BackgroundThis study aims to further clarify whether the addition of metformin to insulin treatment improve cardiovascular and cerebrovascular risk factors in individuals with T1DM.MethodsElectronic databases were searched for randomized controlled trials in which the efficacy and safety of metformin were compared with those of a placebo for risk factors of cardiovascular and cerebrovascular disease among individuals with T1DM, and a meta-analysis was conducted.ResultsThirteen cardiovascular studies were identified. In the metformin group, mean carotid intimal media thickness was significantly reduced by 0.03 mm, ascending aortic pulse wave velocity by 6.3 m/s, descending aortic wall shear stress by 1.77 dyn/cm2 (P = 0.02), insulin daily dose by 0.05 U/kg/d, body weight by 2.27 kg, fat-free mass by 1.32 kg, body mass index by 0.58 kg/m2, hip circumference by 0.29 m, and low-density lipoprotein by 0.16 mmol/L, all above are P < 0.05. In the metformin group, flow-mediated dilation was increased by 1.29 %, glucose infusion rate/insulin by 18.22 mg/(kg⋅min)/μIU/μL, and waist-to-hip ratio by 0.02, all above are P < 0.00001. The metformin group showed no differences in blood pressure, reactive hyperemia index, waist circumference, triglyceride, total cholesterol, high-density lipoprotein cholesterol, or body mass index Z score. For cerebrovascular studies were identified. But none of them had a risk factor assessment.ConclusionsMetformin can ameliorate cardiovascular and cerebrovascular risk factors through non-hypoglycemic multiple pathways in individuals with T1DM.
Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a levels and increased the expression of kelch-like ECH-associated protein 1 ( Keap1 ) – a target of miR-200a and a negative regulator of NRF2. This led to the inactivation of NRF2 signaling and exacerbation of OS and inflammation. miR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG conditions. These effects were completely abolished by knockdown of Keap1 , indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a’s actions. In vivo , miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity, which protects against diabetic ED.
Alzheimer disease (AD) is the most common form of dementia. Amyloid β-peptide (Aβ) deposition is a major neuropathologic feature of AD. When unfolded or misfolded proteins accumulate in mitochondria, the unfolded protein responses (UPRmt) is initiated. Numerous lines of evidence show that AD pathogenesis involves mitochondrial dysfunction. However little is known about whether the UPRmt is engaged in the process of AD development. In this study, we investigated the UPRmt in mouse and cell models of AD. We found that UPRmt was activated in the brain of 3 and 9 months old APP/PS1 mice, and in the SHSY5Y cells after exposure to Aβ25-35, Aβ25-35 triggered UPRmt in SHSY5Y cells could be attenuated upon administration of simvastatin or siRNA for HMGCS-1 to inhibit the mevalonate pathway, and or upon knocking down Serine palmitoyltransferase long chain subunit 1 (SPTLC-1) to lower sphingolipid biosynthesis. We observed that inhibition of UPRmt aggravated cytotoxic effects of Aβ25-35 in SHSY5Y cells. Our research suggests that the UPRmt activation and two pathways necessary for this response, and further provides evidence for the cytoprotective effect of UPRmt during the AD process.
Abstract BackgroundThis study aims to further clarify whether there are cardiovascular and cerebrovascular benefits associated with insulin treatment combined with metformin in individuals with type 1 diabetes.MethodsElectronic databases were searched for randomized controlled trials in which the efficacy and safety of metformin were compared with those of a placebo for the treatment of cardiovascular and cerebrovascular disease among type 1 diabetes patients, and a meta-analysis was conducted.ResultsThirteen cardiovascular studies were identified. In the metformin group, mean carotid intimal media thickness was significantly reduced by 0.03 mm, ascending aortic pulse wave velocity by 6.3 m/s, descending aortic wall shear stress by 1.77 dyn/cm 2 , insulin daily dose by 0.05 U/kg/d, body weight by 2.27 kg, fat-free mass by 1.32 kg, body mass index by 0.58 kg/m 2 , hip circumference by 0.29 m, and low-density lipoprotein by 0.16 mmol/L. In the metformin group, flow-mediated dilation was increased by 1.29%, glucose infusion rate/insulin by 18.22 µIU/µL, and waist-to-hip ratio by 0.02. The metformin group showed no differences in blood pressure, reactive hyperemia index, waist circumference, triglyceride, total cholesterol, high-density lipoprotein cholesterol, or body mass index Z score. For cerebrovascular studies were identified. But none of them had a risk factor assessment.ConclusionsThere is strong evidence supporting wider use of metformin to improve cardiovascular and cerebrovascular disease risk among individuals with type 1 diabetes, not just obese or adults.
Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis is a rare autoimmune disease divided into two subtypes, anti-AMPAR1 encephalitis and anti-AMPAR2 encephalitis, depending on the presence of autoantibodies targeting the GluR1 and GluR2 subunits of the AMPA receptor. The main manifestations are limbic encephalitis, including cognitive impairment, seizures, and psychiatric symptoms. The reported cases of anti-AMPAR encephalitis have grown; however, no research has yet described the clinical characteristics of each subtype. Herein, we present a case of a middle-aged woman with anti-AMPAR2 encephalitis who was admitted to the hospital with sudden-onset seizures. The physical examination did not show noteworthy findings, but the auxiliary examination revealed abnormalities in the temporal lobe. On the third day of her hospitalization, she experienced olfactory hallucinations. AMPAR2 antibodies were detected positive in both serum and cerebrospinal fluid (CSF). After receiving a combination of glucocorticoids and intravenous immunoglobulin (IVIG) treatment, the patient was discharged with improved symptoms. She maintained her regimen of oral prednisone and gradually reduced the dosage following her discharge from the hospital. After 6 months, she was readmitted to the hospital due to a headache and a positive IgG test for serum AMPAR2 antibodies. The patient’s symptoms resolved with glucocorticoid treatment. Additionally, we conducted a literature review and gathered data from 37 individuals with anti-AMPAR2 encephalitis, including our present case. The patients had different levels of AMPAR2 antibodies in their CSF or serum, and some also had other antibodies. There were 23 female and 14 male patients, with a median age of 47 years. Of the patients, 19 (51%) had a history of tumors. The predominant clinical symptoms were memory impairment (78%) and psychobehavioral abnormalities (70%), with other symptoms such as epilepsy, disorders of consciousness, disorientation, hallucinations, dyskinesia, sleep disorders, and cerebellar signs. Most patients exhibited abnormalities on cerebral magnetic resonance imaging (MRI), electroencephalogram (ECG), and CSF examination. Therapeutic interventions such as steroids, IVIg, plasma exchange, or immunosuppressants led to symptom alleviation in the majority of patients. Nevertheless, some patients did not exhibit notable progress or died. This report summarized the clinical features of patients with anti-AMPAR2 encephalitis and discussed its pathogenesis to facilitate early recognition and management.
Abstract Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes‐induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch‐like ECH‐associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA‐induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review.
Background: Alzheimer’s disease (AD) is one of the common neurodegenerative diseases and is characterized by the accumulation of amyloid-β (Aβ). Orexin-A is a neuropeptide produced in the hypothalamus and thought to be involved in the pathogenesis of AD. However, its underlying mechanism and signaling pathway remains unclear. The aim of this work was to investigate the effect of Orexin-A on AD, and to explore its potential mechanism and signaling pathway. Methods: SH-SY5Y cells that were stably transfected with the Swedish mutant amyloid precursor protein (APPswe), a cell model of AD with excessive Aβ production, were used in this study. Cells were treated with Orexin-A, and with or without SB203580, an inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway, one of the key MAPK pathways associated with cell death. Following treatment, cells were collected and analyzed by western blotting, ELISA, electron microscopy, real-time PCR, fluorescence microscopy, and other biochemical assays. Results: Orexin-A increased the level of Aβ1–40 and Aβ1–42 in the cell medium, and activated the p38 MAPK pathway. As evidenced by the CCK-8 and ELISA BrdU assays, Orexin-A decreased cell viability and cell proliferation. Electron microscopic analysis used to observe the morphology of mitochondria, showed that Orexin-A increased the percentage of abnormal mitochondria. Further, decreased activity of cytochrome c oxidase (CCO), level of ATP, and mitochondrial DNA (mtDNA) copy number following Orexin-A treatment showed that Orexin-A exacerbated mitochondrial dysfunction. The level of intracellular reactive oxygen species (ROS), which is mainly generated in mitochondria and reflects mitochondrial dysfunction, was also increased by Orexin-A. SB203580 blocked the cytotoxicity and mitochondrial impairment aggravated by Orexin-A. Conclusions: These findings demonstrate that Orexin-A aggravates cytotoxicity and mitochondrial impairment in SH-SY5Y cells transfected with APPswe through the p38 MAPK pathway, and suggest that Orexin-A participates in the pathogenesis of AD, which may provide a new treatment target in the future.
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