1,8-cineole ameliorates experimental diabetic angiopathy by inhibiting NLRP3 inflammasome-mediated pyroptosis in HUVECs via SIRT2.

Accumulating evidence strongly support the key role of NLRP3-mediated pyroptosis in the pathogenesis and progression of vascular endothelial dysfunction associated with diabetes mellitus. Various studies have demonstrated that the activation or upregulation of Silent Information Regulation 2 homolog 2 (SIRT2) exerts inhibitory effect on the expression of NLRP3. Although 1,8-cineole has been found to protect against endothelial dysfunction and cardiovascular diseases, its role and mechanism in diabetic angiopathy remain unknown. Therefore, the aim of this study was to investigate the ameliorative effect of 1,8-cineole through SIRT2 on pyroptosis associated with diabetic angiopathy in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanism. The findings revealed that 1,8-cineole exhibited a protective effect against vascular injury and ameliorated pathological alterations in the thoracic aorta of diabetic mice. Moreover, it effectively mitigated pyroptosis induced by palmitic acid-high glucose (PA-HG) in HUVECs. Treatment with 1,8-cineole effectively restored the reduced levels of SIRT2 and suppressed the elevated expression of pyroptosis-associated proteins. Additionally, our findings demonstrated the occurrence of NLRP3 deacetylation and the physical interaction between NLRP3 and SIRT2. The SIRT2 inhibitor AGK2 and siRNA-SIRT2 effectively attenuated the effect of 1,8-cineole on NLRP3 deacetylation in HUVECs and compromised its inhibitory effect against pyroptosis in HUVECs. However, overexpression of SIRT2 inhibited PA-HG-induced pyroptosis in HUVECs. 1,8-Cineole inhibited the deacetylation of NLRP3 by regulating SIRT2, thereby reducing pyroptosis in HUVECs. In conclusion, our findings suggest that PA-HG-induced pyroptosis in HUVECs plays a crucial role in the development of diabetic angiopathy, which can be mitigated by 1,8-cineole.

The role of glucagon-like peptide-1/GLP-1R and autophagy in diabetic cardiovascular disease.

Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.

Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes.

Single nucleotide polymorphisms (SNP) in the RAC1 (Rac family small GTPase 1) gene have recently been linked to type 2 diabetes (T2D) and hyperglycemia due to their contribution to impaired redox homeostasis. The present study was designed to determine whether the common SNPs of the RAC1 gene are associated with diabetic complications such as neuropathy (DN), retinopathy (DR), nephropathy, angiopathy of the lower extremities (DA), and diabetic foot syndrome. A total of 1470 DNA samples from T2D patients were genotyped for six common SNPs by the MassArray Analyzer-4 system. The genotype rs7784465-T/C of RAC1 was associated with an increased risk of DR (p = 0.016) and DA (p = 0.03) in males, as well as with DR in females (p = 0.01). Furthermore, the SNP rs836478 showed an association with DR (p = 0.005) and DN (p = 0.025) in males, whereas the SNP rs10238136 was associated with DA in females (p = 0.002). In total, three RAC1 haplotypes showed significant associations (FDR < 0.05) with T2D complications in a sex-specific manner. The study's findings demonstrate, for the first time, that the RAC1 gene's polymorphisms represent novel and sex-specific markers of neuropathy and microvascular complications in type 2 diabetes, and that the gene could be a new target for the pharmacological inhibition of oxidative stress as a means of preventing diabetic complications.

Prediction of microvascular complications in diabetic patients without obstructive coronary stenosis based on peri-coronary adipose tissue attenuation model.

OBJECTIVES: To investigate the predictive value of peri-coronary adipose tissue (PCAT) attenuation for microvascular complications in diabetic patients without significant stenosis and to develop a prediction model for early risk stratification. METHODS: This study retrospectively included patients clinically identified for coronary computed tomography angiography (CCTA) and type 2 diabetes between January 2017 and December 2020. All patients were followed up for at least 1 year. The clinical data and CCTA-based imaging characteristics (including PCAT of major epicardial vessels, high-risk plaque features) were recorded. In the training cohort comprising of 579 patients, two models were developed: model 1 with the inclusion of clinical factors and model 2 incorporating clinical factors + RCAPCAT using multivariable logistic regression analysis. An internal validation cohort comprising 249 patients and an independent external validation cohort of 269 patients were used to validate the proposed models. RESULTS: Microvascular complications occurred in 69.1% (758/1097) of the current cohort during follow-up. In the training cohort, model 2 exhibited improved predictive power over model 1 based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) with lower prediction error (Brier score = 0.146 versus 0.164) compared to model 1. Model 2 accurately categorized 78.58% of patients with diabetic microvascular complications. Similar performance of model 2 in the internal validation cohort and the external validation cohort was further confirmed. CONCLUSIONS: The model incorporating clinical factors and RCAPCAT predicts the development of microvascular complications in diabetic patients without significant coronary stenosis. KEY POINTS: • Hypertension, HbA1c, duration of diabetes, and RCAPCAT were independent risk factors for microvascular complications. • The prediction model integrating RCAPCAT exhibited improved predictive power over the model only based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) and showed lower prediction error (Brier score=0.146 versus 0.164).

Correlación entre pie diabético y retinopatía diabética en pacientes del hospital provincial de Zaire, Angola

Introducción: La diabetes mellitus produce complicaciones, dentro de las cuales se describen la neuropatía diabética y la angiopatía diabética, que en presencia de estas puede llegarse a un cuadro de pie diabético sin dejar de mencionar la pérdida visual por retinopatía diabética. Objetivo: Determinar la correlación existente entre la aparición de pie diabético y la presencia o no de la retinopatía diabética en pacientes del Hospital Provincial "María Eugenia Neto", Zaire, República de Angola, en el período comprendido entre septiembre de 2020 a septiembre de 2022. Método: Se realizó un estudio descriptivo en 181 pacientes de la consulta de pie diabético del hospital antes dicho, donde se describieron variables, tales como: edad, sexo, enfermedades crónicas asociadas, presencia o no de retinopatía diabética, úlceras en miembros inferiores, amputación en miembros inferiores y años con diabetes. Se realizaron pruebas de correlación bivariable, se analizó el coeficiente de correlación de Pearson. Resultados: El promedio de edad fue de 59,3 años, predominó el grupo etario de más de 70 años (28,2 %) y el sexo femenino (57,5 %). Presentaron amputaciones previas un 41,8 % y úlceras un 40,1 %. Sin tratamiento estable el 65,19 %, correlación estadísticamente fuerte y significativa entre pie diabético y la retinopatía diabética. Conclusiones: Se evidencia una fuerte y significativa relación existente entre los pacientes portadores de pie diabético, los cuales pueden padecer determinado grado de retinopatía diabética, más frecuentes en el sexo femenino después de la sexta década de la vida, con los cuales presentan mayor tiempo de evolución de su enfermedad.

Introduction: Diabetes mellitus leads to many associated complications, including diabetic neuropathy and diabetic angiopathy, both with a high incidence in the onset diabetic foot and including also the diabetic retinopathy disease cause of blindness. Objective: Determine if there is any correlation between the onset diabetes foot and whether or not diabetic retinopathy present in patients treated at the Hospital Provincial, María Eugenia Neto, Zaire, Republic of Angola, from September 2020 to September 2020. Method: A descriptive study was carried out in 181 patients treated in the diabetic foot department of the aforementioned hospital; variables described were as follow: age, sex, associated chronic diseases, presence or absence of diabetic retinopathy, lower limb ulcers, limb amputation and years with diabetes. Bivariate correlation tests were performed, and the Pearson´s correlation coefficient was analyzed. Results: The average age was 59.3 years, the age group over 70 years (28.2%) and the female sex (57.5%) predominated. The 41.8% of patients presented previous amputations and 40.1% had ulcers. The 65.19% of patients had irregular treatment patterns, statistically strong and significant correlation between diabetic foot and diabetic retinopathy. Conclusions: There is evidence of a strong and significant relationship between patients with diabetic foot, who may suffer from a certain degree of diabetic retinopathy, more frequent in females after their sixth decade of life that cause a longer evolution of his disease.

Introdução: O diabetes mellitus produz complicações, dentre as quais são descritas a neuropatia diabética e a angiopatia diabética, que na presença destas podem levar ao quadro de pé diabético, sem falar na perda visual pela retinopatia diabética. Objectivo: Determinar a correlação existente entre o aparecimento de pé diabético e a presença ou ausência de retinopatia diabética em doentes do Hospital Provincial "María Eugenia Neto", Zaire, República de Angola, no período de setembro de 2020 a setembro de 2022. Método: Estudo descritivo realizado em 181 pacientes do ambulatório de pé diabético do referido hospital, onde foram descritas variáveis como: idade, sexo, doenças crônicas associadas, presença ou ausência de retinopatia diabética, úlceras de membros inferiores, amputação de membros inferiores e anos com diabetes. Foram realizados testes de correlação bivariada e analisado o coeficiente de correlação de Pearson. Resultados: A média de idade foi de 59,3 anos, predominando a faixa etária acima de 70 anos (28,2%) e o sexo feminino (57,5%). 41,8% tinham amputações anteriores e 40,1% tinham úlceras. Sem tratamento estável 65,19%, correlação estatisticamente forte e significativa entre pé diabético e retinopatia diabética. Conclusões: Existe evidência de uma relação forte e significativa entre os doentes com pé diabético, que podem sofrer de um certo grau de retinopatia diabética, mais frequente no sexo feminino a partir da sexta década de vida, com os quais apresentam maior evolução da sua doença.

Prevalence of diabetic retinopathy in the Eastern Mediterranean Region: a systematic review and meta-analysis.

OBJECTIVES: Individual studies in the Eastern Mediterranean Region (EMR) have shown the high prevalence of diabetic retinopathy. We conducted a meta-analysis to yield an estimate of the prevalence of diabetic (type 1 and 2) retinopathy in the EMR. Additionally, we explored its potential modulators. METHODS: Two-step screening of relevant articles published from 1 January 2000 to 13 December 2019 was carried out. An estimation of summary proportions, subgroup analysis, meta-regression, and publication bias assessment were performed. RESULTS: One hundred nine articles were included in the meta-analysis, involving 280,566 patients. The prevalence of diabetic retinopathy was 31% (95% confidence interval [CI] = 28, 33). The highest and lowest diabetic retinopathy prevalence rates were observed in low human development index (HDI) countries (63.6; 95% CI = 52.4, 74.0) and very high HDI countries 22.6 (95% CI = 20.5, 24.7), respectively. CONCLUSIONS: The prevalence of diabetic retinopathy is high in the EMR. Our results provide important information for diverse healthcare surveillance systems in the EMR to implement the modifiable risk factors, diabetes screening to decrease undiagnosed diabetes, early detection of retinopathy, and proper diabetes care to decrease untreated diabetes.

Protective effect of the curcumin-baicalein combination against macrovascular changes in diabetic angiopathy.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w) were tested in H2O2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats.

Maduración pulmonar fetal en diabetes mellitus pregestacional y complicaciones crónicas / Fetal lung maturation in pregestational diabetes mellitus and chronic complications

Las pacientes embarazadas con diabetes mellitus (DM) pregestacional y complicaciones micro y macroangiopáticas tienen mayor riesgo de empeoramiento de las mismas y de presentar otros trastornos asociados al embarazo. La progresión de la retinopatía diabética ocurre durante el embarazo y el posparto. La nefropatía se asocia con un mayor riesgo de preeclampsia, parto prematuro, restricción del crecimiento fetal y mortalidad perinatal. Cuando hay enfermedad de arterias coronarias o gastroparesia se observa un aumento de la morbilidad materna y fetal. El parto prematuro es una condición prevalente en pacientes con DM. La maduración pulmonar fetal con corticosteroides fue extensamente estudiada, con numerosas pruebas controladas, hasta convertirse en una de las más importantes terapias prenatales basadas en evidencias para reducir la mortalidad perinatal y el síndrome de dificultad respiratoria, la hemorragia intraventricular y la enterocolitis necrosante en los niños prematuros. Sin embargo, en dicha evidencia no se han incluido a embarazadas con DM, por lo cual no se conocen resultados perinatales en este grupo de pacientes.

Pregnant patients with pregestational diabetes mellitus (DM) and micro and macroangiopathic complications have a higher risk of their worsening and of presenting other pregnancyassociated disorders. The progression of diabetic retinopathy occurs during pregnancy and postpartum. Nephropathy is associated with an increased risk of preeclampsia, preterm delivery, fetal growth restriction, and perinatal mortality. When there is coronary artery disease or gastroparesis, an increase in maternal and fetal morbidity is observed Preterm delivery is a prevalent condition in diabetic patients. Corticosteroid fetal lung maturation has been extensively studied, with numerous controlled trials, to become one of the most important evidence-based prenatal therapies to reduce perinatal mortality and decrease respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, in premature infants. Nevertheless, this evidence did not include patients with DM, for this reason perinatal results are not known in this group of patients.

Maduración pulmonar fetal en diabetes mellitus pregestacional y complicaciones crónicas / Fetal lung maturation in pregestational diabetes mellitus and chronic complications

Resumen Las pacientes embarazadas con diabetes mellitus (DM) pregestacional y complicaciones micro y macroangiopáticas tienen mayor riesgo de empeoramiento de las mismas y de presentar otros trastornos asociados al embarazo. La progresión de la retinopatía diabética ocurre durante el embarazo y el posparto. La nefropatía se asocia con un mayor riesgo de preeclampsia, parto prematuro, restricción del crecimiento fetal y mortalidad perinatal. Cuando hay enfermedad de arterias coronarias o gastroparesia se observa un aumento de la morbilidad materna y fetal. El parto prematuro es una condición prevalente en pacientes con DM. La maduración pulmonar fetal con corticosteroides fue extensamente estudiada, con numerosas pruebas controladas, hasta convertirse en una de las más importantes terapias prenatales basadas en evidencias para reducir la mortalidad perinatal y el síndrome de dificultad respiratoria, la hemorragia intraventricular y la enterocolitis necrosante en los niños prematuros. Sin embargo, en dicha evidencia no se han incluido a embarazadas con DM, por lo cual no se conocen resultados perinatales en este grupo de pacientes.

Abstract Pregnant patients with pregestational diabetes mellitus (DM) and micro and macroangiopathic complications have a higher risk of their worsening and of presenting other pregnancyassociated disorders. The progression of diabetic retinopathy occurs during pregnancy and postpartum. Nephropathy is associated with an increased risk of preeclampsia, preterm delivery, fetal growth restriction, and perinatal mortality. When there is coronary artery disease or gastroparesis, an increase in maternal and fetal morbidity is observed Preterm delivery is a prevalent condition in diabetic patients. Corticosteroid fetal lung maturation has been extensively studied, with numerous controlled trials, to become one of the most important evidence-based prenatal therapies to reduce perinatal mortality and decrease respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, in premature infants. Nevertheless, this evidence did not include patients with DM, for this reason perinatal results are not known in this group of patients.

Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications.

Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure (HF) with reduced ejection fraction (EF) and chronic kidney disease (CKD). In monotherapy or as an additive therapy, dapagliflozin aids glycaemic control, is associated with reductions in blood pressure and weight, and promotes a favourable lipid profile. In this review, we address the impact of dapagliflozin on cardiovascular risk factors and common microangiopathic complications such as kidney disease and retinopathy in patients with T2DM. Furthermore, we evaluate its potential beneficial effects on other less frequent complications of diabetes, such as macular oedema, cognitive impairment, non-alcoholic fatty liver disease and respiratory disorders during sleep. Moreover, the underuse of SGLT2i in clinical practice is discussed. Our goal is to help translate this evidence into clinical practice.

Salvia miltiorrhiza in Anti-diabetic Angiopathy.

Salvia miltiorrhiza, a traditional Chinese medicine, also named Danshen in China, is widely used for the treatment of cardiovascular disease. It demonstrates multiple biological functions, such as anti-oxidative stress, anti-inflammation and anti-thrombosis. Diabetic angiopathy is one of the diabetic complications with macro- and microangiopathy. Macroangiopathy mainly occurs in arteries, while the microangiopathy mainly includes diabetic retinopathy and nephropathy. Many factors associated with diabetes, such as metabolic abnormalities and oxidative stress, can induce vascular lesions. These factors promote the accumulation of lipids as well as inflammatory cytokines, increase the production of extracellular cell-matrix, and impair endothelium functions, thereby leading to vascular dysfunction. This review attempts to summarize the progress of the studies of Salvia miltiorrhiza on diabetic angiopathy, including improving endothelial function, anti- oxidative stress, reducing the risk of vascular blockage, inhibiting inflammation as well as regulating lipid metabolism. We also summarize the pharmacological activity of bioactive components in Salvia miltiorrhiza and the delivery systems. We made the conclusion that Salvia miltiorrhiza can be used as a potential auxiliary drug for the treatment of diabetic angiopathy.

Obstructive sleep apnea during rapid eye movement sleep in patients with diabetic kidney disease.

STUDY OBJECTIVES: Although recent studies suggest that obstructive sleep apnea during rapid eye movement (REM) is associated with different cardiometabolic and neurocognitive risks compared with non-REM (NREM) sleep, there is no information on whether obstructive sleep apnea during REM and/or NREM sleep is independently associated with diabetic kidney disease (DKD). METHODS: In this cross-sectional study, 303 patients with type 2 diabetes who were followed up at our diabetes outpatient clinic underwent all-night polysomnography. Logistic regression analysis was performed to determine the separate effects of obstructive sleep apnea during REM and/or NREM sleep (REM and/or NREM-apnea-hypopnea index [AHI]) and several other polysomnography parameters on DKD after adjustment for several known risk factors for DKD. RESULTS: The median (interquartile range) AHI, REM-AHI, and NREM-AHI of the patients (age 57.8 ± 11.8 years, male sex 86.8%, hypertension 64.3%, and DKD 35.2%) were 29.8 (18.0-45.4), 35.4 (21.1-53.3), and 29.1 (16.3-45.4) events/h, respectively. REM-AHI quartiles, but not NREM-AHI quartiles, correlated independently and significantly with DKD (P = .03 for linear trend, odds ratio (OR), and 95% confidence interval for Q2: 3.14 (1.10-8.98), Q3: 3.83 (1.26-11.60), Q4: 4.97 (1.60-15.46), compared with Q1). In addition, categorical AHI (P = .01, OR, and 95% confidence interval for ≥ 15 to < 30: 1.54 (0.64-3.71), ≥ 30: 3.08 (1.36-6.94) compared with < 15), quartiles of AHI (P = .01), quartiles of lowest arterial oxyhemoglobin saturation (P < .01), quartiles of percentage of time spent with arterial oxyhemoglobin saturation < 90 (P < .01), and quartiles of mean arterial oxyhemoglobin saturation were independently associated with DKD. CONCLUSIONS: Obstructive sleep apnea, especially during REM sleep, is a potential risk factor for DKD.

Evaluación oftalmológica de pacientes con úlcera de pie diabético / Ophthalmologic evaluation of patients with diabetic foot ulcer

Introducción: La prevalencia de diabetes aumenta paulatinamente a nivel mundial y con ello, se incrementa el riesgo de complicaciones microvasculares como la retinopatía diabética. El riesgo de ceguera se reduce con control metabólico estable, diagnóstico temprano y tratamiento adecuado. Objetivo: Comparar el resultado del examen oftalmológico realizado antes de iniciar el tratamiento con Heberprot-P, con el realizado a los cinco meses de iniciado, a diferentes dosis. Métodos: Se realizó un estudio observacional, retrospectivo, en 77 pacientes incluidos en cuatro ensayos clínicos de Heberprot-P. Se realizó análisis de las variables examen oftalmológico antes y después del tratamiento, tipo de diabetes y años de evolución. Resultados: Se observó predominio de los diabéticos tipo 2 respecto a los tipo 1 en una razón 11:1, con una media de 16,3 años de evolución de la diabetes. La mitad de los pacientes tenían retinopatía diabética no proliferativa, con predominio de la forma leve, en el examen realizado antes del tratamiento con Heberprot-P. Solo un paciente anciano con otras comorbilidades, desarrolló una retinopatía diabética proliferativa, luego de un examen previo en que se observó retinopatía diabética no proliferativa y edema macular diabético. Conclusiones: La aparición o progresión de retinopatía diabética es infrecuente en pacientes complicados con úlcera del pie diabético tratados con Heberprot-P, hasta cinco meses después de tratamiento(AU)

Introduction: The prevalence of diabetes gradually increases worldwide and with it, the risk of microvascular complications such as diabetic retinopathy. The risk of blindness is reduced with stable metabolic control, early diagnosis and adequate treatment. Objective: To compare the result of the ophthalmological examination performed before starting treatment with Heberprot-P, with that performed five months after initiation, at different doses. Methods: A retrospective observational study was conducted in 77 patients included in four clinical trials of Heberprot-P. Analysis of the ophthalmological examination variables before and after treatment, type of diabetes and years of evolution were performed. Results: Prevalence of type 2 diabetics was observed with respect to type 1 in an 11: 1 ratio, with an average of 16.3 years of diabetes evolution. Half of the patients had nonproliferative diabetic retinopathy, predominantly of the mild form, in the examination performed before treatment with Heberprot-P. Only one elderly patient with other comorbidities developed a proliferative diabetic retinopathy, after a previous examination in which non-proliferative diabetic retinopathy and diabetic macular edema were observed. Conclusions: The appearance or progression of diabetic retinopathy is uncommon in complicated patients with diabetic foot ulcer treated with Heberprot-P, up to five months after treatment(AU)

[Tanatogenetic role of type 2 diabetes in neurosurgical patients]. / Tanatogeneticheskaia rol' sakharnogo diabeta 2-go tipa u neirokhirurgicheskikh bol'nykh.

The idea of diabetes in the aspects of its impact on the course of different diseases and tanatogenesis remains little investigated. OBJECTIVE: To define the tanatogenetic significance of 2 type diabetes in neurosurgical patients. SUBJECT AND METHODS: Forty-three patients aged 22-75 years, who had died after neurosurgery, were examined. Case histories and the time course of changes in blood glucose levels were analyzed. The manifestations of macroangiopathy were taken into account at autopsy; those of microangiopathy were considered at microscopy of the internal organs and tissues; Van Gieson and periodic acid-Schiff staining was additionally applied. The expression of insulin, glucagon, synaptophysin, S100 proteins, and neurofilament protein was found in the pancreas. The number and volume of islets and an insulin-to-glucagon ratio were morphometrically estimated. RESULTS: Type 2 diabetes mellitus was identified in 28 (65.1%) patients: 11 (25.6%), 8 (18.6%), and 9 (20.9%) with clinically obvious, subtle, and latent types, respectively; while it was as a background underlying disease in 3 (7.0%) patients. Among the immediate causes of death, there was a preponderance of local angiogenic complications (hemorrhages, infarctions, swelling, and displacement of the brain) (64%). Indurative pancreatitis was not inferior to cardiovascular diseases among complications and concomitant diseases and was detected in most diabetic patients (n=24, or 85.7%) and in 6 (a quarter) patients with acute pancreatic necrosis, which was the immediate cause of death in 2 cases. In the places of paravasal sclerosis, there was a reduction in the terminals of nerve fibers as a manifestation of diabetic neuropathy. CONCLUSION: Type 2 diabetes mellitus was much more frequently encountered in the most critically ill and dead neurosurgical patients than in the general population and was embodied in the pattern of immediate causes of death. Diabetic neuropathy with a reduction in the terminals of nerve fibers can serve as a substantial basis not only for vascular, but also for ductal dystonia and dyskinesia, which can become an important factor in the pathogenesis of chronic pancreatitis in patients with diabetes mellitus.

Histone methylation and vascular biology.

The vasculature not only transports oxygenated blood, metabolites, and waste products but also serves as a conduit for hormonal communication between distant tissues. Therefore, it is important to maintain homeostasis within the vasculature. Recent studies have greatly expanded our understanding of the regulation of vasculature development and vascular-related diseases at the epigenetic level, including by protein posttranslational modifications, DNA methylation, and noncoding RNAs. Integrating epigenetic mechanisms into the pathophysiologic conceptualization of complex and multifactorial vascular-related diseases may provide promising therapeutic approaches. Several reviews have presented detailed discussions of epigenetic mechanisms not including histone methylation in vascular biology. In this review, we primarily discuss histone methylation in vascular development and maturity, and in vascular diseases.

miR-503/Apelin-12 mediates high glucose-induced microvascular endothelial cells injury via JNK and p38MAPK signaling pathway.

INTRODUCTION: Diabetic patients are often accompanied by complications of diabetic vascular disease, which could lead to heart failure or stroke. In this work, we explored the role of miR-503/Apelin-12 in diabetic angiopathy (DA) in vitro. METHODS: ELISA and qPCR were applied to assess the expression of miR-503 and Apelin-12 in high glucose (HG)-treated microvascular endothelial cells (HMEC-1). The effects of miR-503 on apoptosis, inflammation and oxidative stress were assessed by flow cytometry, western blotting, qPCR, and ELISA. The interaction between miR-503 and Apelin-12 was evaluated by dual-luciferase reporter assay, qPCR and ELISA, respectively. Western blotting was performed to examine the function of miR-503/Apelin-12 on JNK and p38MAPK activation. RESULTS: MiR-503 was markedly increased and Apelin-12 was decreased in HG-treated HMEC-1 cells. MiR-503 inhibitor significantly assuaged apoptosis, inflammation and oxidative stress in HMEC-1 cells. MiR-503 could specifically bind to the 3'UTR of Apelin and inversely downregulate Apelin-12 expression. Furthermore, Apelin-12 suppressed apoptosis, inflammation and oxidative stress. Inhibition of Apelin-12 could partially reverse the decrease of p-JNK and p-p38 expression levels induced by miR-503 suppression. CONCLUSION: In HG-induced microvascular cells injury, miR-503/Apelin-12 enhances inflammation and oxidative stress by regulating JNK and p38MAPK pathway, suggesting a potential therapeutic target for DA.

Inflammatory Activities in Type 2 Diabetes Patients With Co-morbid Angiopathies and Exploring Beneficial Interventions: A Systematic Review.

Background: Diabetes is a long-term condition that can be treated and controlled but do not yet have a cure; it could be induced by inflammation and the goal of managing it is to prevent additional co-morbidities and reduce glycemic fluctuations. There is a need to examine inflammatory activities in diabetes-related angiopathies and explore interventions that could reduce the risk for future outcome or ameliorate its effects to provide insights for improved care and management strategies. Method: The study was conducted in Embase (1946-2020), Ovid Medline (1950-2020), and PubMed databases (1960-2020) using the PICO framework. Primary studies (randomized controlled trials) on type 2 diabetes mellitus and inflammatory activities in diabetes-related angiopathies were included. Terms for the review were retrieved from the Cochrane library and from PROSPERO using its MeSH thesaurus qualifiers. Nine articles out of 454 total hits met the eligibility criteria. The quality assessment for the selected study was done using the Center for Evidence-Based Medicine Critical Appraisal Sheet. Results: Data analysis showed that elevated CRP, TNF-α, and IL-6 were the most commonly found inflammatory indicator in diabetes-related angiopathies, while increased IL-10 and soluble RAGE was an indicator for better outcome. Use of drugs such as salsalate, pioglitazone, simvastatin, and fenofibrate but not glimepiride or benfotiamine reported a significant decrease in inflammatory events. Regular exercise and consumption of dietary supplements such as ginger, hesperidin which have anti-inflammatory properties, and those containing prebiotic fibers (e.g., raspberries) revealed a consistent significant (p < 0.05) reduction in inflammatory activities. Conclusion: Inflammatory activities are implicated in diabetes-related angiopathies; regular exercise, the intake of healthy dietary supplements, and medications with anti-inflammatory properties could result in improved protective risk outcome for diabetes patients by suppressing inflammatory activities and elevating anti-inflammatory events.

Research Progress of Yiqi Huoxue Prescription in Treatment of Diabetic Angiopathy / 中国实验方剂学杂志

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia. Its main complications of diabetes, such as diabetic angiopathy, have seriously affected the quality of life for patients, and have become an important cause of death and disability. The underlying pathological changes include macrovascular lesions and microvascular lesions. Diabetic macrovascular lesions mainly involve thoracic aorta, coronary artery, carotid artery, cerebral artery and peripheral blood vessels, etc., and the common clinical diseases include coronary heart disease, stroke, peripheral neuropathy, lower extremity arteriosclerosis, etc. Diabetic microvascular lesions mainly involve the heart, brain, kidney and other microvessels. Nowadays, various new oral hypoglycemic agents and insulin have emerged in the society and are widely used in clinical practice. However, traditional Chinese medicines(TCMs) have stable curative effect, less side effect, and can improve glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, expression of inflammatory cytokines, vascular endothelial injury, microcirculation disorders, balance of fibrinolysis system and blood coagulation system, and improve the syndromes of TCMs, etc. They have been widely recognized and applied in the prevention and treatment of diabetic angiopathy. A profound understanding on the etiology, pathogenesis and treatment of diabetic angiopathy has been formed in Chinese medicine. Therefore, in this paper, we would summarizes the understanding on Chinese medicine for diabetic angiopathy and the mechanism of Yiqi Huoxue prescription in the treatment of diabetic angiopathy in the past three years.

Evaluation of the Occlusive Arterial Disease and Diabetic Angiopathy Treatment Effects by Hyperbaric Oxygenation.

INTRODUCTION: One of the most severe complications of atherosclerosis is arterial occlusive disease (AOD) and with diabetic angiopathy (DA), is a common chronic problem in clinical practice worldwide. Hyperbaric oxygen (HBO) therapy is a therapeutic modality for solving all forms of hypoxia. AIM: To compare the treatment with HBO therapy in patients with AOD and DA ischemic symptomatology with standard treatment i.e. vasodilators, antibiotics, antiplatelets and statins, and to demonstrate the benefit of the therapeutic modality itself. METHODS: We conducted a clinical prospective study and included a total of 80 patients, divided into two groups: 40 patients with the arterial occlusive disease and lower-extremity wounds, with sub-group (n=20) treated with HBO therapy on the top of the standard therapy and 40 patients with diabetic angiopathy and diabetic lower-extremity wounds, with sub-group (n=20) treated with HBO therapy on top of the standard therapy. RESULTS: The efficacy of therapy in patients treated with HBO therapy on the top of standard therapy was significantly higher than in the group of HBO non-treated patients. There was a significant improvement in 9 patients treated with HBO therapy, while in HBO non-treated patients the significant improvement effect was observed only in one patient. CONCLUSION: HBO therapy is an effective therapeutic component in the healing of diabetic lower-extremity wounds in the patients with AOD and DA. In our patients HBO therapy on the top of standard therapeutic protocol has an effect of reducing the number of lower-limb amputations in patients with AOD and DA. These results support clinical use of HBO therapy for diabetic lower-extremity wound healing.

Protective Effects and Mechanisms of Vaccarin on Vascular Endothelial Dysfunction in Diabetic Angiopathy.

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.