Severe Microvascular Complications Research Articles

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

A study of the genotyping and vascular endothelial growth factor polymorphism differences in diabetic and diabetic retinopathy patients

BackgroundRetinopathy is one of the major causes of visual impairment which is the most severe microvascular complication of diabetes mellitus (DM). The aim of this study was to evaluate the association between diabetic retinopathy (DR) and two SNPs (− 152G > A and − 165C > T) located in the promoter region of the vascular endothelial growth factor (VEGF) gene in a small sample from Egyptian population. One hundred diabetic patients without retinopathy (DWR) and two hundred diabetic patients with retinopathy were included in this study. Genotype analysis for the two SNPs (− 152G > A and − 165C > T) was assessed by using the PCR–RFLP technique. In addition, the serum protein level of VEGF was measured by ELISA assay.ResultsThe results showed a significant relationship between − 152G > A (rs13207351) polymorphism and both proliferative and non-proliferative retinopathy in genotypes (GG, GA, AA). The risk factor increment in the mutant heterozygous genotype (GA) was significantly increased in NPDR compared to PDR (OR = 16.3, 95%CI = 0.80–331.7); (OR = 20.4, 95%CI = 1.08–385.3), respectively. There was no significance between VEGF − 165C > T (rs79469752) gene polymorphism and retinopathy. Moreover, the serum protein level of VEGF showed a highly significant increase (P = 0.0001) in PDR (Mean ± SD = 3691 ± 124.9) when compared to both DWR (Mean ± SD = 497.3 ± 18.51) and NPDR (Mean ± SD = 1674.5 ± 771.7). These results were supported by the increased level of VEGF in serum protein which is positively correlated with the severity of retinopathy. Measuring VEGF protein level in DR patients would help as a biomarker in early diagnosis.ConclusionThe increase in the mutant heterogeneous GA genotype in VEGF − 152G > A SNP could be a risk factor for the progression of severe retinopathy in diabetic patients.

POS-357 CAMP-RESPONSE ELEMENT BINDING PROTEIN MEDIATES PODOCYTE INJURY IN DIABETIC NEPHROPATHY BY TARGETING LNCRNA DLX6-AS1

Diabetic nephropathy (DN) is one of the most severe microvascular complications of diabetic mellitus, and main cause of renal failure in patients with end-stage renal disease. In our previous study, lncRNA DLX6-AS1 (DLX6-AS1, Dlx6-os1 in mice) was found to be associated with the extent of albuminuria in DN patients. Furthermore, the lack of Dlx6-os1 was pivotal in switching off the inflammatory response in a diabetic mouse model. However, the regulatory factors responsible for elevated DLX6-AS1 in DN remains unknown.

Establishment of a human induced pluripotent stem cell line (CSUASOi008-A) from a type 2 diabetic patient with retinopathy

Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes, and the leading cause of preventable blindness in working-aged people. Here, we generated an induced pluripotent stem (iPS) cell line using blood-derived cells from a patient with DR. Peripheral blood mononuclear cells (PBMCs) were reprogrammed with Sendai virus.

The palliative effects of folic acid on retinal microvessels in diabetic retinopathy via regulating the metabolism of DNA methylation and hydroxymethylation

ABSTRACT Diabetic retinopathy (DR) is one of the severe microvascular complications of diabetes. The protective effects of FA on retinal vascular endothelial cells against high glucose levels involve in multiple aspects in DR; however, the underlying mechanism is not fully elucidated. In present study, we investigated the transcriptome as well as genome-wide DNA methylation and hydroxymethylation signature in human retinal microvascular endothelial ACBRI 181 cells cultured within high glucose (HG) medium supplemented with or without FA by RNA-seq, MeDIP-seq, and hMeDIP-seq. Total 3308 differential expressed genes (DEGs) were involved in multiple biological processes and molecular functions containing angiogenesis, inflammation, S-adenosyl methionine metabolism, and hypoxia response. Moreover, the global DNA methylation and hydroxymethylation in ACBRI 181 cells with FA treatment were both compromised compared to HG. Combined with transcriptome data, four subclusters of DEGs with hyper- or hypomethylated promoters were further verified. Unexpectedly, promoters of these 487 genes all displayed a pattern of increased DNA hydroxymethylation. Furthermore, hyperglycemia rat model was established and administered with FA. The DNA methylation and hydroxymethylation changes of selected target genes COL1A1, ITGA7, MMP-14, and VEGFB confirmed by MeDIP-qPCR were consistent with the results in human ACBRI 181 cells. Finally, the presence of activated DNMT1 and TET2 induced by FA was determined in ACBRI 181 cells and hyperglycemia rat. Taken together, this research provided a resource of expression and epigenetic profiles in retinal microvascular endothelial cell, emphasizing a pharmacological mechanism of FA on DNA methylation and hydroxymethylation regulation in retinal microvessel cells of DR.

OCT-A PICTURE OF THE EYEFOOL IN CHRONIC RENAL FAILURE

Renal retinopathy is a severe late microvascular complication of CRF and one of the causes of blindness in the world among people of working age. OCT-A makes it possible to detect microvascular changes in the retina even in the absence of clinical manifestations of renal retinopathy on the fundus. Markers of changes in the microcirculatory bed of the retina in renal retinopathy arequalitative and quantitative changes in the foveal avascular zone and a decrease in the density of the capillary network, which increase with the progression of the disease.Keywords:Renal retinopathy, CRF, OCT, angiography, retinal changes

Circ_0000491 Promotes Apoptosis, Inflammation, Oxidative Stress, and Fibrosis in High Glucose-Induced Mesangial Cells by Regulating miR-455-3p/Hmgb1 Axis

Background: Diabetic nephropathy (DN) is a severe microvascular complication of diabetes. Recently, many circular RNAs can exert crucial roles in DN progression. This study intended to explore the role and mechanism of circ_0000491 in DN. Methods: The DN mouse model was constructed by streptozotocin injection, and the DN cell model was established using high glucose (HG) treatment in mouse mesangial cells (SV40-MES13). The expression of circ_0000491 and microRNA-455-3p (miR-455-3p) was detected by quantitative real-time polymerase chain reaction. Cell apoptosis was evaluated by flow cytometry. The expression levels of high-mobility group box 1 (Hmgb1) protein, apoptosis-related proteins, and fibrosis-related proteins were examined by the Western blot assay. The release of inflammatory cytokines was assessed by enzyme-linked immunosorbent assay. The oxidative stress factors were analyzed by corresponding kits. The predicted interaction between miR-455-3p and circ_0000491 or Hmgb1 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results: Circ_0000491 was overexpressed in the DN mouse model and HG-induced SV40-MES13 cells. Knockdown of circ_0000491 weakened HG-induced apoptosis, inflammation, oxidative stress, and fibrosis in SV40-MES13 cells. miR-455-3p was a direct target of circ_0000491, and miR-455-3p inhibition could reverse the role of circ_0000491 silencing in HG-induced SV40-MES13 cells. Moreover, Hmgb1 was a target gene of miR-455-3p, and miR-455-3p played a protective role against HG-induced cell injury by targeting Hmgb1. In addition, circ_0000491 regulated Hmgb1 expression by sponging miR-455-3p. Conclusion: Circ_0000491 knockdown inhibited HG-induced apoptosis, inflammation, oxidative stress, and fibrosis in SV40-MES13 cells by regulating miR-455-3p/Hmgb1 axis.

Huayu Tongluo Recipe Attenuates Renal Oxidative Stress and Inflammation through the Activation of AMPK/Nrf2 Signaling Pathway in Streptozotocin- (STZ-) Induced Diabetic Rats.

Diabetic nephropathy (DN), a severe microvascular complication of diabetes, is one of the leading causes of end-stage renal disease. Huayu Tongluo Recipe (HTR) has been widely used in the clinical treatment of DN in China, and its efficacy is reliable. This study aimed to explore the renoprotective effect of HTR and the underlying mechanism. Male Sprague-Dawley rats were fed with high sugar and fat diet combined with an intraperitoneal injection of STZ to establish the diabetic model. Rats in each group were respectively given drinking water, HTR, and irbesartan by gavage for 16 weeks. 24-hour urine samples were collected every 4 weeks to detect the content of total protein and 8-OHdG. Blood samples were taken to detect biochemical indicators and inflammatory markers at the end of 16th week. Renal tissue was collected to investigate pathological changes and to detect oxidative stress and inflammatory markers. AMPK/Nrf2 signaling pathway and fibrosis-related proteins were detected by immunohistochemistry, immunofluorescence, real-time PCR, and western blot. 24h urine total protein (24h UTP), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), and triglyceride (TG) were decreased in the rats treated with HTR, while there was no noticeable change of blood glucose. HTR administration decreased malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in kidneys, complying with reduced 8-OHdG in the urine. The levels of TNF-α, IL-1β, and MCP1 and the expression of nuclear NFκB were also lower after HTR treatment. Furthermore, HTR alleviated pathological renal injury and reduced the accumulation of extracellular matrix (ECM). Besides, HTR enhanced the AMPK/Nrf2 signaling and increased the expression of HO-1 while it inhibited the Nox4/TGF-β1 signaling in the kidneys of STZ-induced diabetic rats. HTR can inhibit renal oxidative stress and inflammation to reduce ECM accumulation and protect the kidney through activating the AMPK/Nrf2 signaling pathway in DN.

Roles of Gut Microbial Metabolites in Diabetic Kidney Disease.

Diabetes is a highly prevalent metabolic disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment. Diabetic kidney disease (DKD), which is one of the most frequent and severe microvascular complications of diabetes, is difficult to treat with contemporary glucose-lowering medications. The gut microbiota plays an important role in human health and disease, and its metabolites have both beneficial and harmful effects on vital physiological processes. In this review, we summarize the current findings regarding the role of gut microbial metabolites in the development and progression of DKD, which will help us better understand the possible mechanisms of DKD and explore potential therapeutic approaches for DKD.

Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66Shc.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes. Hyperglycemia-induced glomerular mesangial cells injury is associated with microvascular damage, which is an important step in the development of DN. Piperazine ferulate (PF) has been reported to exert protective effects against the progression of DN. However, whether PF prevents high glucose (HG)-induced mesangial cell injury remains unknown. The aim of the present study was to investigate the effects of PF on HG-induced mesangial cell injury and to elucidate the underlying mechanisms. Protein and mRNA expression levels were determined via western blot analysis and reverse transcription-quantitative PCR, respectively. IL-6 and TNF-α levels were measured using ELISA. Reactive oxygen species levels and NF-κB p65 nuclear translation were determined via immunofluorescence analysis. Apoptosis was assessed by measuring lactate dehydrogenase (LDH) release, as well as using MTT and flow cytometric assays. The mitochondrial membrane potential of mesangial cells was determined using the JC-1 kit. The results revealed that LDH release were increased; however, cell viability and mitochondrial membrane potential were decreased in the HG group compared with the control group. These changes were inhibited after the mesangial cells were treated with PF. Moreover, PF significantly inhibited the HG-induced production of inflammatory cytokines and the activation of NF-κB in mesangial cells. PF also attenuated the HG-induced upregulation of the expression levels of fibronectin and collagen 4A1. Furthermore, the overexpression of p66Src homology/collagen (Shc) abolished the protective effect of PF on HG-induced mesangial cell injury. In vivo experiments revealed that PF inhibited the activation of inflammatory signaling pathways, glomerular cell apoptosis and mesangial matrix expansion in diabetic mice. Collectively, the present findings demonstrated that PF attenuated HG-induced mesangial cells injury by inhibiting p66Shc.

Efficacy and Safety of TangWang Prescription for Type 2 Non-Proliferative Diabetic Retinopathy: A Study Protocol for a Randomized Controlled Trial.

Background: Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes mellitus (DM), which results in blindness among adults worldwide. Presently, the efficacy of drug treatments for diabetic retinopathy (DR) is not satisfactory, thus urgently necessitating effective drug treatment measures. TangWang prescription (TWP) has been found to have retinal protection effects in previous clinical and basic research. However, there is a lack of rigorous, randomized, and controlled studies. This study aims to evaluate the efficacy and safety of TWP in delaying the development of DR. Methods: This study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial, consisting of 384 participants to be randomized in a 1:1 ratio in the treatment and control groups. Furthermore, the treatment and control groups will be administered the TangWang prescription and the placebo, respectively, each at a dose of one bag twice a day. The study period will last for 48 weeks. The primary outcome measure will be the changes in the degree of retinal microvascular lesions before and after treatment. The secondary outcome will be changes in the degree of hemangioma, microvascular bleeding, microvascular leakage, macular edema, and vision. All statistical tests will be two-sided, and a p < 0.05 will be considered statistically significant. Discussion: We hypothesize that the patients with DR will benefit from TangWang prescription, and in addition to the central random system and platform of dynamic information collection, the patients’ conditions will be monitored, and the data collected for analysis. If successful, this study will provide evidence that the TWP formulation delays in the progression of DR. Trial registration: The design of this trial has been registered with the ClinicalTrials.gov (NCT03025399).

Qishen Yiqi Dripping Pill Protects Against Diabetic Nephropathy by Inhibiting the Wnt/β-Catenin and Transforming Growth Factor-β/Smad Signaling Pathways in Rats.

Diabetic nephropathy is a severe microvascular complication of diabetes. Qishen Yiqi dripping pill (QYDP) has been reported to be a renal protective drug. However, the mechanisms remain unclear. This study was performed to investigate the mechanisms. In this study, Sprague-Dawley rats were injected with streptozotocin to generate a diabetes model. Diabetic rats were administered 150 or 300 mg/kg/day QYDP. After 8 weeks of treatment, serum creatinine, serum blood urea nitrogen, and 24-h urinary albumin were measured. Kidney histological staining and immunostaining were analyzed. Then, the renal tissue was analyzed with a genome expression array. The results showed that QYDP treatment reduced serum creatinine, blood urea nitrogen, and 24-h urinary albumin and improved kidney histology and fibrosis. The gene array revealed that the expression of 189 genes was increased, and that of 127 genes was decreased in the high dosage QYDP group compared with the diabetic group. Pathway and gene ontology analyses showed that the differentially expressed genes were involved in the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2 signaling pathways. QYDP reduced the renal Wnt1, catenin β1, Tgfb1, and Smad2 gene expression and β-catenin, TGF-β, Smad2, collagen I, α-smooth muscle actin, and fibronectin protein expression in diabetic rats. Our results provide the first evidence that QYDP performs its renal-protective function by inhibiting the Wnt/β-catenin and TGF-β/Smad2 signaling pathways in diabetic rats.

A Network Pharmacology-Based Approach for Exploring Key Active Compounds and Pharmacological Mechanisms of Tangshen Formula for Treatment of Diabetic Nephropathy

Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM). The occurrence and development of DN are related to multiple factors in the human body, which makes DN a complex disease, and the pathogeneses of DN have not yet been fully illustrated. Furthermore, DN lacks effective drugs for treatment nowadays. Chinese herbal medicine (CHM) often shows the feature of multicomponents, multitargets, multipathways, and synergistic effects and shows a promising source of new therapeutic drugs for DN. As a CHM, Tangshen Formula (TSF) was used to treat DN patients in China. However, its bioactive compounds and holistic pharmacological mechanisms on DN are both unclear. A network pharmacology approach was firstly applied to explore multiple active compounds and multiple key pharmacological mechanisms for TSF treating DN by drug-targeted interaction databases, herb-compound-target network, protein-protein interaction network, compound-target-pathway network, and analysis methods. And the results showed that TSF have the characteristic of multicomponents, multitargets, multipathways, and synergistic effects for treating DN. The quercetin, naringenin, kaempferol, and isorhamnetin as key active compounds and the PI3K-Akt signaling pathway, TNF signaling pathway, nonalcoholic fatty liver disease (NAFLD), focal adhesion, rap1 signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, and insulin resistance as the key molecular mechanisms play important roles in TSF treating DN. Moreover, quercetin, naringenin, kaempferol, and isorhamnetin were successfully detected in TSF by the UHPLC-MS/MS analysis method. And their concentrations were 0.224, 8.295, 0.0564, and 0.0879 mg·kg-1, respectively. The present findings not only provide new insights for a deeper understanding of the constituent basis and pharmacology of TSF but also provide guidance for further pharmacological studies on TSF.

Epiberberine ameliorated diabetic nephropathy by inactivating the angiotensinogen (Agt) to repress TGFβ/Smad2 pathway

BackgroundDiabetic nephropathy (DN) is a severe microvascular complication of diabetes with prominent morbidity and mortality. At present, there are hardly any effective drugs to treat DN. Epiberberine (EPI), an isoquinoline alkaloid, has attracted considerable attention due to its anti-hyperglycemic, anti-hyperlipidemic, and anti-inflammatory functions. However, whether there is a protective effect of EPI on DN has not been reported. PurposeThe research was aimed to investigate the activities of EPI alleviating kidney damage in db/db mice and to explore its possible mechanisms. Study designThe db/db mice and high-glucose (HG) induced glomerular mesangial cells (GMCs) were used to explore the protective effect of EPI on DN in vivo and in vitro. MethodsThe changes in fasting blood glucose, metabolic index, renal function, and histopathological morphology in db/db mice were detected to evaluate the therapeutic effect of EPI. Then, renal transcriptome and molecular docking were used to screen the key targets. Subsequently, HG-induced GMCs through mimicing the pathological changes in DN were utilized to study the renal protective effects of EPI and its potential mechanism. ResultsThe results in vivo showed that EPI administration for 8 weeks significantly alleviated diabetes-related metabolic disorders, improved renal functions, and relieved the histopathological abnormalities of renal tissue, especially renal fibrosis in db/db mice. The results in vitro showed that EPI inhibited the proliferation and induced the G2/M phase arrest of HG-induced GMCs. Moreover, a key gene Angiotensinogen (Agt) was screen out by the RNA-seq of kidney and molecular docking, and EPI reduced Agt, TGFβ1, and Smad2 expression in vitro and in vivo. Noteworthy, Agt knockdown by siRNA significantly attenuated these beneficial efficacies exerted by EPI, indicating that Agt played a crucial role in the process of EPI improving DN. ConclusionThese findings suggested that EPI might be a potential drug for the treatment of DN dependent on the Agt-TGFβ/Smad2 pathway.

Discovery of polypodiside as a Keap1-dependent Nrf2 activator attenuating oxidative stress and accumulation of extracellular matrix in glomerular mesangial cells under high glucose

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. High glucose has resulted in oxidative stress and following renal fibrosis as the crucial nodes of this disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating transcription of many antioxidant genes and suppressing synthesis of extracellular matrix. To discover Nrf2 activators targeting DN, we have evaluated polypodiside using cell-based assays. The results showed polypodiside inhibited the high glucose-induced self-limited proliferation of glomerular meangial cells. Activation of Nrf2 and enhanced transcription to antioxidant response elements were observed in the presence of polypodiside. Oxidative stress and accumulation of extracellular matrix induced by high glucose in glomerular meangial cells have been ameliorated by polypodiside. Further investigations revealed the effects of polypodiside on glomerular meangial cells were associated with activation of Nrf2. Co-immunoprecipitation of Nrf2 disclosed polypodiside disrupted the Kelch-like ECH-associated protein-1 (Keap1)-Nrf2 interaction. Molecular docking elucidated polypodiside could enter the Nrf2 binding cavity of Keap1 via interacting with the residues encompassing that cavity. These findings indicate polypodiside is a Keap1-dependent Nrf2 activator affording the catabatic effects against oxidative stress and accumulation of extracellular matrix in glomerular meangial cells under high glucose.

Comparing the incidence of major cardiovascular events and severe microvascular complications in patients with type 2 diabetes mellitus: A systematic review and meta-analysis

Comparing the incidence of major cardiovascular events and severe microvascular complications in patients with type 2 diabetes mellitus: A systematic review and meta-analysis

Prevalence and Risk Factors for Diabetic Peripheral Neuropathy in Type 2 Diabetic Patients From 14 Countries: Estimates of the INTERPRET-DD Study.

Aim: Diabetic peripheral neuropathy (DPN) is a common, severe microvascular complication of diabetes. Our study was to assess prevalence and risk factors for DPN in subjects with type 2 diabetes from 14 different countries.Methods: A total of 2,733 subjects with type 2 diabetes aged 18–65 years (45.3% men, mean duration of diabetes = 8.8 years) were included to perform this International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study in 14 countries. After a structured questionnaire was used in face-to-face interviews to collect sociodemographic characteristics and medical records of the participating subjects, laboratory tests were carried out for clinical measurement. Depressive symptoms were diagnosed and measured using the Patient Health Questionnaire-9. The potential risk factors for DPN were determined by multilevel mixed-effects logistic regression, accounting for clustering of participants within the country. Robustness of the estimates was assessed by sensitivity analysis.Results: The overall prevalence of DPN across different countries was 26.71%, whereas country-specific prevalences showed considerable variation. Multivariate analysis revealed that duration of diabetes (OR: 1.08 per 1-year increase, 95% CI: 1.06–1.09), poor glycemic control (OR: 1.11 per 1% increase in HbA1c, 95% CI: 1.05–1.18), and history of hypertension (OR: 1.58, 95% CI: 1.18–2.12), cardiovascular disease (OR: 2.07, 95% CI: 1.55–2.78) and depressive symptoms (OR: 1.92, 95% CI: 1.43–2.58) were independently and positively associated with the risk of DPN. Sensitivity analyses including or excluding patients from countries with extreme low or high prevalence of DPN yielded similar estimates in terms of trend and magnitude.Conclusions: This international study illustrates that more than a quarter of individuals with type 2 diabetes developed DPN. The prevalence was positively associated with the duration of diabetes, poor glycemic control, and history of hypertension, cardiovascular disease and depressive symptoms.

Features of the frequency of angio-, retino- and neuropathy, general clinical and anthropometric parameters in patients with type 1 diabetes with different levels of albumin in the urine depending on the level of cystatin C

Cystatin C improves the risk stratification among people with diabetic nephropathy, the risk of mortality, cardiovascular disease, disorders of the visual organ and nervous system in the preclinical and early stages. The aim of the study was to study the frequency of angio-, retino- and neuropathy, as well as differences in general clinical and anthropometric parameters in patients with type 1 diabetes (T1D) with different levels of albumin in the urine depending on cystatin C. The sample was 78 men and 62 women aged 22-26 years, patients with T1D, who were hospitalized in the therapeutic department №1 and №2 of the Vinnytsia Regional Highly Specialized Endocrinology Center. The control group consisted of 8 healthy men and 13 healthy women of the same age. The level of microalbuminuria and cystatin C was determined for all patients by enzyme-linked immunosorbent assay. The frequency of angio-, retino- and neuropathy, general clinical (systolic, diastolic, pulse) and anthropometric (height, weight, body surface area, waist circumference, body mass index) was assessed indicators. Statistical processing of the obtained results was performed in the license package “Statistica 5.5”, using non-parametric evaluation methods. It was found that in the group of men with cystatin C&lt;0.9, and in women with cystatin C&gt;0.9 with increasing albuminuria, the percentage of patients with more severe microvascular complications of T1D. In patients with diabetes mellitus 1 compared with the control group systolic blood pressure is significantly higher and increases with increasing albumin levels in the urine (with cystatin C&lt;0.9 – in men with normo-, microalbuminuria and proteinuria by 7.14%, 8.1% and 10.8%; in women with normo-, microalbuminuria by 7.5% and 10.0%, with cystatin C&gt;0.9 – in men with normo-, microalbuminuria by 4.9% and 7.2%, in women with proteinuria by 19.5%). Similar changes were found for diastolic blood pressure (with cystatin C&lt;0.9 – in men with proteinuria by 13.0%; in women with normo-, microalbuminuria by 11.4% and 13.4%; with cystatin C&gt;0.9 – in men with microalbuminuria by 9.0%; in women with normo- and proteinuria by 9.5% and 21.5%) and heart rate (with cystatin C&lt;0.9 – in men with microalbuminuria and proteinuria by 18.4% and 12.6%, in women with microalbuminuria by 9.13%; with cystatin C&gt;0.9 – in men with microalbuminuria by 12.0%, in women with normo-, microalbuminuria and proteinuria by 10.1%, 16.3% and 25.3%). In patients with T1D compared to the control group, the length of the body is significantly smaller and decreases with increasing levels of albumin in the urine (with cystatin C&lt;0.9 – in men with normo-, microalbuminuria and proteinuria by 3.6%, 6.7% and 9.0%; women with microalbuminuria by 1.9%, with cystatin C&gt;0.9 – in men with normo-, microalbuminuria by 5.2% and 7.3%, in women with normoalbuminuria and proteinuria by 2.6% and 4.3%). Similar changes were found in men for body weight (with cystatin C&lt;0.9 – with microalbuminuria and proteinuria by 13.6% and 30.1%; with cystatin C&gt;0.9 – with normo- and microalbuminuria by 10.2% and 25.4%) and body surface area (with cystatin C&lt;0.9 – with normo-, microalbuminuria and proteinuria by 5.8%, 10.8% and 18.9%; with cystatin C&gt;0.9 – with normo- and microalbuminuria by 8.2% and 16.2%). The size of the waist circumference in patients with T1D with normoalbuminuria is significantly higher, and in patients of other groups significantly less than in healthy subjects (with cystatin C&lt;0.9 – with normo-, microalbuminuria and proteinuria by 3.8%, 1.2% and 5.2%; cystatin C&gt;0.9 – with microalbuminuria by 5.1%). Compared to healthy women, the waist circumference was significantly higher in sick women (with cystatin C&lt;0.9 – with normo- and microalbuminuria by 11.2% and 10.7%; with cystatin C&gt;0.9 – with normo- and proteinuria by 9.7% and 6.0%). In patients with T1D men with proteinuria compared with the control group, the value of the body mass index was significantly lower by 9.7% (cystatin C&lt;0.9). The value of the body mass index was significantly higher in patients with normoalbuminuria and microalbuminuria – by 11.8% and 17.7% (cystatin C&lt;0.9), respectively, and in patients with proteinuria by 7.2% (cystatin C&gt;0.9) compared with healthy women. Thus, between healthy and patients with T1D with varying degrees of albuminuria, differences in general clinical and anthropometric parameters were found, and they are greater the higher the level of cystatin C.

A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy.

Chronic hyperglycemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50-60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients's quality of life. In the present review article, several hypotheses associated with the pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, among them metabolic pathways associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF- κB). The review article also possesses pathogenetic and pharmacologic treatments along with others, including acupressure, lidocaine, and capsaicin for DPN. It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.

Kidney-targeted astaxanthin natural antioxidant nanosystem for diabetic nephropathy therapy

Diabetic nephropathy (DN) is a frequent and severe microvascular complication associated with oxidative stress of diabetes mellitus. A novel astaxanthin-based natural antioxidant nanosystem, namely AST-GLU-LIP, with preferential renal uptake and bioavailability were prepared and applied for treatment of diabetic nephropathy in rats. Our results of kidney-targeted evaluation showed that glucose-PEG600-DSPE ligand modified AST liposomes could be specifically transported by overexpressed GLUT1 on the membrane of glomerular mesangial cells and achieved excellent kidney-targeted drug delivery. In addition, the results of pharmacodynamics and therapeutics in DN rats demonstrated that AST-GLU-LIP could improve the bioavailability and antioxidant capacity of AST to scavenge redundant ROS induced by oxidative stress. AST-GLU-LIP could also significantly improve the renal pathological morphology to protect the kidney as a therapeutic drug for diabetic nephropathy.