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Summary: The prevalence of postoperative low anterior resection syndrome (LARS) in patients with colorectal cancer is high, which seriously affects the quality of life after operation. The purpose of this meta-analysis is to systematically evaluate the related factors of LARS in patients with colorectal cancer and provide reference for clinicians when making reasoned decisions. A systematic electronic search of PubMed, Embase, The Cochrane Library, WANFANG and CNKI was performed from 2012 to Dec 2020. We analyzed the risk factors of LARS by extracting baseline data and clinical results. The odds ratio (OR) was used to analyze binary variables. A total of 5102 patients were included in 21 literatures, of which the prevalence of LARS was 49.7% (2538/5102). Meta-analysis showed that there was no significant difference in the influence of age (P = 0.48) and sex (P = 0.68) on LARS, but low tumor height (P

Objective: To compare the effects of blunt separation combined with early sheath removal and conventional catheterization on the incidence of bleeding, exudation and subcutaneous congestion after peripherally inserted central catheter (PICC). Methods: 250 patients with PICC catheterization in our hospital were selected, including 125 in the control group and 125 in the observation group. The conventional catheterization method was used in the control group: The sheath was removed by scalpel skin expansion and complete tube delivery in place. The observation group used blunt separation combined with early sheath removal. The success rate of one-time sheath delivery, immediate bleeding, 24-hour bleeding and exudation were compared. Results: The success rate of sheath delivery in the observation group was 100%; The amount of immediate blood loss and blood loss 24h after catheterization in observation group was obviously lower than that in the control group, with statistical significance (P < 0.05). There were 6 cases of exudation in the control group and no exudation in the observation group. There was significant difference in the incidence between the two groups (P < 0.05); There were 10 cases of subcutaneous congestion in the control group and 2 cases of subcutaneous congestion in the observation group. There was significant difference in the incidence between the two groups (P < 0.05); Conclusion: Blunt separation combined with early sheath removal can reduce the occurrence of local blood and fluid leakage after PICC catheterization.

Our study aimed to investigate the associations between DEHP exposure and serum thyroid hormone levels in 347 adolescents and young adults. We measured DEHP metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-carboxymethyl)hexyl phthalate (MCMHP) in their urine. Total thyroxine (TT4), total triiodothyronine, free triiodothyronine, free thyroxine (FT4), thyroid-stimulating hormone and the mRNA levels of thyroid peroxidase (TPO), thyroglobulin (TG), sodium iodide symporter (NIS), thyroid transcription factor 1 (TTF-1), and paired box gene 8 (PAX-8) in serum were measured. The results of statistical analysis showed that urinary DEHP metabolites were generally negatively associated with TT4 levels in serum. In the males, the FT4 levels showed positive associations with urinary MEHP, MECPP, MCMHP, and ∑DEHP. The mRNA level of TG was significantly positively correlated with the levels of MECPP, MCMHP, and ∑DEHP, while the levels of TTF-1 and PAX-8 mRNA were significantly positively correlated with the levels of DEHP metabolites. Taken together, DEHP may affect the synthesis of TG by altering the normal transcription of TTF-1 and PAX-8, leading to decreased TT4 levels in Chinese adolescents.

An increasing number of studies have shown that exposure to particulate matter with a diameter ≤ 2.5 μm (PM2.5) could affect the onset and development of cardiovascular diseases. To explore the underlying mechanisms, the studies conducted in vitro investigations using different cell lines. In this review, we examined recently published reports cited by PubMed or Web of Science on the topic of cardiovascular toxicity induced by PM2.5 that carried the term in vitro. Here, we summarized the suggested mechanisms of PM2.5 leading to adverse effects and cardiovascular toxicity including oxidative stress; the increase of vascular endothelial permeability; the injury of vasomotor function and vascular reparative capacity in vascular endothelial cell lines; macrophage polarization and apoptosis in macrophage cell lines; and hypermethylation and apoptosis in the AC16 cell line and the related signaling pathways, which provided a new research direction of cardiovascular toxicity of PM2.5.

NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.

Supplemental Digital Content is available in the text., Immunotherapy has revolutionized the treatment in metastatic melanoma, but alternative biomarkers that are economical, simple and reliable still need to be clarified. In this study, we aimed to comprehensively analyze the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) in melanoma patients with immunotherapy. We searched PubMed, Embase, and Cochrane Library until September 16, 2020. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled to investigate the association of baseline NLR with overall survival (OS) and progression-free survival (PFS). Sensitivity analysis, subgroup analyses, publication bias assessment, and the Duval and Tweedie trim-and-fill method were used to evaluate the stability of results. A total of 18 studies including 2054 patients were included in our analysis. Pooled data demonstrated that higher baseline NLR was associated with a poorer OS (HR=2.46, 95% CI=1.77, 3.43) and PFS (HR=2.38, 95% CI=1.95, 2.89) of melanoma patients receiving immunotherapy. Subgroup analysis according to immunotherapy type showed that the prognostic effects of baseline NLR existed in all the subtypes of immunotherapy, including anticytotoxic T lymphocyte-associated protein 4 therapy (OS HR=2.26, 95% CI=1.43, 3.59; PFS HR=2.68, 95% CI=1.79, 4.02), antiprogrammed cell death-1 therapy (OS HR=3.08, 95% CI=2.21, 4.27; PFS HR=2.01, 95% CI=1.64, 2.47), and combination therapy (OS HR=1.75, 95% CI=1.13, 2.72; PFS HR=3.13, 95% CI=1.63, 6.03). Conclusions were still consistent in subgroup analyses stratified by study year, region, study type, sample size, analysis of HR and cuttoff of baseline NLR. Altogether, baseline NLR is a promising prognostic biomarker for melanoma patients receiving immunotherapy.

Background Breast malignancy is the most frequently diagnosed malignancy in women worldwide, and the diagnosis relies on invasive examinations. However, most clinical breast changes in women are benign, and invasive diagnostic approaches cause unnecessary suffering for the patients. Thus, a novel noninvasive approach for discriminating malignant breast lesions from benign lesions is needed. Methods We performed cell-free DNA (cfDNA) sequencing on plasma samples from 173 malignant breast lesion patients, 158 benign breast lesion patients, and 102 healthy women. We then analyzed the cfDNA-based nucleosome profiles, which reflect the various tissues of origin and transcription factor activities. Moreover, by using machine learning classifiers along with the cfDNA sequencing data, we built classifiers for discriminating benign from malignant breast lesions. Receiver operating characteristic curve analyses were used to evaluate the performance of the classifiers. Results cfDNA-based nucleosome profiles reflected the various tissues of origin and transcription factor activities in benign and malignant breast lesions. The cfDNA-based transcription factor activities and breast malignancy-specific transcription factor-binding site accessibility profiles could accurately distinguish benign and malignant breast lesions, with area under the curve values of 0.777 and 0.824, respectively. Conclusions Our proof-of-principle study established a methodology for noninvasively discriminating benign from malignant breast lesions.

Morin is a natural compound isolated from moraceae family members and has been reported to possess a range of pharmacological activities. However, the effects of morin on bone-associated disorders and the potential mechanism remain unknown. In this study, we investigated the anti-osteoclastogenic effect of morin in vitro and the potential therapeutic effects on ovariectomy (OVX)-induced osteoporosis in vivo. In vitro, by using a bone marrow macrophage-derived osteoclast culture system, we determined that morin attenuated receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation via the inhibition of the mitogen-activated protein kinase (MAPK), NF-κB and calcium pathways. In addition, the subsequent expression of nuclear factor of activated T cells c1 (NFATc1) and c-fos was significantly suppressed by morin. In addition, NFATc1 downregulation led to the reduced expression of osteoclastogenesis-related marker genes, such as V-ATPase-d2 and Integrin β3. In vivo, results provided that morin could effectively attenuate OVX-induced bone loss in C57BL/6 mice. In conclusion, our results demonstrated that morin suppressed RANKL-induced osteoclastogenesis via the NF-κB, MAPK and calcium pathways, in addition, its function of preventing OVX-induced bone loss in vivo, which suggested that morin may be a potential therapeutic agent for postmenopausal osteoporosis treatment.

Background: Panax notoginseng Saponins (PNS) is used as a traditional Chinese medicine for ischemic stroke and cardiovascular disease; it has been proven to possess anticancer activity recently. Objective: In this study, we aimed to explore the curative anticancer effect and potential mechanisms of PNS in pancreatic cancer cells. Methods: Pancreatic cancer Miapaca2 and PANC-1 cells were treated with PNS and Gemcitabine (Gem), respectively. Then the cell viability was assessed by CCK-8 assay, cell proliferation was tested by colony formation assay and EdU cell proliferation assay, cell migration and invasiveness were tested by wound healing assay and transwell assay respectively, and cell apoptosis was detected by flow cytometry. Finally, we detected the expression levels of proteins related to migration, apoptosis and autophagy through Western blotting. Results: PNS not only inhibited the proliferation, migration, invasion and autophagy of Miapaca2 and PANC-1 cells, but also induced apoptosis and promoted chemosensitivity of pancreatic cancer cells to Gem. Conclusion: PNS may exhibit cytotoxicity and increase chemosensitivity of pancreatic cancer cells to Gem by inhibiting autophagy and inducing apoptosis, providing a new strategy and potential treatment option for pancreatic cancer.

Long-term in vivo observation in large animal model is critical for evaluating the potential of small diameter tissue engineering vascular graft (SDTEVG) in clinical application, but is rarely reported. In this study, a SDTEVG is fabricated by the electrospinning of poly(ε-caprolactone) and subsequent heparin modification. SDTEVG is implanted into canine's abdominal aorta for 511 days in order to investigate its clinical feasibility. An active and robust remodeling process was characterized by a confluent endothelium, macrophage infiltrate, extracellular matrix deposition and remodeling on the explanted graft. The immunohistochemical and immunofluorescence analysis further exhibit the regeneration of endothelium and smooth muscle layer on tunica intima and tunica media, respectively. Thus, long-term follow-up reveals viable neovessel formation beyond graft degradation. Furthermore, the von Kossa staining exhibits no occurrence of calcification. However, although no TEVG failure or rupture happens during the follow-up, the aneurysm is found by both Doppler ultrasonic and gross observation. Consequently, as-prepared TEVG shows promising potential in vascular tissue engineering if it can be appropriately strengthened to prevent the occurrence of aneurysm.

BACKGROUND: According to the global cancer burden data released in 2020, breast cancer (BC) has become the most common cancer in the world. Similar to those of other cancers, the present methods used in clinic for diagnosing early BC are invasive, inaccurate, and insensitive. Hence, new non-invasive methods capable of early diagnosis are needed. METHODS: We applied next-generation sequencing and analyzed the messenger RNA (mRNA) profiles of plasma extracellular vesicles (EVs) derived from 14 BC patients and 6 patients with benign breast lesions. We used 3 regression models, namely support vector machine (SVM), linear discriminate analysis (LDA), and logistic regression (LR), to develop classifiers for use in making predictive BC diagnoses; and used 259 plasma samples, including those obtained from 144 patients with BC, 72 patients with benign breast lesions, and 43 healthy women, which were divided into training groups and validation groups to verify their performances as classifiers by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The area under the curve (AUC) and accuracy, sensitivity, and specificity of the classifiers were cross-validated with the leave-1-out cross-validation (LOOCV) method. RESULTS: Among all combinations assessed with the 3 different regression models, an 8-mRNA combination, named EXOB(mRNA), exhibited high performance [accuracy =71.9% and AUC =0.718, 95% confidence interval (CI): 0.652 to 0.784] in the training cohort after LOOCV was performed, showing the largest AUC in the SVM model. The mRNAs in EXOB(mRNA) were HLA-DRB1, HAVCR1, ENPEP, TIMP1, CD36, MARCKS, DAB2, and CXCL14. In the validation cohort, the AUC of EXOB(mRNA) was 0.737 (95% CI: 0.636 to 0.837). In addition, gene function and pathway analyses revealed that different levels of gene expression were associated with cancer. CONCLUSIONS: We developed a high-performing predictive classifiers including 8 mRNAs from plasma extracellular vesicles for diagnosing breast cancer.

BACKGROUND Exposure to a maternal high-fat diet (HFD) predisposes offspring to nonalcoholic fatty liver disease. OBJECTIVES The aim of this study was to explore whether milk fat globule membrane (MFGM) supplementation during suckling exerts a long-term protective effect on hepatic lipid metabolism in adult offspring exposed to maternal HFD. METHODS We fed 5-week-old female C57BL/6J mice either a HFD (60% kcal fat) or control diet (CD; 16.7% kcal fat) for 3 weeks before mating, as well as throughout gestation and lactation. After delivery, male offspring from HFD dams were supplemented with 1 g/(kg body weight·day) MFGM (HFD + MFGM group) or the same volume of vehicle (HFD group) during suckling. Male offspring from CD dams were also supplemented with vehicle during suckling (CD group). All offspring were weaned onto CD for 8 weeks. Histopathology, metabolic parameters, lipogenic level, oxidative stress, and mitochondria function in the liver were analyzed. A 1-way ANOVA and a Kruskal-Wallis test were used for multi-group comparisons. RESULTS As compared to the CD group, the HFD group had more lipid droplets in livers, and exhibited ∼100% higher serum triglycerides, ∼38% higher hepatic triglycerides, ∼75% higher serum aspartate aminotransferase, and ∼130% higher fasting blood glucose (P

Thyroid‐associated ophthalmopathy (TAO) is a serious, progressive, vision‐threatening and difficult‐to‐treat organ‐specific autoimmune disease. The course, therapeutic effects and prognosis of moderate to severe TAO vary greatly. High‐dose intravenous glucocorticoid (IVGC) therapy is considered a first‐line treatment for active moderate‐to‐severe TAO, but there is still insufficient evidence regarding the treatment duration. Long‐term IVGC therapy can influence the metabolism of glucose, lipids, and bone. This study was designed to compare changes in metabolic and immunological indexes as well as the magnetic resonance imaging apparent diffusion coefficient (ADC) of the extraocular muscles after 4 and 12 weeks of IVGC therapy. Forty‐eight patients with active moderate‐to‐severe TAO were included in this retrospective cohort study. Metabolism and immunological indexes were measured before and after therapy. The ADC and clinical activity score (CAS) were used to evaluate the efficacy of treatment in these patients. We found that the patients in the 12‐week group had increased fasting plasma glucose (p = 0.004), glycated hemoglobin (p = 0.028), total cholesterol (p

Qi-Xing Tian,1,* Zhi-Hui Zhang,1,* Qing-Lin Ye,1 Shen Xu,1 Qian Hong,1 Wei-Yang Xing,1 Lei Chen,1 De-Xin Yu,1 De-Xiang Xu,2,3 Dong-Dong Xie1 1Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: De-Xiang XuDepartment of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of ChinaTel +86 138 6674 1832Email xudex@126.comDong-Dong XieDepartment of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of ChinaTel +86 138 6670 0010Email xiedd_urology@163.comPurpose: Gram-negative bacteria are usually found in prostate cancer (PCa) tissues. This study aims to investigate the role of lipopolysaccharide (LPS), a glycolipid compound found in the outer membrane of gram-negative bacteria, on the migration and invasion of PCa cells, and to evaluate the protective effect of melatonin.Materials and Methods: DU145, PC-3 and LNCaP cells were incubated with LPS in the presence or absence of melatonin. Wound healing and Transwell assays were used to analyze migration and invasion of PCa cells. RT-PCR and Western blotting were used to assess the mRNA and protein levels, respectively. Co-IP was used to analyze β-catenin ubiquitination.Results: Our results showed that LPS promoted migration and invasion of PCa cells. In addition, LPS stimulated inflammatory reaction and induced epithelial–mesenchymal transition (EMT) in PCa cells by activating several TLR4 downstream pathways. Specifically, LPS promoted NF-κB/IL-6/STAT3 signal transduction. In addition, LPS upregulated phosphorylation levels of cytoplasmic AKTSer473 and GSK-3βSer9. Moreover, LPS induced phosphorylation of GSK-3βSer9 in the “disruption complex”, and then inhibited phosphorylation and ubiquitination of cytoplasmic β-catenin, leading to β-catenin nuclear translocation. Interestingly, melatonin inhibited invasion and migration not only in LPS-stimulated but also in LPS-unstimulated PCa cells. Melatonin suppressed PCa cells migration and invasion by blocking EMT mediated by IL-6/STAT3, AKT/GSK-3β and β-catenin pathways.Conclusion: This study provides evidence that melatonin inhibits migration and invasion through blocking multiple TLR4 downstream EMT-associated pathways both in LPS-stimulated and -unstimulated PCa cells. Our results provide new insights into the role of bacterial infection in PCa metastasis and a potential therapeutic agent.Keywords: β-catenin, EMT, lipopolysaccharide, melatonin, prostate cancer

Metallothionein (MT1M) belongs to a family of cysteine-rich cytosolic protein and has been reported to be a tumor suppressor gene in multiple cancers. However, its role in esophageal carcinoma carcinogenesis remains unclear. In this study, MT1M expression was correlated with tumor type, stage, drinking and smoking history, as well as patient survival. We also studied the regulation and biological function of MT1M in esophageal squamous cell carcinoma (ESCC). We have found that MT1M is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues. Furthermore, restoration of expression by treatment with the demethylation agent A + T showed that MT1M downregulation might be closely related to hypermethylation in its promoter region. Over-expression of MT1M in ESCC cells significantly altered cell morphology, induced apoptosis, and reduced colony formation, cell viability, migration and epithelial-mesenchymal transition. Moreover, based on reactive oxygen species (ROS) levels, a superoxide dismutase 1 (SOD1) activity assay and protein analysis, we verified that the tumor-suppressive function of MT1M was at least partially caused by its upregulation of ROS levels, downregulation of SOD1 activity and phosphorylation of the SOD1 downstream pathway PI3K/AKT. In conclusion, our results demonstrated that MT1M was a novel tumor-suppressor in ESCC and may be disrupted by promoter CpG methylation during esophageal carcinogenesis.

IL-26 is a newly discovered IL-10 cytokine family member mainly secreted by Th17 cells. However, the relationship between IL-26 and lung cancer remains unclear. The present study reported that IL-26 is involved in the production and promotion of malignant pleural effusion (MPE) for the first time. The concentrations of IL-26 and several Th17-related cytokines in MPE and peripheral blood (PB) from MPE patients were measured. IL-26, IL-10, and IL-6 were elevated in MPE compared to PB. The cell resource of IL-26 was primary Th17 cells measured by flow cytometry, whereas Tc17 cells and macrophages could also contribute to higher concentration of IL-26 in MPE. Abundant IL-6 and IL-23 in MPE could promote the frequency of IL-26 expressed by CD4+ T cells through phosphorylating STAT3 signaling pathway and promoting the expression of a specific Th17 lineage marker RORγt subsequently. IL-26 could selectively increase Th22 proportion through up-regulating the percentage of Ki-67 expressed by CD4+ T cells and the expression of IL-22 secreted by memory CD4+ T cells. In addition, IL-26 could decrease secretion of granzyme B. The tumor-killing activity of CD8+ T cells were inhibited as well when cocultured with malignant cells. Furthermore, the accumulation of IL-26 protein in MPE predicted poor patient survival. In summary, our results indicated that IL-26 was involved in the pathogenesis of MPE by exerting its impacts on both CD4+ T cells and CD8+ T cells.

Jianchang Qian,1,* Sihui Yin,1,* Lin Ye,1 Zhe Wang,2 Sheng Shu,1,3 Zhenxin Mou,1,3 Mingjiang Xu,1 Nipon Chattipakorn,4 Zhiguo Liu,1 Guang Liang1,3,5 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 4Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 5Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guang Liang; Zhiguo LiuChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of ChinaTel/Fax +86-577-86699396Email wzmcliangguang@163.com; lzgcnu@163.comAim: Elevated inflammatory signaling has been shown to play an important role in diabetic kidney disease (DKD). We previously developed a new anti-inflammatory compound LG4. In the present study, we have tested the hypothesis that LG4 could prevent DKD by suppressing inflammation and identified the underlying mechanism.Methods: Streptozotocin-induced type 1 diabetic mice were used to develop DKD and evaluate the effects of LG4 against DKD. To identify the potential targets of LG4, biotin-linked LG4 was synthesized and subjected to proteome microarray screening. The cellular mechanism of LG4 was investigated in HG-challenged SV40MES13 cells.Results: Although LG4 treatment had no effect on the body weight and blood glucose levels, it remarkably reversed the hyperglycemia-induced pathological changes and fibrosis in the kidneys of T1DM mice. Importantly, hyperglycemia-induced renal inflammation evidenced by NF-κB activation and TNFα and IL-6 overexpression was greatly ameliorated with LG4 treatment. Proteosome microarray screening revealed that JNK and ERK were the direct binding proteins of LG4. LG4 significantly reduced HG-induced JNK and ERK phosphorylation and subsequent NF-κB activation in vivo and in vitro. In addition, LG4 did not show further anti-inflammatory effect in HG-challenged mesangial cells with the presence of JNK or ERK inhibitor.Conclusion: LG4 showed renoprotective activity through inhibiting ERK/JNK-mediated inflammation in diabetic mice, indicating that LG4 may be a therapeutic agent for DKD.Keywords: indole-2-carboxamide derivative, diabetic kidney disease, inflammation, MAPK, NF-κB

As an air pollutant, fine particulate matter with a diameter ≤ 2.5 μm (PM2.5) can enter the body through the respiratory tract and cause adverse cardiovascular effects. Here, the effects of PM2.5 on atherosclerosis, hypertension, arrhythmia, myocardial infarction are summarized from the perspective researches of human epidemiology, animal, cell and molecule. The results of this review should be proved useful as a scientific basis for the prevention and treatment of cardiovascular disease caused by PM2.5.

This work presents an investigation on the composition and structure of polysaccharides from the roots of Tetrastigma hemsleyanum (THP) and its associated antioxidant activity. It further explores the protective effect of THP on RAW264.7 cells against cytotoxicity induced by H2O2. Ion chromatography (IC) revealed that THP contained glucose, arabinose, mannose, glucuronic acid, galactose and galacturonic acid, in different molar ratios. Furthermore, gel permeation chromatography-refractive index-multiangle laser light scattering (GPC-RI-MALS) was employed to deduce the relative molecular mass (Mw) of the polysaccharide, which was 177.1 ± 1.8 kDa. Fourier transform infrared spectroscopy (FT-IR) and Congo red binding assay highlighted that the THP had a steady α-triple helix conformation. Similarly, assays of antioxidant activity disclosed that THP had reasonable concentration-dependent hydroxyl radical and superoxide radical scavenging activities, peroxidation inhibition ability and ferrous ion chelating potency, in addition to a significant 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity. Moreover, THP could protect RAW264.7 cells against H2O2-induced cytotoxicity by decreasing intracellular ROS levels, reducing catalase (CAT) and superoxide dismutase (SOD) activities, increasing lactate dehydrogenase (LDH) activity and increment in malondialdehyde (MDA) level. Data retrieved from the in vitro models explicitly established the antioxidant capability of polysaccharides from T. hemsleyanum root extracts.

Summary Coronavirus disease 2019 (COVID-19) occurs in the influenza season and has become a global pandemic. The present study aimed to examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection with influenza A virus (IAV) in an attempt to provide clues for the antiviral interventions of co-infected patients. We described two patients who were co-infected with SARS-CoV-2 and IAV treated at Wuhan Union Hospital, China. In addition, we performed a review in PubMed, Web of Science and CNKI (from January 1 up to November 1, 2020) with combinations of the following key words: “COVID-19, SARS-COV-2, influenza A and co-infection”. A total of 28 co-infected patients were enrolled in the analysis. Of the 28 patients, the median age was 54.5 years (IQR, 34.25–67.5) and 14 cases (50.0%) were classified as severe types. The most common symptoms were fever (85.71%), cough (82.14%) and dyspnea (60.71%). Sixteen patients had lymphocytopenia on admission and 23 patients exhibited abnormal radiological changes. The median time from symptom onset to hospital admission was 4 days (IQR, 3–6), and the median time of hospital stay was 14 days (IQR, 8.5–16.75). In conclusion, patients with SARS-COV-2 and IAV co-infection were similar to those infected with SARS-COV-2 alone in symptoms and radiological images. SARS-COV-2 co-infection with IAV could lead to more severe clinical condition but did not experience longer hospital stay compared with patients infected with SARS-COV-2 alone.

Rationale: Breast cancer (BrCa) is the most common cancer worldwide, and the 5-year relative survival rate has declined in patients diagnosed at stage IV. Advanced BrCa is considered as incurable, which still lack effective treatment strategies. Identifying and characterizing new tumor suppression genes is important to establish effective prognostic biomarkers or therapeutic targets for late-stage BrCa. Methods: RNA-seq was applied in BrCa tissues and normal breast tissues. Through analyzing differentially expressed genes, DRD2 was selected for further analysis. And expression and promoter methylation status of DRD2 were also determined. DRD2 functions were analyzed by various cell biology assays in vitro. Subcutaneous tumor model was used to explore DRD2 effects in vivo. A co-cultivated system was constructed to investigate interactions of DRD2 and macrophages in vitro. WB, IHC, IF, TUNEL, qRT-PCR, Co-IP, Antibody Array, and Mass Spectrum analysis were further applied to determine the detailed mechanism. Results: In BrCa, DRD2 was found to be downregulated due to promoter methylation. Higher expression of DRD2 positively correlated with longer survival times especially in HER2-positive patients. DRD2 also promoted BrCa cells sensitivity to Paclitaxel. Ectopic expression of DRD2 significantly inhibited BrCa tumorigenesis. DRD2 also induced apoptosis as well as necroptosis in vitro and in vivo. DRD2 restricted NF-κB signaling pathway activation through interacting with β-arrestin2, DDX5 and eEF1A2. Interestingly, DRD2 also regulated microenvironment as it facilitated M1 polarization of macrophages, and triggered GSDME-executed pyroptosis. Conclusion: Collectively, this study novelly manifests the role of DRD2 in suppressing BrCa tumorigenesis, predicting prognosis and treatment response. And this study further reveals the critical role of DRD2 in educating M1 macrophages, restricting NF-κB signaling pathway and triggering different processes of programmed cell death in BrCa. Taking together, those findings represent a predictive and therapeutic target for BrCa.

Background To understand the prevalence of diabetic retinopathy (DR) in Shenzhen and to analyze the risk factors for the occurrence and development of DR. Based on the comprehensive information system for diabetes prevention and control in the communities of Shenzhen in 2019, six community health service centers in Shenzhen were used as research sites to carry out multicenter, cross-sectional screening studies. Methods Cluster random sampling was used to collect data from 904 patients with diabetes in Shenzhen. The occurrence of DR and vision-threatening diabetic retinopathy (VTDR) was analyzed, and multivariate logistic regression was performed to analyze the risk factors for DR and VTDR. EpiData version 3.1 (EpiData Association, Odense, Denmark) statistical software was used to build a database, and Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp., Armonk, N.Y., USA) was used to sort up and analyze the data. Results The prevalence of DR among diabetic patients in Shenzhen was 18.58% [95% confidence interval (CI): 16.13-21.3%], and the prevalence of VTDR was 2.43% (95% CI: 1.57-1.2%). The prevalence of DR and VTDR was higher in males than in females. Logistic regression analysis showed that age, disease duration, medication mode, and the occurrence of diabetic peripheral neuropathy (DPN) were associated with the incidence of DR in diabetic patients, and that disease duration, the occurrence of DPN, and diabetic nephropathy were associated with the occurrence of VTDR. Conclusions The prevalence of DR in the communities of Shenzhen is high. Age, disease duration, medications, and DPN are the major risk factors for the occurrence of DR.

Aims Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol. Methods In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses. Results It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis. Conclusion We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.

Hereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β-thalassaemia. The homozygous mutation c.-196 C>T in the Aγ-globin (HBG1) promoter, which causes Sardinian δβ0 -thalassaemia, is able to completely rescue the β-major thalassaemia phenotype caused by the β0 39-thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood. Here, we describe a CRISPR/Cas9 genome-editing approach, combined with the non-homologous end joining (NHEJ) pathway repair, aimed at reproducing the effects of this naturally occurring HPFH mutation in both HBG promoters. After selecting the most efficient guide RNA in K562 cells, we edited the HBG promoters in human umbilical cord blood-derived erythroid progenitor 2 cells (HUDEP-2) and in haematopoietic stem and progenitor cells (HSPCs) from β0 -thalassaemia patients to assess the therapeutic potential of HbF induction. Our results indicate that small deletions targeting the -196-promoter region restore high levels of fetal haemoglobin (HbF) synthesis in all cell types tested. In pools of HSPCs derived from homozygous β0 39-thalassaemia patients, a 20% editing determined a parallel 20% increase of HbF compared to unedited pools. These results suggest that editing the region of HBG promoters around the -196 position has the potential to induce therapeutic levels of HbF in patients with most types of β-thalassaemia irrespective of the β-globin gene (HBB) mutations.

Through the dual-anchoring effect, hydroxyapatite (HA) molecules were intercalated into graphene oxide (GO) layers to form a GO–PEG–HA hybrid, and PVA/GO–PEG–HA nanocomposite hydrogels were prepare...

Background: This study aims to investigate the efficacy and safety of heat and moisture exchanger on airway resistance in a cardiothoracic surgery intensive care unit. Methods: A total of 31 patients (18 males, 13 females; mean age 51.5 years; range, 39 to 61 years) who were treated with long-term mechanical ventilation due to low cardiac output syndrome after cardiopulmonary bypass and cardiac surgery were retrospectively analyzed between December 2014 and December 2018. In addition, an in vitro lung model and different doses of hydroxyethyl starch in the heat and moisture exchangers to mimic the airway secretions were used and the proper interval to change heat and moisture exchangers was evaluated. Results: In the in vitro lung model, the mean airway resistance was 19.4±0.2 cmH2O/L/sec in the 5 mL group (p=0.060), 20.3±1.0 cmH2O/L/sec in the 10 mL group (p=0.065), and 30.2±1.7 cmH2O/L/sec in the 15 mL group (p

As a specific microvascular complication of diabetes, diabetic retinopathy (DR) causes severe visual impairment in patients with diabetes. The expression of microRNA‑126 (miRNA/miR‑126) has previously been found to be significantly decreased in the serum of patients with DR. In the present study, the functions of miR‑126 and its mechanisms of action in experimental diabetic retinopathy were examined in rats with streptozotocin (STZ)‑induced diabetes and in high glucose (HG)‑induced human retinal capillary endothelial cells (HRCECs). In vivo, diabetic rat models were established and the rats were intravitreally injected with lentivirus expressing rno‑miR‑126 (lenti‑miR‑126) or negative control (lenti‑NC). RT‑qPCR was used to determine the miR‑126 level in the serum and retina. Paraffin sections and retinal vasculature were used to determine the extent of retinopathy. The protein content of vascular endothelial growth factor (VEGF) and pigment epithelium‑derived factor (PEDF) in the retina was used as an auxiliary measurement of retinopathy. Western blot analysis and immunofluorescence staining were used to measure the expression of polo‑like kinase 4 (PLK4) in rat retinal tissue. In vitro, the cells were transfected with miR‑126 inhibitor or mimic and treated with the PLK4 inhibitor, CFI‑400945 fumarate. RT‑qPCR and western blot analysis were used to detect the miR‑126 level and PLK4 expression. Cell proliferation and migration were measured by EdU and Transwell assays. The diabetic rats were found to exhibit downregulated serum and retinal miR‑126 levels compared with the non‑diabetic rats. The intravitreal delivery of miR‑126 alleviated retinopathy and reduced the diabetes‑induced upregulation of PLK4 in retinal tissues. Luciferase reporter assays confirmed that PLK4 mRNA was the target of miR‑126. In HG‑induced HRCECs, transfection with miR‑126 mimic increased the miR‑126 level, whereas it downregulated that of its downstream target, PLK4, which was opposite to the effects exerted by the miR‑126 inhibitor. Furthermore, miR‑126 mimic and CFI‑400945 fumarate reduced the HG‑induced upregulation of PLK4 expression, as well as cell proliferation and migration. On the whole, the findings of the present study demonstrate that miR‑126 reduces experimental diabetic retinopathy and suppresses endothelial cell proliferation and migration by targeting PLK4. Thus, miR‑126 and CFI‑400945 fumarate may be therapeutic targets for DR.

Through retrieving the relevant experimental researches from Pubmed, CNKI, Wanfang and VIP databases, it is discovered that the effects of moxibustion on liver are mainly reflected in the following three aspects, namely, maintaining the normal functions of liver, promoting the repair of liver injury and delaying liver aging. By further analysis and in view of experiments, the factors influencing these effects may include stimulation site, stimulation intensity and heat source. The effects of moxibustion on liver and its influencing factors are explored and discovered in the perspective of experimental researches and these discoveries have been verified in clinical practice correspondingly. Based on the current study situation, moxibustion therapy is still limited in clinical studies on liver disorders as compared with the experimental researches. Hence, the deep exploration of moxibustion on its specific biological effect and mechanism and the excavation of moxibustion on its clinical application are likely to be the coming emphasis of the basic research and clinical practice for moxibustion.

Aim: To explore the biological functions and clinical significance of CAVIN2 in lung cancer. Materials & methods: Methylation-specific PCR was used to measure promoter methylation of CAVIN2. The function of CAVIN2 was tested by Cell Counting Kit-8, colony formation, Transwell, flow cytometric analysis, acridine orange/ethidium bromide, chemosensitivity assay and xenograft assay. Results: CAVIN2 is significantly downregulated by promoter methylation in lung cancer. CAVIN2 overexpression inhibits lung cancer cell migration and invasion. Furthermore, ectopic expression of CAVIN2 inhibits cell proliferation in vivo and in vitro by inducing G2/M cell cycle arrest, which sensitizes the chemosensitivity of lung cancer cells to paclitaxel and 5-fluorouracil, but not cisplatin. Conclusion: CAVIN2 is a tumor suppressor in non-small-cell lung cancer and can sensitize lung cancer cells to paclitaxel and 5-fluorouracil.

In thoracoscopic segmentectomy, accurate preoperative identification of intersegmental vessels, bronchi, and the surgical safety margin is vital. We applied three dimensional computed tomography bronchography and angiography (3D-CTBA) reconstruction to appropriately plan thoracoscopic segmentectomy for Patients with pulmonary nodules. In this study, we evaluated the effectiveness and accuracy of 3D-CTBA reconstruction for the identification of segmental anatomical structures and variation during thoracoscopic segmentectomy.We retrospectively analyzed data of 30 patients who underwent 3D-CTBA reconstruction before thoracoscopic segmentectomy between January and May 2019 in the Department of Thoracic Surgery, First Affiliated Hospital of Nanchang University. We compared the individual target segment arteries, veins, and bronchi identified during surgery with the preoperative 3D-CTBA model to evaluate its effectiveness and accuracy. The accuracy of the preoperative 3D-CTBA model for the identification of target segmental arteries, veins, and bronchi was 99.08% (108/109), 98.39% (122/124), and 100% (118/118), respectively. Through 3DCTBA modeling, we found mediastinal and interlobar types of lingular segmental arteries in six patients, and central veins were not found in seven patients. In addition, we detected rare anatomical variations in two patients; one patient had the right apical segmental bronchus that stemmed solely from the right primary bronchus (tracheal bronchus), and the other had rare right basal segmental variant bronchi and vessels. The 3D-CTBA model can precisely predict segmental bronchi and vessels and identify anatomical structure variations before operation, which can aid surgeons to avoid incorrect operation and improve surgical efficiency. This has important implications for thoracoscopic segmentectomy.