Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to β-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.
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http://dx.doi.org/10.1093/stcltm/szae038 | DOI Listing |
Mol Psychiatry
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Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease.
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December 2024
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.
Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγ) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations.
View Article and Find Full Text PDFPhytother Res
December 2024
Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China.
Glioma is recognized as one of the most lethal and aggressive brain tumors. Although the standard-of-care treatment for glioblastoma (GBM) involves maximal surgical resection and temozolomide (TMZ) chemotherapy, the discovery of novel anti-tumor agents from nature sources is an effective strategy for glioma treatment. In this study, we conducted a screening process to identify the bisindole alkaloid melodinine J (MDJ) from Melodinus tenuicaudatus.
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December 2024
National Taiwan University Hospital, Immune Research Core, Department of Medical Research, TAIWAN.
The development of multifunctional therapeutic agents is crucial for addressing complex diseases such as Alzheimer's disease. Herein, we report a ruthenium-rhenium (Ru-Re) complex that combines photodynamic therapy (PDT) and carbon monoxide (CO) generation capabilities. The Ru-Re complex shows promising photophysical property and significant therapeutic potential.
View Article and Find Full Text PDFMol Cell Biochem
December 2024
Department XIII Infectious Diseases-Parasitology, "Victor Babeș" University of Medicine and Pharmacy of Timișoara, Timișoara, Romania.
The global burden of cancer as a major cause of death and invalidity has been constantly increasing in the past decades. Monoamine oxidases (MAO) with two isoforms, MAO-A and MAO-B, are mammalian mitochondrial enzymes responsible for the oxidative deamination of neurotransmitters and amines in the central nervous system and peripheral tissues with the constant generation of hydrogen peroxide as the main deleterious ancillary product. However, given the complexity of cancer biology, MAO involvement in tumorigenesis is multifaceted with different tumors displaying either an increased or decreased MAO profile.
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