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1.
J Neuroinflammation ; 21(1): 137, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38802820

ABSTRACT

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.


Subject(s)
Astrocytes , Brain , Hyperglycemia , Lipopolysaccharides , Mice, Inbred C57BL , Neuroinflammatory Diseases , Animals , Hyperglycemia/chemically induced , Hyperglycemia/pathology , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Mice , Lipopolysaccharides/toxicity , Lipopolysaccharides/pharmacology , Brain/pathology , Brain/metabolism , Brain/drug effects , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Neuroinflammatory Diseases/chemically induced , Male , Cellular Reprogramming/drug effects , Cellular Reprogramming/physiology , Mice, Transgenic , Cells, Cultured
2.
Dis Model Mech ; 17(5)2024 May 01.
Article in English | MEDLINE | ID: mdl-38747698

ABSTRACT

Diabetic nephropathy (DN), as a complication of diabetes, is a substantial healthcare challenge owing to the high risk of morbidity and mortality involved. Although significant progress has been made in understanding the pathogenesis of DN, more efficient models are required to develop new therapeutics. Here, we created a DN model in zebrafish by crossing diabetic Tg(acta1:dnIGF1R-EGFP) and proteinuria-tracing Tg(l-fabp::VDBP-GFP) lines, named zMIR/VDBP. Overfed adult zMIR/VDBP fish developed severe hyperglycemia and proteinuria, which were not observed in wild-type zebrafish. Renal histopathology revealed human DN-like characteristics, such as glomerular basement membrane thickening, foot process effacement and glomerular sclerosis. Glomerular dysfunction was restored upon calorie restriction. RNA sequencing analysis demonstrated that DN zebrafish kidneys exhibited transcriptional patterns similar to those seen in human DN pathogenesis. Notably, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was activated, a phenomenon observed in the early phase of human DN. In addition, metformin improved hyperglycemia and proteinuria in DN zebrafish by modulating Akt phosphorylation. Our results indicate that zMIR/VDBP fish are suitable for elucidating the mechanisms underlying human DN and could be a powerful tool for therapeutic discovery.


Subject(s)
Diabetic Nephropathies , Disease Models, Animal , Hyperglycemia , Proteinuria , Proto-Oncogene Proteins c-akt , Signal Transduction , Zebrafish , Animals , Hyperglycemia/complications , Hyperglycemia/pathology , Proto-Oncogene Proteins c-akt/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/metabolism , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Humans , Phosphorylation/drug effects , Animals, Genetically Modified , Metformin/pharmacology , Metformin/therapeutic use , Zebrafish Proteins/metabolism , Zebrafish Proteins/genetics , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Kidney Glomerulus/pathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Enzyme Activation/drug effects
3.
Mini Rev Med Chem ; 24(3): 341-354, 2024.
Article in English | MEDLINE | ID: mdl-38282447

ABSTRACT

PURPOSE: Diabetes is one of the important and growing diseases in the world. Among the most common diabetic complications are renal adverse effects. The use of apigenin may prevent the development and progression of diabetes-related injuries. The current study aims to review the effects of apigenin in the treatment of diabetic nephropathy. METHODS: In this review, a systematic search was performed based on PRISMA guidelines for obtaining all relevant studies on "the effects of apigenin against diabetic nephropathy" in various electronic databases up to September 2022. Ninety-one articles were obtained and screened in accordance with the predefined inclusion and exclusion criteria. Seven eligible articles were finally included in this review. RESULTS: The experimental findings revealed that hyperglycemia led to the decreased cell viability of kidney cells and body weight loss and an increased kidney weight of rats; however, apigenin administration had a reverse effect on these evaluated parameters. It was also found that hyperglycemia could induce alterations in the biochemical and renal function-related parameters as well as histopathological injuries in kidney cells or tissue; in contrast, the apigenin administration could ameliorate the hyperglycemia-induced renal adverse effects. CONCLUSION: The results indicated that the use of apigenin could mitigate diabetes-induced renal adverse effects, mainly through its antioxidant, anti-apoptotic, and anti-inflammatory activities. Since the findings of this study are based on experimental studies, suggesting the use of apigenin (as a nephroprotective agent) against diabetic nephropathy requires further clinical studies.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Hyperglycemia , Rats , Animals , Diabetic Nephropathies/drug therapy , Apigenin/pharmacology , Apigenin/therapeutic use , Apigenin/metabolism , Oxidative Stress , Kidney , Hyperglycemia/metabolism , Hyperglycemia/pathology , Hyperglycemia/prevention & control , Diabetes Mellitus/pathology
4.
Perit Dial Int ; 44(2): 125-132, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37525525

ABSTRACT

BACKGROUND: Peritoneal dialysis (PD) is a crucial dialysis method for treating end-stage kidney disease. However, its use is restricted due to high glucose-induced peritoneal injury and hyperglycaemia, particularly in patients with diabetes mellitus. In this study, we investigated whether partially replacing d-glucose with the rare sugar d-allose could ameliorate peritoneal injury and hyperglycaemia induced by peritoneal dialysis fluid (PDF). METHODS: Rat peritoneal mesothelial cells (RPMCs) were exposed to a medium containing d-glucose or d-glucose partially replaced with different concentrations of d-allose. Cell viability, oxidative stress and cytokine production were evaluated. Sprague-Dawley (SD) rats were administrated saline, a PDF containing 4% d-glucose (PDF-G4.0%) or a PDF containing 3.6% d-glucose and 0.4% d-allose (PDF-G3.6%/A0.4%) once a day for 4 weeks. Peritoneal injury and PD efficiency were assessed using immuno-histological staining and peritoneal equilibration test, respectively. Blood glucose levels were measured over 120 min following a single injection of saline or PDFs to 24-h fasted SD rats. RESULTS: In RPMCs, the partial replacement of d-glucose with d-allose increased cell viability and decreased oxidative stress and cytokine production compared to d-glucose alone. Despite the PDF-G3.6%/A0.4% having a lower d-glucose concentration compared to PDF-G4.0%, there were no significant changes in osmolality. When administered to SD rats, the PDF-G3.6%/A0.4% suppressed the elevation of peritoneal thickness and blood d-glucose levels induced by PDF-G4.0%, without impacting PD efficiency. CONCLUSIONS: Partial replacement of d-glucose with d-allose ameliorated peritoneal injury and hyperglycaemia induced by high concentration of d-glucose in PDF, indicating that d-allose could be a potential treatment option in PD.


Subject(s)
Hyperglycemia , Peritoneal Dialysis , Humans , Rats , Animals , Peritoneal Dialysis/adverse effects , Peritoneal Dialysis/methods , Hyperglycemia/pathology , Rats, Sprague-Dawley , Dialysis Solutions/adverse effects , Peritoneum/pathology , Glucose , Cytokines
5.
Graefes Arch Clin Exp Ophthalmol ; 262(1): 81-91, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37367995

ABSTRACT

PURPOSES: This work aimed to assess the possible role of TRIM25 in regulating hyperglycemia-induced inflammation, senescence, and oxidative stress in retinal microvascular endothelial cells, all of which exert critical roles in the pathological process of diabetic retinopathy. METHODS: The effects of TRIM25 were investigated using streptozotocin-induced diabetic mice, human primary retinal microvascular endothelial cells cultured in high glucose, and adenoviruses for TRIM25 knockdown and overexpression. TRIM25 expression was evaluated by western blot and immunofluorescence staining. Inflammatory cytokines were detected by western blot and quantitative real-time PCR. Cellular senescence level was assessed by detecting senescent marker p21 and senescence-associated-ß-galactosidase activity. The oxidative stress state was accessed by detecting reactive oxygen species and mitochondrial superoxide dismutase. RESULTS: TRIM25 expression is elevated in the endothelial cells of the retinal fibrovascular membrane from diabetic patients compared with that of the macular epiretinal membrane from non-diabetic patients. Moreover, we have also observed a significant increase in TRIM25 expression in diabetic mouse retina and retinal microvascular endothelial cells under hyperglycemia. TRIM25 knockdown suppressed hyperglycemia-induced inflammation, senescence, and oxidative stress in human primary retinal microvascular endothelial cells while TRIM25 overexpression further aggregates those injuries. Further investigation revealed that TRIM25 promoted the inflammatory responses mediated by the TNF-α/NF-κB pathway and TRIM25 knockdown improved cellular senescence by increasing SIRT3. However, TRIM25 knockdown alleviated the oxidative stress independent of both SIRT3 and mitochondrial biogenesis. CONCLUSION: Our study proposed TRIM25 as a potential therapeutic target for the protection of microvascular function during the progression of diabetic retinopathy.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Retinopathy , Hyperglycemia , Sirtuin 3 , Animals , Humans , Mice , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Retinopathy/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Hyperglycemia/metabolism , Hyperglycemia/pathology , Inflammation/metabolism , Oxidative Stress , Retina/pathology , Sirtuin 3/metabolism , Sirtuin 3/pharmacology , Transcription Factors , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/pharmacology , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/pharmacology
6.
Cardiovasc Pathol ; 69: 107601, 2024.
Article in English | MEDLINE | ID: mdl-38072092

ABSTRACT

BACKGROUND: This study aims to develop a fetal rat model of ventricular noncompaction (NVM) using streptozotocin (STZ)-induced gestational hyperglycemia and compare it with a retinoic acid (RA) model. METHODS: Female SD rats were categorized into STZ, RA, and normal control (NC) groups. The STZ group was given a high-fat diet pre-pregnancy and 35 mg/kg of 2% STZ postpregnancy. The RA group received a 90 mg/kg dose of RA on day 13 postpregnancy. Embryonic myocardial morphology was analyzed through HE staining, and embryonic cardiomyocyte ultrastructures were studied using electron microscopy. Diagnoses of NVM were based on a ratio of noncompact myocardium (N) to compact myocardium (C) >1.4, accompanied by thick myocardial trabeculae and a thin myocardial compaction layer. Kruskal-Wallis test determined N/C ratio differences among groups. RESULTS: Both STZ and RA groups displayed significant NVM characteristics. The left ventricular (LV) N/C in the STZ, RA, and NC groups were 1.983 (1.423-3.527), 1.640 (1.197-2.895), and 0.927 (0.806-1.087), respectively, with a statistically significant difference (P<0.001). The right ventricular (RV) N/C in the STZ, RA, and NC groups were 2.097 (1.364-3.081), 1.897 (1.337-2.662), and 0.869 (0.732-1.022), respectively, with a significant difference (P<0.001). Electron microscopy highlighted marked endoplasmic reticulum swelling in embryonic cardiomyocytes from both STZ and RA groups. CONCLUSION: Our model underscores the pivotal role of an adverse intrauterine developmental environment in the onset of NVM. This insight holds significant implications for future studies exploring the pathogenesis of NVM.


Subject(s)
Heart Ventricles , Hyperglycemia , Pregnancy , Rats , Animals , Female , Rats, Sprague-Dawley , Myocardium/pathology , Hyperglycemia/complications , Hyperglycemia/pathology , Tretinoin
7.
Ageing Res Rev ; 93: 102142, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38030091

ABSTRACT

Ageing retina is prone to ferroptosis due to the iron accumulation and impaired efficiency of intracellular antioxidant defense system. Ferroptosis acts as a cell death modality that is characterized by the iron-dependent accumulation of lipid peroxidation. Ferroptosis is distinctively different from other types of regulated cell death (RCD) at the morphological, biochemical, and genetic levels. Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Its prevalence and severity increase progressively with age. Recent reports have shown that ferroptosis is implicated in the pathophysiology of DR. Under hyperglycemia condition, the endothelial cell and retinal pigment epithelium (RPE) cell will undergo ferroptosis, which contributes to the increased vascular permeability and the disrupted blood retinal barrier (BRB). The underlying etiology of DR can be attributed to the impaired BRB integrity and subsequent damages of the neurovascular units. In the absence of timely intervention, the compromised BRB can ultimately cause profound visual impairments. In particular, the ageing retina is vulnerable to ferroptosis, and hyperglycemia will accelerate the progression of this pathological process. In this article, we discuss the contributory role of ferroptosis in DR pathogenesis, and summarize recent therapeutic trials that targeting the ferroptosis. Further study on the ferroptosis mediated damage would enrich our knowledge of DR pathology, and promote the development of clinical treatment for this degenerative retinopathy.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Retinopathy , Ferroptosis , Hyperglycemia , Humans , Aging , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Retinopathy/etiology , Diabetic Retinopathy/drug therapy , Diabetic Retinopathy/metabolism , Hyperglycemia/complications , Hyperglycemia/metabolism , Hyperglycemia/pathology , Iron/metabolism , Retina/metabolism
8.
J Mol Cell Biol ; 15(12)2024 04 10.
Article in English | MEDLINE | ID: mdl-38140943

ABSTRACT

Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients, contributing to morbidity and mortality. Although hyperglycemia has been identified as a damaging effector, the detailed mechanisms remain elusive. In this study, identified by ATAC-seq and RNA-seq, JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose, mainly through the cell cycle and p53 signaling pathways. Furthermore, JunB undergoes phase separation in the nucleus and in vitro, mediated by its intrinsic disordered region and DNA-binding domain. Nuclear localization and condensation behaviors are required for JunB-mediated proliferation and apoptosis. Thus, our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose, elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.


Subject(s)
Apoptosis , Cell Proliferation , Glucose , Human Umbilical Vein Endothelial Cells , Hyperglycemia , Humans , Human Umbilical Vein Endothelial Cells/metabolism , Hyperglycemia/metabolism , Hyperglycemia/pathology , Hyperglycemia/complications , Glucose/metabolism , Glucose/pharmacology , Tumor Suppressor Protein p53/metabolism , Signal Transduction , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Cell Cycle , Cell Nucleus/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics
9.
Front Endocrinol (Lausanne) ; 14: 1280060, 2023.
Article in English | MEDLINE | ID: mdl-38152132

ABSTRACT

Background: Metabolic disorders are involved in the development of numerous cancers, but their association with the progression of cervical cancer is unclear. This study aims to investigate the association between metabolic disorders and the pathological risk factors and survival in patients with early cervical cancer. Methods: Patients with FIGO IB1 (2009) primary cervical cancer who underwent radical hysterectomy and systematic pelvic lymph node dissection at our institution from October 2014 to December 2017 were included retrospectively. Clinical data regarding the metabolic syndrome and surgical pathology of the patient were collected. The correlations between metabolic disorders (hypertension, hyperglycemia, and obesity) and clinicopathological characteristics as well as survival after surgery were analyzed. Results: The study included 246 patients with clinical IB1 cervical cancer, 111 (45.1%) of whom had at least one of the comorbidities of hypertension, obesity, or hyperglycemia. Hypertension was positively correlated with parametrial invasion and poorly differentiated histology; hyperglycemia was positively correlated with stromal invasion; obesity was negatively associated with lymph node metastasis; but arbitrary disorder did not show any correlation with pathologic features. Hypertension was an independent risk factor for parametrial invasion (OR=6.54, 95% CI: 1.60-26.69); hyperglycemia was an independent risk factor for stromal invasion (OR=2.05, 95% CI: 1.07-3.95); and obesity was an independent protective factor for lymph node metastasis (OR=0.07, 95% CI: 0.01-0.60). Moreover, the patients with hypertension had a significantly lower 5-year OS rate (70.0% vs. 95.3%, P<0.0001) and a significantly lower 5-year PFS rate than those without hypertension (70.0% vs. 91.2%, P=0.010). Conclusion: Hypertension and hyperglycemia are positively associated with local invasion of early cervical cancer, which need to be verified in multi-center, large scale studies.


Subject(s)
Hyperglycemia , Hypertension , Uterine Cervical Neoplasms , Female , Humans , Uterine Cervical Neoplasms/complications , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/surgery , Retrospective Studies , Lymphatic Metastasis , Hyperglycemia/complications , Hyperglycemia/pathology , Neoplasm Staging , Hypertension/complications , Hypertension/epidemiology , Hypertension/pathology , Obesity/complications , Obesity/pathology
10.
Endocr J ; 70(12): 1131-1140, 2023 Dec 28.
Article in English | MEDLINE | ID: mdl-37914275

ABSTRACT

To examine the association between prediabetes/type 2 diabetes mellitus (T2DM) and hippocampal subfields and to investigate the effects of glycemic control (HbA1c and FBG)/diabetes duration on the volume of hippocampal subfields in T2DM patients. This cross-sectional study included 268 participants from Tianjin Union Medical Center between August 2019 and July 2022. The participants were divided into three groups: T2DM, prediabetes and no diabetes. All participants underwent brain MRI examination on a 3T MRI scanner. FreeSurfer was performed to segment hippocampus automatically based on T1 MPRAGE images. The relationships between glycemic status/glycemic control/diabetes duration and hippocampal subfield volumes were estimated by multiple linear regression analysis/generalized additive modeling (GAM). Among all participants, 76 (28.36%) had prediabetes, and 96 (35.82%) had T2DM. In multi-adjusted linear regression models, those with prediabetes had a significantly lower volume of bilateral parasubiculum (ßright = -5.540; ßleft = -6.497). Those with diabetes had lower volume of parasubiculum (ßleft = -7.868), presubiculum-head (ßleft = -6.244) and fimbria (ßleft = -7.187). We did not find relationship between diabetes duration and hippocampal subfield volumes. In stratified analysis, long duration with high FBG related with lower volume of right fimbria (ßright = -15.583). Long duration with high HbA1c related with lower volume of presubiculum-head (ßright = -19.693), subiculum-head (ßright = -28.303), subiculum-body (ßleft = -38.599), CA1-head (ßright = -62.300, ßleft = -47.922), CA1-body (ßright = -19.043), CA4-body (ßright = -14.392), GC-ML-DG-head (ßright = -20.521), GC-ML-DG-body (ßright = -16.293, ßleft = -12.799), molecular_layer_HP-head (ßright = -44.202, ßleft = -26.071) and molecular_layer_HP-body, (ßright = -31.368), hippocampal_tail (ßleft = -80.073). Prediabetes related with lower bilateral parasubiculum volume, and T2DM related with lower left parasubiculum, presubiculum-head and fimbria. T2DM with chronic poor glycemic control had lower volume in multiple hippocampal subregions.


Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Prediabetic State , Humans , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Prediabetic State/complications , Prediabetic State/pathology , Glycated Hemoglobin , Glycemic Control , Hippocampus/diagnostic imaging , Hippocampus/pathology , Magnetic Resonance Imaging/methods , Hyperglycemia/pathology , Atrophy/pathology
11.
Free Radic Biol Med ; 208: 153-164, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37543166

ABSTRACT

Diabetes is one of the significant risk factors for ischemic stroke. Hyperglycemia exacerbates the pathogenesis of stroke, leading to more extensive cerebral damage and, as a result, to more severe consequences. However, the mechanism whereby the hyperglycemic status in diabetes affects biochemical processes during the development of ischemic injury is still not fully understood. In the present work, we record for the first time the real-time dynamics of H2O2 in the matrix of neuronal mitochondria in vitro in culture and in vivo in the brain tissues of rats during development of ischemic stroke under conditions of hyperglycemia and normal glucose levels. To accomplish this, we used a highly sensitive HyPer7 biosensor and a fiber-optic interface technology. We demonstrated that a high glycemic status does not affect the generation of H2O2 in the tissues of the ischemic core, while significantly exacerbating the consequences of pathogenesis. For the first time using Raman microspectroscopy approach, we have shown how a sharp increase in the blood glucose level increases the relative amount of reduced cytochromes in the mitochondrial electron transport chain in neurons under normal conditions in awake mice.


Subject(s)
Brain Ischemia , Diabetes Mellitus , Hyperglycemia , Ischemic Stroke , Stroke , Rats , Mice , Animals , Hydrogen Peroxide , Stroke/pathology , Hyperglycemia/pathology , Brain Ischemia/pathology
12.
J Mol Med (Berl) ; 101(8): 1015-1028, 2023 08.
Article in English | MEDLINE | ID: mdl-37462767

ABSTRACT

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. KEY MESSAGES: Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Diabetic Neuropathies , Hyperglycemia , Animals , Mice , Receptor for Advanced Glycation End Products/genetics , Receptor for Advanced Glycation End Products/metabolism , Diabetic Neuropathies/genetics , Diabetic Neuropathies/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Cathepsin E , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Sciatic Nerve/pathology , Hyperglycemia/genetics , Hyperglycemia/pathology
13.
BMC Musculoskelet Disord ; 24(1): 585, 2023 Jul 18.
Article in English | MEDLINE | ID: mdl-37464323

ABSTRACT

BACKGROUND: Diabetes mellitus (DM) causes bone dysfunction due to poor bone quality, leading to severe deterioration in patient of quality of life. The mechanisms of bone metabolism in DM remain unclear, although chemical and/or mechanical factors are known to disrupt the homeostasis of osteoblasts and osteoclasts. The purpose of this study was to identify the changes of osteoblasts and osteoclasts under long-term hyperglycaemic conditions, using a mouse fracture model of long-term hyperglycemia (LT-HG). METHODS: C57BL/6J mice and green fluorescent protein (GFP) -positive bone marrow transplanted C57BL/6J mice with LT-HG, maintained under a state of hyperglycaemia for 2 months, were used in this study. After the experimental fracture, we examined the immunohistochemical expression of proinsulin and tumor necrosis factor (TNF) -α at the fracture site. C57BL/6J fracture model mice without hyperglycaemia were used as controls. RESULTS: In the LT-HG mice, chondrocyte resorption was delayed, and osteoblasts showed an irregular arrangement at the callus site. The osteoclasts were scattered with a decrement in the number of nuclei. The expression of proinsulin was confirmed in bone marrow derived cells (BMDCs) with neovascularization 2 and 3 weeks after fracture. Immunopositivity for TNF-α was also confirmed in immature chondrocytes and BMDCs with neovascularization at 2 weeks, and the number of positive cells was not decreased at 3 weeks. Examination of GFP-grafted hyperglycaemic mice showed that the majority of cells at the fracture site were GFP-positive. Immunohistochemistry showed that the rate of double positives was 15% for GFP and proinsulin and 47% for GFP and TNF-α. CONCLUSION: LT-HG induces an increase in the number of proinsulin and TNF-α positive cells derived from BMDCs. We suggest that proinsulin and TNF-α positive cells are involved in both bone formation and bone resorption after fracture under hyperglycaemic conditions, resulting in the delay of bone healing.


Subject(s)
Diabetes Mellitus, Experimental , Fractures, Bone , Hyperglycemia , Animals , Mice , Fracture Healing , Cytokines , Tumor Necrosis Factor-alpha/metabolism , Proinsulin , Bone Marrow/pathology , Diabetes Mellitus, Experimental/complications , Quality of Life , Mice, Inbred C57BL , Bony Callus/pathology , Fractures, Bone/pathology , Hyperglycemia/complications , Hyperglycemia/pathology , Bone Marrow Cells/metabolism
14.
Front Endocrinol (Lausanne) ; 14: 1134530, 2023.
Article in English | MEDLINE | ID: mdl-37324273

ABSTRACT

Introduction: Diabetic neuropathy and diabetic eye disease are well known complications of type 1 diabetes. We hypothesized that chronic hyperglycemia also damages the optic tract, which can be measured using routine magnetic resonance imaging. Our aim was to compare morphological differences in the optic tract between individuals with type 1 diabetes and healthy control subjects. Associations between optic tract atrophy and metabolic measures, cerebrovascular and microvascular diabetic complications were further studied among individuals with type 1 diabetes. Methods: We included 188 subjects with type 1 diabetes and 30 healthy controls, all recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent a clinical examination, biochemical work-up, and brain magnetic resonance imaging (MRI). Two different raters manually measured the optic tract. Results: The coronal area of the optic chiasm was smaller among those with type 1 diabetes compared to non-diabetic controls (median area 24.7 [21.0-28.5] vs 30.0 [26.7-33.3] mm2, p<0.001). In participants with type 1 diabetes, a smaller chiasmatic area was associated with duration of diabetes, glycated hemoglobin, and body mass index. Diabetic eye disease, kidney disease, neuropathy and the presence of cerebral microbleeds (CMBs) in brain MRI were associated with smaller chiasmatic size (p<0.05 for all). Conclusion: Individuals with type 1 diabetes had smaller optic chiasms than healthy controls, suggesting that diabetic neurodegenerative changes extend to the optic nerve tract. This hypothesis was further supported by the association of smaller chiasm with chronic hyperglycemia, duration of diabetes, diabetic microvascular complications, as well as and CMBs in individuals with type 1 diabetes.


Subject(s)
Diabetes Complications , Diabetes Mellitus, Type 1 , Hyperglycemia , Humans , Optic Chiasm/pathology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/pathology , Diabetes Complications/pathology , Chronic Disease , Atrophy , Hyperglycemia/pathology
15.
Int J Mol Sci ; 24(12)2023 Jun 15.
Article in English | MEDLINE | ID: mdl-37373317

ABSTRACT

An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in "remission" and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of "at-risk phenotypes" such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.


Subject(s)
Diabetes Mellitus , Diabetic Foot , Hyperglycemia , Humans , Cicatrix/pathology , Ulcer/pathology , Diabetic Foot/pathology , Lower Extremity/pathology , Hyperglycemia/pathology , Recurrence , Diabetes Mellitus/pathology
16.
Bull Math Biol ; 85(7): 58, 2023 05 27.
Article in English | MEDLINE | ID: mdl-37243841

ABSTRACT

In this paper, we investigate the disruption of the glucose homeostasis at the whole-body level by the presence of cancer disease. Of particular interest are the potentially different responses of patients with or without hyperglycemia (including diabetes mellitus) to the cancer challenge, and how tumor growth, in turn, responds to hyperglycemia and its medical management. We propose a mathematical model that describes the competition between cancer cells and glucose-dependent healthy cells for a shared glucose resource. We also include the metabolic reprogramming of healthy cells by cancer-cell-initiated mechanism to reflect the interplay between the two cell populations. We parametrize this model and carry out numerical simulations of various scenarios, with growth of tumor mass and loss of healthy body mass as endpoints. We report sets of cancer characteristics that show plausible disease histories. We investigate parameters that change cancer cells' aggressiveness, and we exhibit differing responses in diabetic and non-diabetic, in the absence or presence of glycemic control. Our model predictions are in line with observations of weight loss in cancer patients and the increased growth (or earlier onset) of tumor in diabetic individuals. The model will also aid future studies on countermeasures such as the reduction of circulating glucose in cancer patients.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus , Hyperglycemia , Insulin Resistance , Neoplasms , Humans , Blood Glucose/metabolism , Insulin/metabolism , Mathematical Concepts , Models, Biological , Hyperglycemia/metabolism , Hyperglycemia/pathology , Glucose/metabolism , Models, Theoretical , Homeostasis
17.
Exp Eye Res ; 231: 109494, 2023 06.
Article in English | MEDLINE | ID: mdl-37149278

ABSTRACT

Diabetes mellitus has been a major cause of concern for the past few decades. As the number of diabetic patients increases, so too does the occurrence of its complications. Diabetic retinopathy (DR) is one of these and constitutes the most common cause of blindness amongst working-age individuals. Chronic exposure to a hyperglycaemic environment remains the driving force of a cascade of molecular events that disrupt the microvasculature of the retina and if left untreated can lead to blindness. In this review, we identify oxidative stress as a major implication in the pathway to the development of DR and speculate that it plays a central role especially in the early stages of the disease. Cells lose their antioxidant capacity under a hyperglycaemic state, free radicals are formed and eventually apoptosis ensues. The polyol pathway; advanced glycation end-product formation; the protein kinase C pathway, and the hexosamine pathway are found to contribute to the increase in oxidative stress observed in diabetic patients. We also investigate the use of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in DR. These molecules possess antioxidant and anti-inflammatory properties and have been previously investigated for use in other ocular pathologies with promising results. In this review we present the latest findings in pre-clinical and clinical studies for the use of ω-3 PUFAs in DR. We hypothesise that ω-3 PUFAs could be beneficial for DR in ways of reducing the oxidative stress and limiting the progression of the disease that threatens the eyesight of the patient, in conjunction with conventional therapy.


Subject(s)
Diabetes Mellitus , Diabetic Retinopathy , Fatty Acids, Omega-3 , Hyperglycemia , Humans , Diabetic Retinopathy/metabolism , Antioxidants/therapeutic use , Antioxidants/metabolism , Oxidative Stress , Fatty Acids, Omega-3/therapeutic use , Hyperglycemia/pathology , Blindness
18.
Int J Immunopathol Pharmacol ; 37: 3946320231172745, 2023.
Article in English | MEDLINE | ID: mdl-37099672

ABSTRACT

OBJECTIVES: Testicular dysfunction has been associated with chronic hyperglycemia in diabetes mellitus patients. We investigated taurine's possible mechanisms and protective effects against testicular damage using a rat model of streptozotocin-induced diabetes. METHODS: Wistar rats (N = 56) were divided into seven equal groups. Untreated control rats received saline, and treated control rats received taurine 50 mg/kg orally. To induce diabetes, rats received a single dose of streptozotocin. Metformin-treated diabetic rats received metformin at a dose of 300 mg/kg. Taurine-treated groups received 10, 25, or 50 mg/kg. All treatments were provided orally once a day for 9 weeks following the streptozotocin injection. Levels of blood glucose, serum insulin, cholesterol, testicular tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1ß), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), and catalase (CAT) were examined. Sperm count, progressive sperm motility, and sperm abnormalities were examined. Body and relative reproductive gland weights were assessed. Histopathological examinations of the testes and epididymis were performed. RESULTS: Metformin as well as taurine (in a dose-dependent manner) resulted in significant improvements in body and relative reproductive gland weights, blood glucose, serum cholesterol, and insulin levels, as well as cytokine and oxidative parameters. These findings were associated with significant improvement in sperm count, progressive sperm motility, sperm abnormalities, and histopathological lesions in the testes and epididymis. CONCLUSION: Taurine can potentially improve hyperglycemia, hypercholesterolemia, and testicular damage associated with diabetes mellitus, possibly by controlling inflammation and oxidative stress.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Hyperglycemia , Insulins , Metformin , Rats , Male , Animals , Testis , Streptozocin/pharmacology , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Experimental/drug therapy , Blood Glucose , Taurine/pharmacology , Rats, Wistar , Sperm Motility , Semen , Oxidative Stress , Antioxidants/metabolism , Metformin/pharmacology , Cholesterol/metabolism , Hyperglycemia/complications , Hyperglycemia/metabolism , Hyperglycemia/pathology , Insulins/metabolism , Insulins/pharmacology , Insulins/therapeutic use , Superoxide Dismutase
19.
Am J Pathol ; 193(7): 913-926, 2023 07.
Article in English | MEDLINE | ID: mdl-37088455

ABSTRACT

Dry eye syndrome is a common complication in diabetic patients with a prevalence of up to 54.3%. However, the pathogenic mechanisms underlying hyperglycemia-induced tear reduction and dry eye remain less understood. The present study indicated that both norepinephrine (NE) and tyrosine hydroxylase levels were elevated in the lacrimal gland of diabetic mice, accompanied by increased Fos proto-oncogene (c-FOS)+ cells in the superior cervical ganglion. However, the elimination of NE accumulation by surgical and chemical sympathectomy significantly ameliorated the reduction in tear production, suppressed abnormal inflammation of the lacrimal gland, and improved the severity of dry eye symptoms in diabetic mice. Among various adrenergic receptors (ARs), the α1 subtype played a predominant role in the regulation of tear production, as treatments of α1AR antagonists improved tear secretion in diabetic mice compared with ßAR antagonist propranolol. Moreover, the α1AR antagonist alfuzosin treatment also alleviated functional impairments of the meibomian gland and goblet cells in diabetic mice. Mechanically, the α1AR antagonist rescued the mitochondrial bioenergetic deficit, increased the mitochondrial DNA copy numbers, and elevated the glutathione levels of the diabetic lacrimal gland. Overall, these results deciphered a previously unrecognized involvement of the NE-α1AR-mitochondrial bioenergetics axis in the regulation of tear production in the lacrimal gland, which may provide a potential strategy to counteract diabetic dry eye by interfering with the α1AR activity.


Subject(s)
Diabetes Mellitus, Experimental , Dry Eye Syndromes , Hyperglycemia , Lacerations , Lacrimal Apparatus , Mice , Animals , Lacrimal Apparatus/pathology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathology , Norepinephrine , Tears , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/etiology , Dry Eye Syndromes/pathology , Hyperglycemia/complications , Hyperglycemia/pathology , Lacerations/pathology , Receptors, Adrenergic
20.
Ann Hepatol ; 28(4): 101111, 2023.
Article in English | MEDLINE | ID: mdl-37100383

ABSTRACT

INTRODUCTION AND OBJECTIVES: South America is one of the regions with the highest rates of non-alcoholic fatty liver disease (NAFLD). This study aimed to assess the prevalence and severity of NAFLD in suburban Argentina. PATIENTS AND METHODS: The study involved a general community cohort of 993 subjects evaluated sequentially with a comprehensive lifestyle questionnaire, laboratory testing, abdominal ultrasound (US) and transient elastography with XL probe. NAFLD was diagnosed according to standard criteria. RESULTS: The prevalence of NAFLD by the US was 37.2% (326/875) overall, 50.3% in subjects with overweight/obesity, 58.6% with hypertriglyceridemia, 62.3% with diabetes/hyperglycemia and 72.1% with all three risk factors. Male gender (OR 1.42, 95% CI 1.03-1.47, p = 0.029), age (50-59 years: OR 1.98, 95 CI 1.16-3.39, p = 0.013 and ≥60 years: OR 1.86, 95% CI 1.13-3.09, p = 0.015), BMI (25-29: OR 2.87, 95% CI 1.86-4.51, p<0.001 and ≥30: OR 9.57, 95% CI 6.14-15.20, p<0.001), diabetes/hyperglycemia (OR 1.65, 95% CI 1.05-2.61, p = 0.029) and hypertriglyceridemia (OR 1.73, 95% CI 1.20-2.48, p = 0.002) were independent predictors of NAFLD. Among patients with steatosis, 22.2% (69/311) had ≥F2 fibrosis (overweight 25%, hypertriglyceridemia 32%, diabetes/hyperglycemia 34%). BMI (OR 5.22, 95% CI 2.64-11.74, p<0.001), diabetes/hyperglycemia (OR 2.12, 95% CI 1.05-4.29, p = 0.04) and hypertriglyceridemia (OR 1.94, 95% CI 1.03-3.68, p = 0.040) were independent predictors of liver fibrosis. CONCLUSIONS: This general population study from Argentina showed a high prevalence of NAFLD. Significant liver fibrosis was present in 22% of subjects with NAFLD. This information adds to the existing knowledge of NAFLD epidemiology in Latin America.


Subject(s)
Diabetes Mellitus , Hyperglycemia , Hypertriglyceridemia , Non-alcoholic Fatty Liver Disease , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Non-alcoholic Fatty Liver Disease/epidemiology , Overweight , Prevalence , Argentina/epidemiology , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/epidemiology , Diabetes Mellitus/etiology , Hyperglycemia/complications , Hyperglycemia/pathology , Hypertriglyceridemia/complications , Hypertriglyceridemia/pathology , Liver/pathology
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