Exploring the shared molecular mechanism of microvascular and macrovascular complications in diabetes: Seeking the hub of circulatory system injury

BackgroundMicrovascular complications, such as diabetic retinopathy (DR) and diabetic nephropathy (DN), and macrovascular complications, referring to atherosclerosis (AS), are the main complications of diabetes. Blindness or fatal microvascular diseases are considered to be identified earlier than fatal macrovascular complications. Exploring the intrinsic relationship between microvascular and macrovascular complications and the hub of pathogenesis is of vital importance for prolonging the life span of patients with diabetes and improving the quality of life.Materials and methodsThe expression profiles of GSE28829, GSE30529, GSE146615 and GSE134998 were downloaded from the Gene Expression Omnibus database, which contained 29 atherosclerotic plaque samples, including 16 AS samples and 13 normal controls; 22 renal glomeruli and tubules samples from diabetes nephropathy including 12 DN samples and 10 normal controls; 73 lymphoblastoid cell line samples, including 52 DR samples and 21 normal controls. The microarray datasets were consolidated and DEGs were acquired and further analyzed by bioinformatics techniques including GSEA analysis, GO-KEGG functional clustering by R (version 4.0.5), PPI analysis by Cytoscape (version 3.8.2) and String database, miRNA analysis by Diana database, and hub genes analysis by Metascape database. The drug sensitivity of characteristic DEGs was analyzed.ResultA total of 3709, 4185 and 8086 DEGs were recognized in AS, DN, DR, respectively, with 1820, 1666, 888 upregulated and 1889, 2519, 7198 downregulated. GO and KEGG pathway analyses of DEGs and GSEA analysis of common differential genes demonstrated that these significant sites focused primarily on inflammation-oxidative stress and immune regulation pathways. PPI networks show the connection and regulation on top-250 significant sites of AS, DN, DR. MiRNA analysis explored the non-coding RNA upstream regulation network and significant pathway in AS, DN, DR. The joint analysis of multiple diseases shows the common influenced pathways of AS, DN, DR and explored the interaction between top-1000 DEGs at the same time.ConclusionIn the microvascular and macrovascular complications of diabetes, immune-mediated inflammatory response, chronic inflammation caused by endothelial cell activation and oxidative stress are the three links linking atherosclerosis, diabetes retinopathy and diabetes nephropathy together. Our study has clarified the intrinsic relationship and common tissue damage mechanism of microcirculation and circulatory system complications in diabetes, and explored the mechanism center of these two vascular complications. It has far-reaching clinical and social value for reducing the incidence of fatal events and early controlling the progress of disabling and fatal circulatory complications in diabetes

Genetically programmed chiral organoborane synthesis

Recent advances in enzyme engineering and design have expanded nature’s catalytic repertoire to functions that are new to biology. However, only a subset of these engineered enzymes can function in living systems. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus8 (Rma cyt c) were found to form carbon–boron bonds in the presence of borane–Lewis base complexes, through carbene insertion into boron–hydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100 h^(–1), a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems

Assessing the restoration status and potential of ecosystem services on the Loess Plateau

An ecosystem service assessment can directly reflect the effectiveness of ecological restoration, reveal the process and driving mechanism of ecosystem change, and guide the future management. However, most studies have focused on analyzing the historical dynamic changes in ecosystem services (ESs), and few studies have clarified what level the ecosystem should be restored to. Therefore, this study proposed the concept of a zonal climax background based on the ESs in natural reserves, which can present the best state of ecosystem in the same region. We regarded the zonal climax background as the ultimate goal of ecological restoration, and described the recovery process and gap compared with the actual state. Taking the forest, grassland and wetland ecosystems of the Loess Plateau (LP) as the research object, we quantitatively simulated the zonal climax background and actual conditions of carbon fixation, water conservation, soil conservation and sand fixation. The results showed that the annual average carbon fixation of the zonal climax background of the LP was 44.88 MgC/km2/a, the water conservation was 4.39 × 106 m3/km2/a, the soil conservation was 8416.64 t/km2/a and the sand fixation was 1051.97 t/km2/a, which represented the annual average recovery degrees were 94.10%, 38.46%, 64.73% and 87.59%, respectively. In addition, the study categorized the four ESs of the regionalization of comprehensive control of the LP through the superimposed analysis of the recovery space and the recovery degree and clarified the main focus of future ES improvement, such as carbon fixation in the loss hilly and valley region (LHGR) and Loss Plateau valley region (LPGR); soil conservation in the LHGR, LPGR and earth rock mountains area (ERMA); and water conservation in the LHGR and plain area (PA). Water and soil conservation in irrigated regions (IRs) and sandy areas (SAs) were not the main ESs and should not be prioritized over other ESs

视网膜神经血管单元自噬:糖尿病视网膜病变的新视角

Abstract Diabetic retinopathy (DR) is one of the most prevalent retinal disorders worldwide, and it is a major cause of vision impairment in individuals of productive age. Research has demonstrated the significance of autophagy in DR, which is a critical intracellular homeostasis mechanism required for the destruction and recovery of cytoplasmic components. Autophagy maintains the physiological function of senescent and impaired organelles under stress situations, thereby regulating cell fate via various signals. As the retina's functional and fundamental unit, the retinal neurovascular unit (NVU) is critical in keeping the retinal environment's stability and supporting the needs of retinal metabolism. However, autophagy is essential for the normal NVU structure and function. We discuss the strong association between DR and autophagy in this review, as well as the many kinds of autophagy and its crucial physiological activities in the retina. By evaluating the pathological changes of retinal NVU in DR and the latest advancements in the molecular mechanisms of autophagy that may be involved in the pathophysiology of DR in NVU, we seek to propose new ideas and methods for the prevention and treatment of DR

The Ecological Healthcare Benefits and Influences of Plant Communities in Urban Wetland Parks

Plant communities in urban wetland parks (UWP) have significant eco-healthcare benefits in terms of regulating the climate and improving the human living environment. However, factors influencing the regulation of eco-healthcare benefits are unclear. Taking Huaxi Ten Mile Beach National Urban Wetland Park as an example, the urban wetland park comprehensive healthcare index (UPCHI) was constructed based on an outdoor survey and indoor analysis to evaluate the UWP’s eco-healthcare benefits. Pathway analysis was used to investigate how climatic, geographic, and plant factors interact to affect the UPCHI. The results show that, over the whole year, tree–shrub–herb showed the best performance in terms of reducing PM2.5, PM10, and noise, as well as raising negative air ion concentrations; however, human comfort performed the worst. The UPCHI was generally beyond level Ⅲ (0.49–0.58) in the spring and summer, indicating that there are eco-healthcare benefits. Overall, the deciduous tree–shrub–herb community had the highest annual mean UPCHI, and more than half of the plant communities’ eco-healthcare benefits were class Ⅱ, which is very beneficial for eco-healthcare. The main direct factors on UPCHI were illumination intensity (0.68) and tree height (0.90), while canopy height (0.64–0.59) and tree crown radius/canopy height (0.72–0.14) directly or indirectly influenced UPCHI. The distance from the edge of the mountain (−0.39–−0.322) had a direct negative, but minor, effect on UPCHI. This study will assist residents with selecting suitable times and places for wetland recreation and healthcare activities, and it offers a valuable reference for the future planning and design of UWP plant communities

Potential Protective Function of Adiponectin in Diabetic Retinopathy

Abstract Adiponectin, one of the most ubiquitous adipokines found in the blood, plays a major role in glucolipid metabolism and energy metabolism and regulation. In recent years, a growing body of research indicates that adiponectin also plays a significant role in diabetic retinopathy. In the present review, we specifically address the protective effects of adiponectin on the development and progression of diabetic retinopathy through improvement in insulin resistance, alleviation of oxidative stress, limiting of inflammation, and prevention of vascular remodeling, with the aim to explore new potential approaches and targets for the prevention and treatment of diabetic retinopathy

Encapsulating atomic molybdenum into hierarchical nitrogen-doped carbon nanoboxes for efficient oxygen reduction

Construction of single-atom catalysts (SACs) with maximally exposed active sites remains a challenging task mainly because of the lack of suitable host matrices. In this study, hierarchical N-doped carbon nanoboxes composed of ultrathin nanosheets with dispersed atomic Mo (denoted as hierarchical SA-Mo-C nanoboxes) were fabricated via a template-engaged multistep synthesis process. Comprehensive characterizations, including X-ray absorption fine structure analysis, reveal the formation of Mo-N atomic sites uniformly anchored on the hierarchical carbon nanoboxes. The prepared catalysts offer structural and morphological advantages, including ultrathin nanosheet units, unique hollow structures and abundant active Mo-N species, that result in excellent activity with a half-wave potential of 0.86 V vs. RHE and superb stability for the oxygen reduction reaction in 0.1 M KOH; thus, the catalysts are promising air-cathode catalysts for Zn-air batteries with a high peak power density of 157.6 mW cm

Cardiac CaMKIIδ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells

Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression

Acrylamide-Aggravated Liver Injury by Activating Endoplasmic Reticulum Stress in Female Mice with Diabetes

Acrylamide (ACR) is a common industrial contaminant with endocrine-disrupting toxicity. Numerous studies have indicated that females and diabetics are more sensitive to environmental contaminants. However, it remains unknown whether female diabetics are susceptible to ACR-induced toxicity and its potential mechanisms. Thus, the female ACR-exposure diabetic Balb/c mice model was established to address these issues. Results showed that ACR could induce liver injury in normal mice and cause more serious inflammatory cell infiltration, hepatocyte volume increase, and fusion in diabetic mice liver. Meanwhile, ACR could lead to exacerbation of diabetic symptoms in diabetic mice by disturbing the glucose and lipid metabolism in the liver, which mainly manifests as the accumulation of liver glycogen and liver lipids, the reduction of the activity/content of glycolytic and metabolizing enzyme as well as pentose phosphatase, upregulation of the gene expression in fatty acid transporter and gluconeogenesis, and downregulation of the gene expression in fatty acid synthesis and metabolism. Moreover, ACR exposure could induce oxidative stress, inflammation, and endoplasmic reticulum stress in the liver by a decrease in hepatic antioxidant enzyme activity and antioxidant content, an increase in inflammatory factor levels, and a change in the related protein expression of endoplasmic reticulum stress (ERS) and apoptosis-related pathways in diabetic mice. Statistical analysis results revealed that ACR-induced liver injury was highly correlated with inflammation and oxidative stress, and ERS and diabetic mice had a higher risk of liver injury than normal mice. Overall results suggested that female diabetic mice easily suffer from ACR-induced toxicity, and the reason was that ACR could induce further damage to the liver by worsening the condition of inflammation, oxidative stress, and ERS in the liver

Increased Circulating Cathepsin K in Patients with Chronic Heart Failure.

Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF