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The ongoing coronavirus disease 2019 (COVID-19) pandemic represents one of the most exigent threats of our lifetime to global public health and economy. As part of the pandemic, from January 10 to March 10, 2020, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began to spread in Hefei (Anhui Province, China) with a total of 174 confirmed cases of COVID-19. During this period, we were able to gather critical information on the transmission and evolution of pathogens through genomic surveillance. Particularly, the objective of our study was to track putative variants of SARS-CoV-2 circulating in Hefei for the first time and contribute to the global effort toward elucidating the molecular epidemic profile of the virus. Patients who showed symptoms of COVID-19 were routinely tested for SARS-CoV-2 infections via RT-PCR at the First Affiliated Hospital of Anhui Medical University. Whole-genome sequencing was performed on 97 clinical samples collected from 29 confirmed COVID-19 patients. As a result, we identified a local novel single-nucleotide polymorphism site (10,380) harboring a G → T mutation (Gly → Val) in Hefei. Further phylogenetic network analysis with all the sequences of SARS-CoV-2 deposited in GenBank collected in East and Southeast Asia revealed a local subtype of S-type SARS-CoV-2 (a1) harboring a C → T synonymous mutation (Leu) at position 18,060 of ORF1b, likely representing a local SARS-CoV-2 mutation site that is obviously concentrated in Hefei and the Yangtze River Delta region. Moreover, clinical investigation on the inflammatory cytokine profile of the patients suggested that mutations at positions 18,060 (the shared variable site of subtype a1) and 28,253(harboring a C → T synonymous mutation, Phe) were associated with milder immune responses in the patients.

It has been shown that non-coding RNAs (ncRNAs) play an important regulatory role in pathophysiological processes involving inflammation. The vascular endothelial growth factor A (VEGFA) gene also participates in the inflammatory process. However, the relationships between ncRNAs and VEGFA are currently unclear. Here, this study was designed to determine the relationship between long non-coding RNA (lncRNA) H19, mircoRNA29b (miR-29b), and VEGFA in the development of diabetes mellitus (DM). We demonstrate that H19 is upregulated and miR-29b downregulated in individuals with DM and directly binds miR-29b. VEGFA is the target of miR-29b in the vascular endothelium of individuals with DM. We found that positive modulation of miR29b and inhibition of H19 and VEGFA significantly attenuates high glucose-induced endothelial inflammation and oxidative stress. We also found that the protein kinase B/endothelial nitric oxide synthase (AKT/eNOS) signal pathway in endothelial cells is activated through regulation of miR29b and H19 endogenous RNAs. We conclude that H19 suppression protects the endothelium against high glucose-induced inflammation and oxidative stress in endothelial cells by upregulation of miR-29b and downregulation of VEGFA through AKT/eNOS signal pathway activation. These results suggest a novel link between dysregulated ncRNA expression, inflammation, and the signaling pathway in the vascular endothelium of individuals with DM, indicating a promising strategy for preventing cardiovascular disease in such individuals.

Objective: Glucagon-like peptide-1 (GLP-1) showed protective effects on endothelium-dependent dilatation. Since endothelial barrier dysfunction also plays a pivotal role in atherosclerosis, this study was designed to investigate the effects of GLP-1 on endothelial barrier function in diabetic aortic endothelium and explore the underlying mechanism. Methods: For in vivo studies, diabetic rats were established and subjected to 12- and 24-week treatment of exenatide. The morphological changes of aortic endothelium were observed with transmission electron microscope. A permeability assay of aortic endothelium was performed using the surface biotinylation technique. Protein expression was detected by immunohistochemical analysis and Western blots. For in vitro studies, human umbilical vein endothelial cells (HUVECs) were cultured in medium enriched with advanced glycation end products (AGEs) or AGEs plus GLP-1 and other reagents. The integrity of endothelium was evaluated by endothelial monolayer permeability assay and transendothelial resistance. The in vitro expressions of relevant proteins in signaling pathways were also detected by immunofluorescence and Western blots. Results: In vivo, the enhanced aortic endothelial permeability in diabetic aortas were attenuated by exenatide treatment. Additionally, myosin light chain (MLC) phosphorylation, related to actomyosin contractility, and activation of its upstream targets in diabetic aorta were inhibited after administration of exenatide. In vitro, the endothelial monolayer permeability and the assembly of stress fibers were reduced by GLP-1 intervention under diabetic condition. Meanwhile, AGE-induced MLC phosphorylation mediating ECs contractility was inhibited by GLP-1. Furthermore, GLP-1 down-regulated the upstream targets of MLC phosphorylation, including RAGE, Rho/ROCK and MAPK signaling pathways. Intriguingly, the effects of GLP-1 elicited on ECs contractility and barrier function in diabetes were blunted by inhibition of GLP-1R, cAMP or PKA and stimulation of Rho/ROCK and MAPK signaling pathways. Conclusion: The findings of this study suggest that the stabilizing effect of GLP-1 on the endothelial barrier and contraction of AGE-treated ECs is caused by GLP-1R/cAMP/PKA activation and the subsequent inactivation of RAGE/Rho/ROCK as well as MAPK signaling pathways.

Endothelial dysfunction and apoptosis have key roles in the initiation and progression of atherosclerosis (AS). AS has been demonstrated to be associated with a high‑fat diet, which may increase endothelial permeability and apoptosis; however, the exact mechanisms underlying the development of AS remain poorly understood. MicroRNAs (miRNAs) are vital for the regulation of cardiovascular disease, and dysregulated miRNAs have been implicated in AS. The present study investigated whether miRNA (miR)‑126 regulates high‑fat diet‑induced endothelial permeability and apoptosis by targeting transforming growth factor β (TGFβ), a secreted protein that controls cellular proliferation and apoptosis. In the present study, apolipoprotein E (apoE)‑/‑ mice were fed a high‑fat diet in order to establish a model of AS. Mice were subcutaneously injected with a miR‑126 mimic, a miR‑126 antagomir or control miRNA. Reverse transcription‑quantitative polymerase chain reaction was used to assess miR‑126 expression, and a fluorometric assay was used to evaluate caspase‑3 activity. The effects of miR‑126 on the endothelial permeability of the aortic intima were also explored. Western blotting and immunohistochemical analysis were used to investigate the effects of miR‑126 on B‑cell lymphoma‑2 (Bcl‑2) and transforming growth factor (TGF) β protein expression levels. Furthermore, a luciferase assay was performed to verify whether TGFβ may be a direct target gene of miR‑126. In apolipoprotein E‑knockout mice, a high‑fat diet reduced miR‑126 expression and induced apoptosis as determined by the upregulation of caspase‑3 activity. A miR‑126 antagomir increased endothelial permeability and apoptosis in mice fed a high‑fat diet. By contrast, an miR‑126 mimic attenuated endothelial permeability and apoptosis. The reduction in miR‑126 was associated with a reduction in protein expression levels of Bcl‑2 and an increase of TGFβ in mice fed a high‑fat diet. In addition, the present study demonstrated that miR‑126 reduced TGFβ expression following binding to the 3'‑untranslated region of TGFβ mRNA. The current study demonstrated a role for miR‑126 in AS and identified TGFβ as a direct target of miR‑126. Furthermore, the present study demonstrated that miR‑126 contributed to endothelial permeability and apoptosis, and suggested that the downregulation of TGFβ may be involved in the molecular mechanisms underlying the actions of miR‑126. miR‑126 may therefore have potential as a novel therapeutic target for the treatment of AS. [ABSTRACT FROM AUTHOR]

The pathology of acute respiratory distress syndrome (ARDS) is closely associated with the failure of alveolar-capillary barrier integrity and alveolar filling by high protein pulmonary edema, resulting from hyperpermeability. High mobility group box 1 (HMGB1) is a novel late mediator of sepsis, which is specifically involved in endotoxin-induced acute lung injury and sepsis-associated lethality. Although the role of HMGB1 in endothelial cell cytoskeletal rearrangement and vascular permeability have been investigated preliminarily, the molecular mechanisms remain to be fully elucidated. As the ras-related C3 botulinum toxin substrate 1 (Rac1) gene is important role in regulating microvascular barrier maintenance, the present study was designed to determine whether Rac1 is involved in HMGB1-induced hyperpermeability in pulmonary microvascular endothelial cells (PMVECs). The results of the present study demonstrated that HMGB1 induced dose and time-dependent decreases in transendothelial electrical resistance (TER). Notably, HMGB1 induced a dose-dependent increase in the activity and expression levels of Rac1. Using small interfering RNA and an agonist of Rac1, the present study demonstrated that Rac1 was a novel factor mediating the HMGB1-induced decrease in TER via extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK) activation. These data suggested that Rac1 is involved in HMGB1-induced hyperpermeability in PMVECs via MAPK signal transduction. [ABSTRACT FROM AUTHOR]

Background: Standardized chemotherapy used in cancer patients with severe kidney insufficiency is ineffective. Although there are some pharmacokinetic studies on cyclophosphamide in kidney insufficiency patients, to the best of our knowledge, the pharmacokinetics and safety of combination of cyclophosphamide and docetaxel as postoperative chemotherapy in a patient with early stage breast cancer undergoing hemodialysis is unclear thus far.Case Presentation: The patient received regular TC regimen (cyclophosphamide 600 mg/m2, docetaxel 75 mg/m2). She underwent hemodialysis 48 h after chemotherapy. Blood samples at multiple time-points were collected for determination of plasma levels of cyclophosphamide and docetaxel. Pharmacokinetic analyses indicated that compared with the reference data, the in vivo half-life (66.96 h) and drug exposure (150%) of cyclophosphamide significantly increased; however, pharmacokinetic parameters of docetaxel was unaffected. Patient developed grade I thrombocytopenia and grade III leukopenia without any other severe adverse reactions. In total, four cycles of treatment were completed. After the chemotherapy, the patient received tamoxifen as endocrine therapy for one and a half years. No recurrence was reported.Conclusion: These results suggest that the standard TC regimen is mostly safe and could be used as postoperative adjuvant chemotherapy for hemodialysis patients with early stage breast cancer. [ABSTRACT FROM AUTHOR]

The study was devised to investigate the effect of retinoic acid trifloromethyl chalcone (RAFC) on mammary carcinogenesis in female rats. The data revealed a significant decrease in number of rats with mammary tumor, number of tumors per rat and tumor volume by 54, 72 and 75% respectively in RAFC group compared to control group. The ibuprofen treated rats also showed a significant decrease in number of rats with tumor, number of tumors per rat and tumor volumes by 43%, 55%, and 59%, respectively. Treatment of rats with RAFC also increased the latency period of tumor induction significantly. Median detection period (50% of tumors) was 92, 83 and 56 days respectively in the rats from RAFC, ibuprofen and control groups respectively after DMBA induction. These results demonstrate that RAFC possesses strong chemopreventive activity against mammary carcinogenesis. [ABSTRACT FROM AUTHOR]