Microvascular Complication Of Diabetes Mellitus Research Articles

Leonurine Ameliorates Diabetic Nephropathy through GPX4-Mediated Ferroptosis of Endothelial Cells.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM). Ferroptosis is an atypical form of iron-dependent, modulated cell death that has been shown to occur in human umbilical vein endothelial cells (HUVECs). Leonurine (LEO) is a single active ingredient extracted from Leonurus japonicus Houtt. It has various biological activities, including anti-inflammatory and anti-cancer effects. However, whether LEO affects ferroptosis in DN has yet to be investigated. An animal model of DN was established by subjecting C57/BL6 mice to a high-fat diet (HFD) while being induced with Streptozotocin (STZ). A cellular model of DN was established by exposing HUVECs to a high glucose (HG) concentration of 30 mM. LEO was found to improve DN and to attenuate the degree of glomerulosclerosis and tubular atrophy in the mouse model. Additionally, it markedly decreased the levels of ferroptosis markers. Molecular analyses revealed that LEO inhibited HG-induced oxidative stress in HUVECs, thereby decreasing endothelial cell (EC) dysfunction. Furthermore, LEO was found to reduce ferroptosis and reverse EC dysfunction by increasing the expression of glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The suppression of Nrf2 in HG-induced HUVECs inhibited LEO-GPX4 axis-mediated ferroptosis and increased EC dysfunction. LEO exerts anti-DN effects both in vivo and in vitro by suppressing GPX4-mediated EC ferroptosis. Mechanistically, LEO appears to induce Nrf2-mediated GPX4 expression to inhibit ferroptosis, thereby reducing EC dysfunction. This study provides a new perspective on the treatment of diseases using natural medicines. It involves a novel form of cell death that could potentially lead to better treatment of DN.

Mitochondrial dysfunction in diabetic nephropathy: insights and therapeutic avenues from traditional Chinese medicine.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. The progressive damage to glomeruli, tubules, and interstitium in the kidneys can lead to the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Most of the energy we need comes from mitochondria. Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. The pathogenesis of DN involves a variety of factors, such as altered haemodynamics, oxidative stress, and inflammation, and studies from animal models suggest that mitochondrial dysfunction plays an important role in the development of DN. Traditional Chinese medicine (TCM) has a history of more than 2,500 years and has rich experience and remarkable efficacy in the treatment of DN. Recent studies have found that TCM may have great potential in regulating mitochondrial dysfunction in the treatment of DN. This review will elucidate the main causes of mitochondrial dysfunction and the relationship with DN, and explore in depth the potential mechanisms of TCM to protect the kidney by improving mitochondrial dysfunction. Current pharmacological treatments for patients with DN do not prevent the inevitable progression to ESRD. With the rich variety of Chinese herbs, TCM is expected to be the most promising candidate for the treatment of DN as we continue to learn more about the mechanisms of DN and incorporate the current advances in extraction techniques.

Evaluation of serum levels of sestrin 2 and betatrophin in type 2 diabetic patients with diabetic nephropathy

BackgroundDiabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control.MethodsThis cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR < 30 mg/g), group IIB (20 patients) with micro albuminuria (ACR = 30 to 300 mg/g) and group IIC (20 patients) with macro albuminuria (ACR > 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique.ResultsSerum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value < 0.05). The cut off value of serum sestrin 2 was 0.98 ng/ml with sensitivity 99%, specificity 66% while the cut off value of serum betatrophin was > 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy.ConclusionsPatients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage.

Dynamics of indicators of the vascular membrane of the ciliary body in predicting the risk of diabetic retinopathy in pregnant women with diabetes mellitus

BACKGROUND: According to statistics, microvascular complications of diabetes mellitus are registered in a third of patients during their lifetime, and diabetic retinopathy is the main cause of irreversible blindness in people of reproductive age. Changes in the vascular membrane of the eye in patients with diabetes mellitus are currently being studied as predictors of the progression of diabetic retinopathy. Further study of changes in the vascular membrane in pregnant women with type 1 and type 2 diabetes may help in identifying criteria for the manifestation and progression of diabetic microangiopathy. AIM: To develop a methodology for predicting the risk of diabetic retinopathy progression by analyzing the dynamics of the state of the vascular membrane of the ciliary body. METHODS: The study was conducted in each trimester of pregnancy. A pregnant patient with confirmed diabetes mellitus 1 or diabetes mellitus 2 underwent a comprehensive ophthalmological examination, including visometry with maximally corrected visual acuity, tonometry, biomicroscopy of the anterior segment of the eye, ophthalmoscopy under conditions of drug-induced mydriasis (phenylephrine) with a high-diopter lens (78–90 D), and optical coherence tomography of the anterior and posterior eye segments. RESULTS: With an increase in the thickness of the vascular layer of the ciliary body by ≥10% at one or more points compared with the study conducted in the first trimester of pregnancy, the patients exhibited diabetic retinopathy progression during subsequent routine examinations. Quantitative analysis of the vascular layer of ciliary body revealed the transition of diabetic retinopathy to its next stage; however, photoregistration of the fundus did not show obvious signs of transformation into another stage of the disease. CONCLUSION: Dynamic examination of the thickness of the vascular layer of the ciliary body during gestation and its increase by 10% from the initial one enables prediction of progression of diabetic retinopathy to the next stage.

Serum neopterin and orexin-A levels in different stages of diabetic retinopathy

ABSTRACT Clinical Relevance Retinopathy is one of the most common microvascular complications of diabetes mellitus and is the leading cause of vision loss in the working middle-aged population. Background This study aimed to investigate the value of neopterin and orexin-A levels in patients with diabetes mellitus with different stages of diabetic retinopathy and without diabetic retinopathy and to compare those findings with results from healthy individuals without diabetes mellitus. Methods In total, 65 patients with type 2 diabetes mellitus and 22 healthy individuals without diabetes mellitus were enrolled in this prospective study. The participants were separated into four subgroups. The first subgroup included 25 patients without diabetic retinopathy, the second subgroup included 20 patients non-proliferative diabetic retinopathy, the third subgroup included 20 patients with proliferative diabetic retinopathy, and the fourth subgroup included 22 healthy individuals without diabetes mellitus as controls. Serum neopterin and orexin-A levels were analysed and compared among the groups. Results The age and gender of the participants between the four subgroups were not statistically significantly different (p > 0.05). The mean neopterin levels were significantly higher in patients included in the diabetes mellitus subgroups compared with the controls (p < 0.001). Neopterin levels significantly increased as diabetic retinopathy progressed within the diabetes mellitus subgroups. Mean orexin-A levels were significantly lower in the diabetes mellitus subgroups compared with the controls (p < 0.001); however, orexin-A levels were not significantly different within the diabetes mellitus subgroups (p > 0.05). Conclusion Patients with diabetes mellitus have higher serum neopterin and lower serum orexin-A levels compared with healthy individuals without diabetes mellitus. Moreover, serum neopterin levels increase with progression of diabetic retinopathy.

Study of the Relationship between Diabetic Retinopathy, Basal Insulin Therapy (Glargine or NPH) and Insulin-Like Growth Factor 1 Serum Level

Abstract Background Diabetic retinopathy (DR) is the major cause of preventable blindness worldwide. DR is a microvascular complication of diabetes mellitus that is more prevalent in patients with type 1 diabetes. Type 1 diabetes mellitus is an autoimmune disease that leads to insulin deficiency so patients require long term therapy with basal insulin for optimum glycemic control. Insulin- like growth factor 1 (IGF-1) is an important growth factor that is involved in cell proliferation and angiogenesis. There is a lot of evidence that IGF-1 is tightly related to DR development. Insulin Glargine is a long-acting insulin analogue which is peak-free and less hypoglycemic as compared to the intermediate-acting NPH insulin. Glargine has an increased affinity to IGF-1 receptor and this raised concern about its role in development of DR. The relationship between diabetic retinopathy, basal insulin therapy and IGF-1 serum level is still in debate. Aim we aimed to compare the incidence and severity of diabetic retinopathy in type 1 diabetic patients on basal insulin therapy (Glargine or NPH) and its relation to serum IGF-1 level. Methods The current study included 88 subjects with type 1 diabetes divided into 44 on basal insulin therapy with Glargine and actrapid ( Group A) and 44 on NPH and actrapid ( Group B). Hemoglobin A1c, Total cholesterol, Triglycerides, High density lipoproteins, Low density lipoproteins and serum IGF-1 levels were assessed. Full clinical examination including (weight, height, BMI), vital signs (pulse, blood pressure) was done and Fundus examination by Optomed Aurora® IQ handheld fundus camera. Results On comparing the 2 studied groups, There was no statistical significant difference as regarding fundus examination findings between studied groups (P value = 0.429). There was no statistically significant relation between diabetic retinopathy and serum IGF-1 (P value = .080 with Mean ± SD of serum IGF-1 level in patients with Normal fundus 14.8 ± 11 vs. Patients with Diabetic retinopathy 21.3 ± 16.9). There was statistically significant association between diabetic retinopathy and duration of diabetes (P value&amp;lt; 0.05 with Mean ± SD of diabetes duration in patients with Diabetic retinopathy 17.7 ± 6.9 vs. Patients with Normal fundus 14.6 ± 5.6). There was a statistical significant difference as regarding age (P value&amp;lt; 0.05 with Mean ± SD of age in Group B regimen 28.4 ± 6.7 vs. Group A 25.5 ± 4.9). Conclusion Serum IGF-1 levels showed no statistically significant difference in patients either on Glargine or NPH and also in patients either with normal fundus or with diabetic retinopathy. The incidence and severity of diabetic retinopathy in patients with type 1 diabetes mellitus is directly proportionate to duration of disease. No noted difference concerning diabetic retinopathy changes between patients on basal insulin therapy either Glargine or NPH.

Correlations between distal sensorimotor polyneuropathy and cardiovascular complications in diabetic patients in the North-Eastern region of Hungary.

Distal sensorimotor polyneuropathy (DSPN) is the earliest detectable and the most frequent microvascular complication in diabetes mellitus. Several studies have previously demonstrated correlations between cardiovascular risk factors in diabetic patients and independent risk factors for diabetic neuropathy. Our objective was to retrospectively analyze data from diabetic patients in the North-East region of Hungary who underwent neuropathy screening at the Diabetic Neuropathy Center, University of Debrecen, between 2017 and 2021. We aimed to investigate the correlations between cardiovascular risk factors and microvascular complications among patients with DSPN. The median age of the patients was 67 years, 59,6% were female, and 91,1% had type 2 diabetes. The prevalence of DSPN among the study subjects was 71.7%. A significantly longer duration of diabetes (p<0.01) was noted in patients with DSPN. Those with DSPN demonstrated a significantly higher HbA1c level (p<0.001) and a greater frequency of insulin use (p = 0.001). We observed a significantly elevated albumin/creatinine ratio (p<0.001) and a significantly lower eGFR (p<0.001) in patients with DSPN. Diabetic retinopathy exhibited a significantly higher prevalence in patients with DSPN (p<0.001). A higher prevalence of myocardial infarction (p<0.05), ischemic heart disease (p<0.001), peripheral arterial disease (p<0.05) and a history of atherosclerosis (p<0.05) was observed in patients with DSPN. In a multivariate logistic regression analysis, the following factors were independently associated with the presence of DSPN: higher HbA1c (OR:2.58, 95% CI:1.89-3.52, p<0.001), age (OR:1.03, 95% CI:1.01-1.05, p = 0.006), albumin/creatinine ratio above 3 mg/mmol (OR:1.23, 95% CI:1.06-1.45, p = 0.008), retinopathy (OR:6.06, 95% CI:1.33-27.53, p = 0.02), and composite cardiovascular endpoint (OR:1.95, 95% CI:1.19-3.19, p = 0.008). Our study revealed that age, elevated HbA1c levels, significant albuminuria, retinopathy, and cardiovascular complications may increase the risk of DSPN. Further investigation of these associations is necessary to understand the impact of patient characteristics during the treatment of diabetic neuropathy.

Hypomagnesemia in Patients with Type 2 Diabetes Mellitus.

Recent research has shown that low serum levels of magnesium are often linked to both microvascular and macrovascular complications in individuals with diabetes mellitus. Hence, monitoring of serum magnesium levels is needed in diabetic patients. Furthermore, the addition of magnesium through supplementation may present a novel therapeutic strategy for mitigating vascular complications in individuals with diabetes. To assess the prevalence of hypomagnesemia in type 2 diabetes mellitus patients and to assess the association between hypomagnesemia and microvascular complications of diabetes mellitus in a tertiary care hospital in North Kerala. An analytical cross-sectional study was conducted at a tertiary care hospital involving 230 diabetic patients receiving outpatient and inpatient care in the Department of Internal Medicine at Government Medical College, Kozhikode, Kerala. The study took place from January 2018 to December 2018, during which serum magnesium levels were assessed and analyzed in relation to the patients' microvascular complications and glycemic control. We observed that 19.13% of the participants had hypomagnesemia. This condition was found to be more common among older individuals with diabetes, as indicated by a p-value of 0.022. However, there were no significant differences in serum magnesium levels based on gender (p-value 0.18), body mass index (BMI) (p-value 0.223), or the duration of diabetes (p-value 0.36). The prevalence of diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy was higher in diabetics with hypomagnesemia than their counterparts with normal magnesium, with a p-value of 0.001, 0.001, and 0.001, respectively. There was a significant negative correlation obtained between serum magnesium and glycated hemoglobin (HbA1C) values (Pearson coefficient = -0.240 and p-value = <0.01) and fasting blood sugar (FBS) values (Pearson coefficient = -0.265 and p-value = <0.01). Hypomagnesemia is negatively correlated with HbA1C and FBS but not related to duration of diabetes and gender. The prevalence of microvascular complications was higher among the diabetics with hypomagnesemia.

A Study of the Mean Platelet Volume and Plasma Fibrinogen in Type Two Diabetes Mellitus Patients Versus Healthy Controls and Their Role as Early Markers of Diabetic Microvascular Complications.

Background Mean platelet volume (MPV) is considered an emerging biological marker of platelet function and activity. Higher MPV has been scientifically linked to diabetes mellitus, metabolic syndrome, stroke, and coronary artery disease. Plasma fibrinogen is a circulating glycoprotein, serving as an acute inflammatory marker ultimately leading to enhanced atherogenic plaque formation. We conducted this study to evaluate the crucial role of MPV and plasma fibrinogen, which showed elevated levels in diabetes mellitus patients compared to non-diabetic healthy individuals. This study also elaborates on the pivotal role that MPV and plasma fibrinogen levels play in the pathogenesis of microvascular complications, which progress and eventually lead to mortality in patients with type 2 diabetes mellitus. Methodology This study is a single-center hospital-based study including120 type 2 diabetes mellitus patients and 120 healthy non-diabetic individuals. It is across-sectional and observational study. The study wasconductedover a period of one and a half years in a medical college and hospital in a semi-urban locality in Western Maharashtra, India. We obtained informed written consent from the patients. All patients underwent thorough clinical assessment, and data were collectedusing proformas, which were latertabulated and entered in Microsoft Excel sheets. Later, the statistical data analysis was performed.Plasma fibrinogen was performed by photo-optical clot detection. MPV was analyzed by coulter principle in the central laboratory department of the parent institute. Patients above 18 years with cases of type 2 diabetes mellitus with or without any related complications, while the controls are healthy non-diabetic individuals attending the outpatient and inpatient departments of General Medicine. We excluded patients under the age of 18 years, those diagnosed with type 1 diabetes mellitus, hematological conditions associated with anemia and abnormal platelet counts, pregnant females, any acute or chronic infections, patients currently on antiplatelet medication and other drugs affecting the platelets, and all critical patients. Results The majority of patients in our study were in the age group of 41-50 years, with 49.2% having one or more microvascular complications of diabetes mellitus. In our study, out of 120 cases, 3.3% and 23.3% had raised MPV and fibrinogen levels, respectively, above the normal range. When compared with males and females, there was no statistically significant difference in the mean value of MPV and fibrinogen. On the t-test (p < 0.05), there was a statistically significant difference in the mean value of MPV and fibrinogen level between diabetics with and without microvascular complications. The t-test (p < 0.05) showed that there was a statistically significant difference among cases in the mean values of MPV and plasma fibrinogen in relation to retinopathy, nephropathy, and neuropathy, which are all microvascular complications of diabetes. Conclusion The study reveals higher levels of MPV and fibrinogen in diabetic patients compared to non-diabetic healthy individuals. In addition,higher levels of MPV and fibrinogen were present in patients with microvascular complications, correlated with age and diabetes duration.

Hybrid Explainable Artificial Intelligence Models for Targeted Metabolomics Analysis of Diabetic Retinopathy.

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes mellitus, and early detection is crucial for effective management. Metabolomics profiling has emerged as a promising approach for identifying potential biomarkers associated with DR progression. This study aimed to develop a hybrid explainable artificial intelligence (XAI) model for targeted metabolomics analysis of patients with DR, utilizing a focused approach to identify specific metabolites exhibiting varying concentrations among individuals without DR (NDR), those with non-proliferative DR (NPDR), and individuals with proliferative DR (PDR) who have type 2 diabetes mellitus (T2DM). A total of 317 T2DM patients, including 143 NDR, 123 NPDR, and 51 PDR cases, were included in the study. Serum samples underwent targeted metabolomics analysis using liquid chromatography and mass spectrometry. Several machine learning models, including Support Vector Machines (SVC), Random Forest (RF), Decision Tree (DT), Logistic Regression (LR), and Multilayer Perceptrons (MLP), were implemented as solo models and in a two-stage ensemble hybrid approach. The models were trained and validated using 10-fold cross-validation. SHapley Additive exPlanations (SHAP) were employed to interpret the contributions of each feature to the model predictions. Statistical analyses were conducted using the Shapiro-Wilk test for normality, the Kruskal-Wallis H test for group differences, and the Mann-Whitney U test with Bonferroni correction for post-hoc comparisons. The hybrid SVC + MLP model achieved the highest performance, with an accuracy of 89.58%, a precision of 87.18%, an F1-score of 88.20%, and an F-beta score of 87.55%. SHAP analysis revealed that glucose, glycine, and age were consistently important features across all DR classes, while creatinine and various phosphatidylcholines exhibited higher importance in the PDR class, suggesting their potential as biomarkers for severe DR. The hybrid XAI models, particularly the SVC + MLP ensemble, demonstrated superior performance in predicting DR progression compared to solo models. The application of SHAP facilitates the interpretation of feature importance, providing valuable insights into the metabolic and physiological markers associated with different stages of DR. These findings highlight the potential of hybrid XAI models combined with explainable techniques for early detection, targeted interventions, and personalized treatment strategies in DR management.

Advances in Structural and Functional Retinal Imaging and Biomarkers for Early Detection of Diabetic Retinopathy.

Diabetic retinopathy (DR), a vision-threatening microvascular complication of diabetes mellitus (DM), is a leading cause of blindness worldwide that requires early detection and intervention. However, diagnosing DR early remains challenging due to the subtle nature of initial pathological changes. This review explores developments in multimodal imaging and functional tests for early DR detection. Where conventional color fundus photography is limited in the field of view and resolution, advanced quantitative analysis of retinal vessel traits such as retinal microvascular caliber, tortuosity, and fractal dimension (FD) can provide additional prognostic value. Optical coherence tomography (OCT) has also emerged as a reliable structural imaging tool for assessing retinal and choroidal neurodegenerative changes, which show potential as early DR biomarkers. Optical coherence tomography angiography (OCTA) enables the evaluation of vascular perfusion and the contours of the foveal avascular zone (FAZ), providing valuable insights into early retinal and choroidal vascular changes. Functional tests, including multifocal electroretinography (mfERG), visual evoked potential (VEP), multifocal pupillographic objective perimetry (mfPOP), microperimetry, and contrast sensitivity (CS), offer complementary data on early functional deficits in DR. More importantly, combining structural and functional imaging data may facilitate earlier detection of DR and targeted management strategies based on disease progression. Artificial intelligence (AI) techniques show promise for automated lesion detection, risk stratification, and biomarker discovery from various imaging data. Additionally, hematological parameters, such as neutrophil-lymphocyte ratio (NLR) and neutrophil extracellular traps (NETs), may be useful in predicting DR risk and progression. Although current methods can detect early DR, there is still a need for further research and development of reliable, cost-effective methods for large-scale screening and monitoring of individuals with DM.

PLK-3-mediated phosphorylation of BAP1 prevents diabetic retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, and its main clinical manifestation is retinal vascular dysfunction. DR causes blindness and is a problem with significant global health implications. However, treating DR is still challenging. In this study, we aimed to explore the role of polo-like kinase-3 (PLK-3) and the potential regulatory mechanism in DR. Sprague-Dawley rats were injected intraperitoneally with streptozotocin (STZ, 60 mg/kg) to induce a rat model of DR, and rat retinal microvascular endothelial cells (RRMECs) were treated with high glucose (HG, 25 mmol/L glucose) to develop a cell model of DR. We found that PLK-3 was significantly downregulated in the retinal tissues of STZ-induced diabetic rats and HG-induced RRMECs. Lentivirus-mediated PLK-3 overexpression alleviated the histological damages in DR rats. After HG stimulation, cell proliferation, migration, and angiogenesis in RRMECs were inhibited after PLK-3 upregulation. By using label-free proteomics, we identified 82 differentially expressed proteins downstream of PLK-3, including BRCA1-associated protein 1 (BAP1), which was significantly upregulated in PLK-3-overexpressed RRMECs compared to control cells under the HG condition. In vivo and in vitro assays indicated that the forced expression of PLK-3 increased the phosphorylation of BAP1 at serine 592 and caspase-8 expression. Detailed evidence showed that BAP1-shRNA-mediated knockdown restored the cell function in HG-treated RRMECs when PLK-3 was overexpressed. Collectively, this study shows that PLK-3 alleviates retinal vascular dysfunction in DR by inhibiting the phosphorylation of BAP1. Thus, PLK-3 may develop as a promising target for the therapy of DR.

Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy.

Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the well-known anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and in vitro models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different in vitro models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively), was able to significantly reduce (p < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly (p < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose vs . axitinib 1 µM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action.

NR2E3 inhibits the inflammation and apoptosis in diabetic retinopathy by regulating the AHR/IL-17A signaling pathway.

Diabetic retinopathy (DR) is the most prevalent microvascular complication of diabetes mellitus, and it is the primary cause of blindness in the working-age population worldwide. Nevertheless, the pathogenic molecular mechanisms of DR remain elusive. Hub genes were identified through bioinformatics analysis in the GSE102485 and GSE60436 datasets. The DR mouse model was induced using streptozotocin (STZ, 150mg/kg), and pathological changes in retinal tissue were assessed via HE staining. Apoptosis in retinal tissue cells was evaluated by the TUNEL assay. RT-qPCR and ELISA assays were employed to measure hub genes and inflammatory factor levels, respectively. The aryl hydrocarbon receptor (AHR)/interleukin (IL)-17A (AHR/IL-17A) pathway-associated proteins were detected by western blot. In the high glucose (HG)-induced ARPE-19 cells, CCK-8 and flow cytometry were used to perform cell function studies. Six hub genes associated with DR were screened. The expression levels of RHO, PRPH2, CRX, RCVRN, and NR2E3 were reduced, while the COL1A2 was elevated. NR2E3 overexpression reduced inflammatory factor (TNF-α, IL-1β, and IL-6) and cell apoptosis levels in DR. Furthermore, NR2E3 overexpression promoted HG-induced ARPE-19 cell proliferation. Mechanistically, NR2E3 overexpression facilitated the protein expression of AHR, while suppressing the IL-17 and ACT1 expressions. The introduction of Kyn-101, an AHR inhibitor, notably reversed the inhibitory effects of NR2E3 overexpression on inflammation and apoptosis, which were validated both in vivo and in vitro. NR2E3 inhibits the inflammation and apoptosis by regulating the AHR/IL-17A pathway, providing new insights into the DR treatment.

Diabetic nephropathy in patients with type 2 diabetes mellitus and its correlation with diabetic retinopathy

Objective: the present study aimed to evaluate the prevalence of diabetic nephropathy and diabetic retinopathy, in addition to the associations that can be established between these microvascular complications of diabetes mellitus. Methods: this was a retrospective study, a systematic review without meta-analysis. The authors used the Pubmed and SciELO databases to search the terms “diabetic nephropathy”, “diabetic retinopathy” and “type 2 diabetes”, including publications dated 2011 to 2021. Results/Discussion: the results presented were a synthesis of patients with both pathologies and their correlations, in addition to associated laboratory changes and agreement between the stages or severity of both conditions. Conclusions: DN and DR are pathologies that are directly interconnected and cause repercussions for patients.

STAT3-induced upregulation of lncRNA TTN-AS1 aggravates podocyte injury in diabetic nephropathy by promoting oxidative stress.

Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus (DM), being the second cause of end-stage renal disease globally. Podocyte injury is closely associated with DN developmen. Our study aimed to investigate the role of long non-coding RNA (lncRNA) TTN-AS1 in DN-associated podocyte injury. The mouse podocyte cell line (MPC5) and human primary podocytes were stimulated by high glucose (HG; 30nM glucose) to establish the cellular model of DN. Before HG stimulation, both podocytes were transfected with sh-TTN-AS1#1/2 or pcDNA3.1/STAT3 to evaluate the influence of TTN-AS1 knockdown or STAT3 overexpression on HG-induced podocyte injury. TTN-AS1 and STAT3 expression in both podocytes was examined by RT-qPCR. Cell viability and death were assessed by CCK-8 and LDH release assay. ELISA was adopted for testing IL-6 and TNF-α contents in cell supernatants. The levels of oxidative stress markers (ROS, MDA, SOD, and GSH) in cell supernatants were determined by commercial kits. Western blotting was used for measuring the expression of fibrosis markers (fibronectin and α-SMA and podocyte function markers (podocin and nephrin) in podocytes. HG stimulation led to decreased cell viability, increased cell death, fibrosis, inflammation, cell dysfunction and oxidative stress in podocytes. However, knockdown of TTN-AS1 ameliorated HG-induced podocyte injury. Mechanically, the transcription factor STAT3 interacted with TTN-AS1 promoter and upregulated TTN-AS1 expression. STAT3 overexpression offset the protective effect of TTN-AS1 silencing on HG-induced podocyte damage. Overall, STAT3-mediated upregulation of lncRNA TTN-AS1 could exacerbate podocyte injury in DN through suppressing inflammation and oxidative stress.

Serum vascular endothelial growth factor levels and some characteristics of diabetic retinopathy patients

Diabetic retinopathy (DR) is a dangerous microvascular complication of diabetes mellitus (DM). The escalating prevalence of diabetes increases the rate of DR patients in Vietnam. Numerous studies have indicated that serum vascular endothelial growth factor (VEGF) can be used as a marker for monitoring the progression of this disease. Our study included 150 diabetic patients and 75 healthy individuals in the control group. Our study included 150 diabetic patients and a control group of 75 healthy individuals. We investigated the association between serum VEGF levels and some characteristics in diabetic retinopathy patients. Clinical data (pulse, blood pressure, medical history, and body mass index) and paraclinical data (Glucose, HbA1c) were collected. Serum samples were analyzed to determine VEGF concentrations. Our study fond that serum VEGF levels were higher in the group with DR compared to the other two groups and exhibited a correlation with glucose levels in diabetic patients (p &lt; 0.05).

Research Progress on Podocyte Pyroptosis in Diabetic Nephropathy.

Pyroptosis is a recently discovered type of lytic-programmed cell necrosis. The process involves cells assembling an inflammasome and cleaving gasdermin (GSDM) to trigger the release of pro-inflammatory cytokines that eventually induce inflammatory cell death. Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus, which leads to end-stage renal disease. Podocyte damage or loss is an important feature of diabetic kidney injury. Pyroptosis involvement in podocyte injury is closely associated with DN progression, manifesting as increased renal fibrosis, glomerulosclerosis, and tubular injury. The study aims to elucidate the mechanism of pyroptosis and summarize the pathways and potential inhibitors related to pyroptosis activation in DN podocytes. We undertook a search of bibliographic databases for peer-reviewed research literature on various aspects of pyroptosis. Multiple different pathways mediate podocyte pyroptosis to promote DN progression. Inhibition of pyroptosis can reduce podocyte damage and improve renal function in DN, suggesting that pyroptosis may help identify potential new therapeutic targets for DN treatment.

Study on the bioactive ingredients and mechanism of Huangqi against diabetic retinopathy based on network pharmacology and experimental verification.

Diabetic retinopathy (DR) is one of the most well-known microvascular complications of diabetes mellitus. As a traditional Chinese medicine, Huangqi (HQ), has been used for treating DR for a long time. However, its anti-DR active ingredients and mechanism are still unknown. Therefore, we designed this study to explore the active components and mechanism of HQ against DR via network pharmacology analysis. The ingredients of HQ, and potential targets of HQ and DR were obtained from public databases. We used the protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment, and Gene Ontology (GO) analysis to identify core targets and pathways of HQ against DR. Finally, molecular docking and vitro experiments were applied to validate our results. A total of 34 potential targets of HQ against DR were obtained. Based on PPI network, VEGFA, PTGS2, Interleukin-6 (IL-6), and CCL2 were considered as core targets. GO analysis involved 692 biological processes, 21 cellular components, and 35 molecular functions. KEGG enrichment analysis manifested that the anti-DR effect of HQ was mainly mediated via the AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that kaempferol had higher affinity with CCL2, IL-6, VEGFA, and PTGS2. The vitro experiments showed that the mRNA expressions of CCL2, IL-6, VEGFA, and PTGS2 in ARPE-19 cells were differentially decreased after kaempferol treatment. This study preliminarily unveiled that the therapeutic efficacy of HQ against DR might be attributed to the reduced expression of CCL2, IL-6, VEGFA, and PTGS2.

Developing screening tools to estimate the risk of diabetic kidney disease in patients with type 2 diabetes mellitus.

Diabetic kidney disease (DKD) is an important microvascular complication of diabetes mellitus (DM). This study aimed to develop predictive nomograms to estimate the risk of DKD in patients with type 2 diabetes mellitus (T2DM). The medical records of patients with T2DM in our hospital from March 2022 to March 2023 were retrospectively reviewed. The enrolled patients were randomly selected for training and validation sets in a 7:3 ratio. The models for predicting risk of DKD were virtualized by the nomograms using logistic regression analysis. Among the enrolled 597 patients, 418 were assigned to the training set, while 179 were assigned to the validation set. Using the predictors included glycated hemoglobin A1c (HbA1c), high density lipoprotein cholesterol (HDL-C), presence of diabetic retinopathy (DR) and duration of diabetes (DD), we constructed a full model (model 1) for predicting DKD. And using the laboratory indexes of HbA1c, HDL-C, and cystatin C (Cys-C), we developed a laboratory-based model (model 2). The C-indexes were 0.897 for model 1 and 0.867 for model 2, respectively. The calibration curves demonstrated a good agreement between prediction and observation in the two models. The decision curve analysis (DCA) curves showed that the two models achieved a net benefit across all threshold probabilities. We successfully constructed two prediction models to evaluate the risk of DKD in patients with T2DM. The two models exhibited good predictive performance and could be recommended for DKD screening and early detection.