Diabetic endothelial microangiopathy and pulmonary dysfunction.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Microvascular Disease and Severe COVID-19 Outcomes in UKBiobank Diabetic Cohort (preprint)

Background: Early in the COVID-19 pandemic, evidence emerged to suggest that people with diabetic retinopathy (DR) or other microvascular diseases were at greater risk of severe short-term outcomes. Evaluation of outcomes over the longer term and more generalisable evidence were needed. Methods: We identified a cohort of UKBiobank participants with diabetes and retrieved their diagnostic codes for a variety of microvascular diseases, other diabetic complications and systemic comorbidities from hospital admissions data. We investigated the relationship between these diagnoses and the study outcome: admission to Critical Care or death from COVID-19, taking age, sex and diabetes duration into account. We tested the relationships further by adding more baseline covariates, and weighting diagnostic codes according to their recency prior to testing positive for COVID-19.Findings: In univariate analyses, DR (OR: 1·519, p= 0·016) and microvascular disease (OR: 2·001, p=0·000) were both associated with greater risk of the study outcome. In multivariate analyses, as may be expected, respiratory disease was the comorbidity most strongly associated with the study outcome, with microvascular disease second. Adjusting the analyses by number of hospital admissions (a proxy for general health) and weighted diagnostic coding (an indicator of comorbidity recency or severity at the time of COVID-19 diagnosis), did not improve the predictive power of the model.Interpretation: The presence of microvascular disease in routinely-collected healthcare data predicts the risk of severe outcomes of COVID-19, independently of general health, in a diabetic cohort. Funding Information: This work was supported by a grant from Diabetes UK (20/0006221). The funders did not influence the study design or methodology.Declaration of Interests: The authors declare no conflict of interest.

Evolution and diabetic vasculopathy.

Evolution of blood sugar, glycation, receptor for advanced glycation end-products and diabetic vasculopathy.

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function.

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

One year into the clash of pandemics of diabetes and COVID-19: Lessons learnt and future perspectives.

There is a bidirectional relationship between coronavirus disease 2019 (COVID-19) and diabetes. Furthermore, the COVID-19 pandemic has catalyzed the use of technology in diabetes care. Future research is required to assess the impact of COVID-19 on new-onset diabetes and the influence of diabetes on responses to COVID-19 vaccines.

COVID-19 and peripheral arterial complications in people with diabetes and hypertension: A systematic review.

AIMS: Identify the prevalence, risk factors and outcomes of lower extremity ischemic complications. METHODS: A systematic review was conducted by searching PubMed and SCOPUS databases for SARS-CoV-2, COVID-19 and peripheral arterial complications. RESULTS: Overall 476 articles were retrieved and 31 articles describing 133 patients were included. The mean age was 65.4 years. Pain and gangrene were the most common presentation. Hypertension (51.3%), diabetes (31.9%) and hypercholesterolemia (17.6%) were associated co-morbidities. Overall, 30.1% of patients died and amputation was required in 11.8% patients. CONCLUSIONS: COVID-19 patients with diabetes or hypertension are susceptible for lower limb complications and require therapeutic anti-coagulation.

Crosstalk of TLR4, vascular NADPH oxidase, and COVID-19 in diabetes: What are the potential implications?

Toll-like receptor 4 (TLR4) contributes to the pathophysiology of diabetes. This happens, at least in part, because TLR4 modulates the enzyme NADPH oxidase, a primary source of ROS in vascular structures. Increased oxidative stress disrupts key vascular signaling mechanisms and drives the progression of diabetes, elevating the likelihood of cardiovascular diseases. Recently, it has been shown that patients with diabetes are also at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Given the importance of the interaction between TLR4 and NADPH oxidase to the disrupted diabetic vascular system, we put forward the hypothesis that TLR4-mediated NADPH oxidase-derived ROS might be a critical mechanism to help explain why this disparity appears in diabetic patients, but unfortunately, conclusive experimental evidence still lacks in the literature. Herein, we focus on discussing the pathological implications of this signaling communication in the diabetic vasculature and exploring this crosstalk in the context of diabetes-associated severe COVID-19.

Managing breast gangrene during the COVID-19 pandemic.

At the onset of the COVID-19 crisis, a 63-year-old woman with multiple life-limiting comorbidities was referred with a necrotic infected left breast mass on a background of breast cancer treated with conservation surgery and radiotherapy 22 years previously. The clinical diagnosis was locally advanced breast cancer, but four separate biopsies were non-diagnostic. Deteriorating renal function and incipient sepsis and endocarditis resulted in urgent salvage mastectomy during the peak of the COVID19 pandemic. The final diagnosis was infected ischaemic/infarcted breast (wet gangrene) secondary to vascular insufficiency related to diabetes, cardiac revascularisation surgery and breast radiotherapy.

COVID19 Associated Thrombotic Angiopathy Improved After Plasma Exchange (preprint)

Woman admitted for COVID-19 respiratory failure requiring intubation, renal failure and rising bilirubin, requiring CVVHD. Due to dropping hemoglobin and platelets, TTP was suspected and empiric plasma exchange initiated. Platelets normalized; she improved; ADAMTS13 level resulted 50.7%, indicating possible benefit of plasma exchange for COVID19 thrombotic microangiopathy despite normal ADAMTS13.

Identification of common key genes and pathways between Covid-19 and lung cancer by using protein-protein interaction network analysis (preprint)

COVID-19 is indeed an infection that is caused by a recently found coronavirus group, a type of virus proven to cause human respiratory diseases. The high mortality rate was observed in patients who had pre-existing health conditions like cancer. However, the molecular mechanism of SARS-CoV-2 infection in lung cancer patients was not discovered yet at the pathway level. This study was about determining the common key genes of COVID-19 and lung cancer through network analysis. The hub genes associated with COVID-19 and lung cancer were identified through Protein-Protein interaction analysis. The hub genes are ALB, CXCL8, FGF2, IL6, INS, MMP2, MMP9, PTGS2, STAT3 and VEGFA. Through gene enrichment, it is identified both COVID-19 and lung cancer have a common pathway in EGFR tyrosine kinase inhibitor resistance, IL-17 signalling pathway, AGE-RAGE signalling pathway in diabetic complications, HIF-1 signalling pathway and pathways in cancer.

Minireview: The Introduction of COVID-19 and Microvascular Disease-Introduction of COVID-19 and the Relationship between Its Receptor and Diabetic Vascular Complications.

In December of 2019, a novel coronavirus, which is SARS-CoV-2, broke out in the world and caused tremendous human and financial losses. According to a descriptive study by the relative hospital about the epidemiological and clinical features of 52 critically ill patients, the expert panel found that people with cardiovascular disease and diabetes comprise a large proportion of the patients with chronic disease. In this review, we discuss the structural biology of the SARS-CoV-2 in combination with the characteristics of its binding protein, ACE2, which is an important receptor in the cardiovascular system and may have potential relationships with various diabetic diseases. We hope we can provide useful recommendations for patients with diabetes after becoming infected by the virus or provide directions to doctors on treatment options.

The Impact of Coronavirus Disease 2019 Pandemic on People with Diabetes in Indonesia: A Cross Sectional National Scale Web-Survey (preprint)

Background As the country with the 7th largest number of People with Diabetes (PWD) in the world, the COVID-19 pandemic, and the Large Social Scale Restriction (LSSR) policy taken by the Indonesian government to reduce the number of COVID-19 transmissions is estimated to interfere diabetes management and will increase the incidence of diabetes complications. This study aims to determine the difficulties of diabetes management and its impact on diabetes morbidity during the COVID-19 pandemic in Indonesia. Methods This study is a cross-sectional study using a national scale web survey. This research was conducted in Indonesia enrolling 1,124 PWD aged 18 years or older. Diabetes complications are defined as any incidence of hypoglycaemia, or Diabetic Foot Ulcer (DFU), or hospital admission experienced by PWD in Indonesia during the COVID-19 pandemic. The correlation between diabetes management difficulties and diabetes-related complications was measured using a modified cox regression test. Results Diabetes management difficulties were experienced by 69.8% of PWD in Indonesia. The difficulties include attending diabetes consultation 30.1%, access to diabetes medication 12.4%, checking blood sugar levels 9.5%, controlling diet 23.8%, and performing regular exercise 36.5%. Diabetes-related complications occurred in 24.6% of subjects. Those who had diabetes management difficulties during the COVID-19 pandemic are prone to have diabetes complications by 1.4 times greater (PR: 1.41, 95% CI: 1.09-1.83) than those who did not. Conclusion The COVID-19 pandemic and LSSR have a substantial impact on diabetes management and indirectly increased diabetes morbidity in Indonesia.

Research on active compounds regarding SGMD for the treatment of COVID-19 based on network pharmacology and molecular docking (preprint)

Background: Retrieve Curative effect of Six Gentlemen Modified Decoction (SGMD) in treating with coronavirus disease ( COVID-19 ) by network pharmacology and verify its authenticity by molecular docking. Methods: The chemical constituents, effective components, and action targets were screened using TCMSP. COVID-19 related targets were retrieved by the GeneCards and NCBI databases, and drug targets and disease targets were mapped by Venny to obtain potential targets for treatment. The regulatory network of traditional Chinese medicine (TCM) compounds was established with Cytoscape to obtain the key components, and the PPI network and its network topology were established with the Bisogenet and CytoNCA plug-ins to obtain the core targets. Bioconductor was used for GO function analysis and KEGG pathway analysis to obtain the relevant functions and pathways. Results: 173 effective components, 253 targets, and 348 targets related to COVID-19 were obtained after screening, 50 cross targets were shown, and the key components of the top 15 are flavonoids such as quercetin, luteolin, kaempferol, naringenin, licochalcone A, etc. The top 28 core targets include TP53, EGFR, SRC, AR, ABL1, and others. Biological processes such as the responses to metal ions, molecules of bacterial origin, lipopolysaccharide, toxic substances, and oxidative stress were involved. The main pathway involved the AGE−RAGE signaling pathway in diabetic complications as well as the TNF and IL-17 signaling pathways. The average binding energies of the first three core components connected with 6LU7 and 1R42 were -4.16 kJ/mol and -4.12 kJ/mol, respectively.Conclusion: The core compounds of SGMD can spontaneously combine with SARS-CoV-2 3CL hydrolase and ACE2 to treat COVID-19.

Exploring the Mechanisms of Lian Hua Qing Wen Capsule against COVID-19 by Network Pharmacology and Molecular Docking Approach (preprint)

Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) disease has led to a wide-spread global pandemic. There is no specific antiviral drug proven effective for the treatment of patients with COVID-19 at present. Combination of western and traditional Chinese medicine (TCM) is recommended, and Lian Hua Qing Wen (LHQW) capsule is a basic prescription and widely used to treat COVID-19 in China. However, the mechanisms of LHQW capsule treating COVID-19 are not clear. The aim of the study is to explore the mechanisms of LHQW capsule treating COVID-19 based on network pharmacy and molecular docking approach. Methods The active compounds and targets of LHQW capsule were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). COVID-19 related target genes were obtained from GeneCards database and OMIM database. Protein–protein interaction (PPI) networks of LHQW capsule targets and COVID-19-related genes were visualized and merged to identify the candidate targets for LHQW capsule treating COVID-19. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed. The hub genes involved in the gene-related pathways were screened and their corresponding compounds were used for in vitro validation of molecular docking predictions.Results A total of 185 active compounds of LHQW capsule were screened out, and 263 targets were predicted. Third hundred and fifty-two COVID-19 related target genes were obtained from GeneCards database and OMIM database. GO functional enrichment analysis showed that the biological processes of LHQW capsule treating COVID-19 were closely linked with the regulation of inflammation, immunity, cytokines production, vascular permeability, oxidative stress and apoptosis. KEGG enrichment analysis revealed that the pathways of LHQW capsule treating COVID-19 were significantly enriched in AGE−RAGE signaling pathway in diabetic complications, Kaposi sarcoma−associated herpesvirus infection, TNF, IL−17, and Toll−like receptor (TLR) signaling pathway. The hub targets genes in the gene-related pathways analysis of LHQW capsule treating COVID-19 included MAPK1, MAPK3, RELA, IL-6 and CASP8, which closely associated with inflammation, cytokines storm and apoptosis. Finally, molecular docking showed that top 5 compounds of LHQW capsule also had good binding activities to the important targets in COVID-19.Conclusions The mechanisms of LHQW capsule treating COVID-19 may involve in inhibiting inflammatory response, cytokine storm and virus infection, and regulating immune reactions, apoptosis and endothelial barrier.

The contribution of diabetic micro-angiopathy to adverse outcomes in COVID-19.

Increasing evidence points to endothelial cell dysfunction as a key pathophysiological factor in severe coronavirus disease-19 (COVID-19), manifested by platelet aggregation, microthrombi and altered vasomotor tone. This may be driven by direct endothelial cell entry by the virus, or indirectly by activated inflammatory cascade. Major risk groups identified for adverse outcomes in COVID-19 are diabetes, and those from the Black, Asian and ethnic minority (BAME) populations. Hyperglycaemia (expressed as glycated haemoglobin or mean hospital glucose) correlates with worse outcomes in COVID-19. It is not known whether hyperglycaemia is causative or is a surrogate marker - persistent hyperglycaemia is well known as an aetiological agent in microangiopathy. In this article, we propose that pre-existing endothelial dysfunction of microangiopathy, more commonly evident in diabetes and BAME groups, makes an individual vulnerable to the subsequent 'endothelitis' of COVID-19 infection.