different microbial communities were analyzed through full-length 16 S glycosomal RNA gene sequencing.
RESULTS
After metformin treatment, fasting plasma glucose levels and IR degree of PCOS-IR patients were significantly improved. The 16 S analysis of plasma EVs from metformin-treated patients showed higher microbial diversity. There were significant differences in EVs derived from some environmental bacteria before and after metformin treatment. Notably, Streptococcus salivarius was more abundant in the metformin-treated group, suggesting it may be a potential probiotic.
DISCUSSION
The study demonstrated changes in the microbial composition of plasma EVs before and after metformin treatment. The findings may offer new insights into the pathogenesis of PCOS-IR and provide new avenues for research.
Topics: Humans; Polycystic Ovary Syndrome; Metformin; Female; Extracellular Vesicles; Insulin Resistance; Adult; Case-Control Studies; Hypoglycemic Agents; Young Adult
PubMed: 38956672
DOI: 10.1186/s13048-024-01444-x -
Stem Cell Research & Therapy Jul 2024Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation...
BACKGROUND
Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation.
METHODS
MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography.
RESULT
Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator.
CONCLUSIONS
In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.
Topics: Mesenchymal Stem Cells; Autophagy; Mitochondria; Adenine; Humans; Nanotubes; Apoptosis; Animals; Metformin; Cells, Cultured; Wnt Signaling Pathway; Cell Membrane Structures
PubMed: 38956646
DOI: 10.1186/s13287-024-03813-1 -
Bone & Joint Research Jul 2024The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule...
AIMS
The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.
METHODS
Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro.
RESULTS
The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 () in WT mouse cells.
CONCLUSION
Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis.
PubMed: 38955349
DOI: 10.1302/2046-3758.137.BJR-2023-0384.R1 -
Journal of Complementary & Integrative... Jul 2024This study investigated the antidiabetic effects of the methanolic extract of (MEEA) stem bark on streptozotocin (STZ)-induced diabetic nephropathy (DN) in Wistar rats.
OBJECTIVES
This study investigated the antidiabetic effects of the methanolic extract of (MEEA) stem bark on streptozotocin (STZ)-induced diabetic nephropathy (DN) in Wistar rats.
METHODS
The enzyme (α-amylase) inhibitory activity of MEEA was measured using a standard procedure. Diabetic rats with fasting blood glucose above 250 mg/dL were considered diabetic and were divided into the following groups: control (distilled water-treated), diabetic-control, diabetic metformin (100 mg/kg), diabetes + MEEA (150 mg/kg), and diabetes + MEEA (300 mg/kg) via oral gavage once daily for 14 days. At the end of the experimental period, kidney tissues were collected for biochemical and histological analyses. Kidney apoptosis and marker gene expression were measured by real-time quantitative PCR.
RESULTS
MEEA exhibited α-amylase inhibitory effects. MEEA significantly (p<0.05) reduced the STZ-induced increases in blood glucose, serum urea, serum creatinine, uric acid, alanine aminotransferase, alkaline phosphatase, and malondialdehyde and increased the STZ-induced decreases in superoxide dismutase, catalase, and reduced glutathione. In addition, MEEA protects against DN by significantly downregulating the mRNA expression of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response binding protein (CREB), and cFOS and upregulating B-cell lymphoma 2 (Bcl-2), suggesting that the nephroprotective ability of MEEA is due to the modulation of the cAMP/PKA/CREB/cFOS signaling pathway. Furthermore, MEEA treatment protected against histopathological alterations observed in diabetic rats.
CONCLUSIONS
The data from this study suggest that MEEA modulates glucose homeostasis and inhibits redox imbalance in DN rats.
PubMed: 38954410
DOI: 10.1515/jcim-2024-0090 -
Cell Biochemistry and Biophysics Jul 2024Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million... (Review)
Review
Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.
PubMed: 38954353
DOI: 10.1007/s12013-024-01387-6 -
Acta Diabetologica Jul 2024This study investigates the therapeutic mechanisms of Cai's Herbal Tea in Type 1 Diabetes Mellitus (T1DM) mice, focusing on its effects on mitochondrial change and...
BACKGROUND
This study investigates the therapeutic mechanisms of Cai's Herbal Tea in Type 1 Diabetes Mellitus (T1DM) mice, focusing on its effects on mitochondrial change and autophagy via the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway.
METHODS
The composition of Cai's Herbal Tea was analyzed by Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-Q/TOF-MS). C57BL/6 mice and Min6 pancreatic beta cells were divided into control, diabetic mellitus (DM)/high glucose (HG), and treatment groups (low, medium, and high doses of Cai's Tea, and Metformin). Key physiological parameters, pancreatic islet health, Min6 cell morphology, viability, and insulin (INS) secretion were assessed. Small Interfering RNA-AMPK (si-AMPK) was utilized to confirm the pathway involvement.
RESULTS
Cai's Herbal Tea improved body weight, pancreatic islet pathological injury, and INS secretion whereas reduced total triglycerides, fasting blood sugar, and Interferon gamma (INF-γ) in T1DM mice, particularly at higher doses. In Min6 cells, Cai's Tea mitigated HG-induced damage and proinflammatory response, enhancing cell viability and INS secretion. Notably, it reduced swelling and improved cristae structure in treated groups of mitochondria and promoted autophagy via the AMPK-mTOR pathway, evidenced by increased LC3II/LC3I and P-AMPK/AMPK ratios, and decreased P-mTOR/mTOR and P62 expressions in pancreatic islet β-cells. Furthermore, these effects were converted by si-AMPK interference.
CONCLUSION
Cai's Herbal Tea exhibits significant therapeutic efficacy in T1DM mice by improving mitochondrial health and inducing autophagy through the AMPK-mTOR pathway in pancreatic islet β-cells. These findings highlight its potential as a therapeutic approach for T1DM management.
PubMed: 38954041
DOI: 10.1007/s00592-024-02316-y -
Naunyn-Schmiedeberg's Archives of... Jul 2024The risk of adhesive capsulitis of shoulder in diabetic patients taking metformin has not been evaluated. We aimed for evaluating the relative risk of adhesive...
The risk of adhesive capsulitis of shoulder in diabetic patients taking metformin has not been evaluated. We aimed for evaluating the relative risk of adhesive capsulitis of shoulder in diabetic patients taking metformin at the level of the whole country population. We conducted a retrospective cohort study using a national health insurance database in Taiwan from 2000 to2015. We used International Classification of Diseases, Ninth Revision, to categorise the medical condition for study group and comparison group. We used Cox proportional hazard regression analyses to determined adjusted hazard ratios (aHRs) of adhesive capsulitis of shoulder between study and comparison group after adjusting for sex, age, and comorbidities.Among 30,412 diabetic patients using metformin, 3020 patients were diagnosis with adhesive capsulitis of shoulder during follow up. Of the 121,648 patients without the use of metformin, 11,375 patients developed adhesive capsulitis of shoulder. Adhesive capsulitis of shoulder risk was elevated in patients taking metformin than in non-metformin group (adjusted hazard ratio [HR] 1.179, 95% confidence interval [95% CI] 1.022 to 1.268; p = 0.039). Risk of adhesive capsulitis of shoulder among the diabetic patients taking metformin was higher than those did not taking metformin.
PubMed: 38953970
DOI: 10.1007/s00210-024-03246-w -
Journal of Molecular Medicine (Berlin,... Jul 2024Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the...
Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1β, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.
PubMed: 38953935
DOI: 10.1007/s00109-024-02465-1