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Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro . Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.

Previous studies have suggested that Helicobacter pylori ( H. pylori ) infection is associated with nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to investigate the effect of H. pylori eradication treatment on NAFLD patients. Two hundred NAFLD patients who tested positive for H. pylori infection were randomized into the H. pylori eradication treatment group or the control group. Metabolic and inflammatory parameters and FibroScan were measured in all subjects at baseline and 1 year after treatment. At 1 year after treatment, the decrease in metabolic indicators, such as fasting blood glucose, glycosylated haemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, body mass index and controlled attenuation parameter values, were more obvious in the treatment group. Moreover, the inflammatory indicators white blood count and high-sensitivity C-reactive protein (hs-CRP) and the inflammatory factors interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were also significantly decreased. H. pylori eradication can further reduce the metabolic indices of NAFLD and the degree of liver steatosis. H. pylori infection may participate in the occurrence and development of NAFLD through its influence on inflammatory factors. Thus, checking for the presence of H. pylori infection in patients at risk of NAFLD may be beneficial.

This study aimed to find a safe and effective cumulative cisplatin dose (CCD) for concurrent chemoradiotherapy (CCRT) beneficiaries among elderly nasopharyngeal carcinoma (NPC) patients. A total of 765 elderly (≥ 60 years old) NPC patients treated with cisplatin-based CCRT and IMRT-alone from 2007 to 2018 were included in this study. RPA-generated risk stratification was used to identify CCRT beneficiaries. CCDs were divided into CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m 2 and their OS and nephrotoxicity compared. Pre-treatment plasma EBV DNA and clinical stage were incorporated into the RPA model to perform risk stratification. All patients were classified into either a high-risk group (n = 158, Stage IV), an intermediate-risk group (n = 193, EBV DNA > 2000 copy/mL & Stage I, II, III) or a low-risk group (n = 414, EBV DNA ≤ 2000 copy/mL & Stage I, II, III). The 5 year OS of CCRT vs. IMRT alone in the high-, intermediate- and low-risk groups after balancing covariate bias were 60.1 vs 46.6% (p = 0.02), 77.8 vs 64.6% (p = 0.03) and 86.2 vs 85.0% (p = 0.81), respectively. The 5 year OS of patients receiving CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m 2 after balancing covariate bias in the high-risk group were 45.2, 48.9, 73.4 and 58.3% (p = 0.029), in the intermediate-risk group they were 64.6, 65.2, 76.8 and 83.6% (p = 0.038), and in the low-risk group they were 85.0, 68.1, 84.8 and 94.0% (p = 0.029), respectively. In the low-risk group, the 5 year OS of Stage III patients receiving CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m 2 were 83.5, 76.9, 85.5 and 95.5% (p = 0.044), respectively. No Grade 3–4 nephrotoxicity occurred. Therefore, in our study, Stage I, II, & EBV DNA > 2000copy/ml and Stage III, IV elderly NPC patients may be CCRT beneficiaries. 80 < CCD ≤ 300 mg/m 2 is recommended for the high-risk (Stage IV) group, and 160 < CCD ≤ 300 mg/m 2 for the intermediate-risk (Stage I, II, III & EBV DNA > 2000copy/ml) and low-risk (Stage III & EBV DNA ≤ 2000 copy/ml) groups. No grade 3–4 nephrotoxicity occurred in any of the CCD groups.

Objective This study aims to evaluate the risk stratification among elderly Nasopharyngeal carcinoma (NPC) patients (≥60 years old) and select the beneficiaries from concurrent chemotherapy (CCRT) combined with induction chemotherapy (IC). Materials and Methods A total of 909 elderly non‐metastatic NPC patients treated with cisplatin‐based CCRT or IC + CCRT between January 2007 and December 2016 were included. Prognostic nomograms were generated according to clinical characteristics and serum biomarkers. The survival outcomes of patients treated with CCRT versus IC + CCRT were compared in three well‐matched risk groups (high, medium, and low risk) after PSM analysis. Benefit of IC in people older or younger than 70 years and effect of different IC regimens and cycles on prognosis were analyzed. Results Nomograms of overall survival (OS) (C‐index: 0.64, 95% CI, 0.61–0.89) and disease special survival (DSS) (C‐index: 0.65, 95% CI, 0.62–0.71) showed good prognostic accuracy. The nomogram for DSS included variables of age, gender, ACE, EBV DNA, N stage, and T stage. OS included variables of age, smoking history, ACE, ALB, EBV DNA, N stage, and T stage. The corresponding 5‐year OS rates of high, medium and low risk groups were 87.4%, 82.2%, and 60.9%, respectively (p < 0.001), while the 5‐year DSS rates were 92.2%, 84.3%, and 69.0%, respectively (p < 0.001). In the high risk group, IC + CCRT led to significantly higher 5‐year OS and DSS rate compared with CCRT (5‐year OS rate, 73.5% versus 51.8%, p = 0.006; 5‐year DSS rate, 81.4% versus 61.3%, p = 0.002). While in the medium and low risk groups, OS and DSS were not significantly different (OS: p = 0.259, 0.186; DSS: p = 0.29, 0.094). Subgroup analysis showed in the high risk group, only people younger than 70 years old could benefit from IC. TPF and IC cycles of three could lead to the best survival results. Conclusion Compared with CCRT, OS, and DSS among high risk elderly patients were significantly improved by the addition of IC in patients younger than 70 years old. TPF and three IC cycles were recommended. Elderly NPC patients <70 years of age in the high‐risk group have survival benefits from CCRT, and TOF regimen, 3 cycles of induction chemotherapy, has significantly improved survival.

This study was performed to explore the preventive and therapeutic effects of ZFM4 on H. pylori infections of the stomach tissue in C57BL/6 mice. In this study, 40 specific-pathogen-free female C57BL/6 mice were randomly divided into five groups, namely, the control, ZFM4 pretreatment) ZFM4 pretreatment before infected), model ( infected), triple therapy ( infected and treated with triple therapy), and ZFM4 treatment groups ( infected and treated with ZFM4). The preventive and therapeutic effects of ZFM4 were evaluated in infected C57BL/6 mice by assessing gastric tissue morphology, inflammatory cytokine levels, microbial composition, and microbial diversity. ZFM4 was able to survive in low gastric pH and play a role in preventing infection. This was evident from a reduction in both, the gastric inflammatory response and expression of inflammatory factors caused by infection. ZFM4 could also inhibit the growth of via its beneficial impact on the gastric microbiota. Our findings suggest that ZFM4 offers superior preventive effects against infections when used alone. However, the therapeutic effect on established infections is weaker. Further clinical trials are needed to confirm the specific dosage, duration, and other aspects of administration.

Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j-4 can significantly induce the apoptosis of MDA-MB-231 cells (IC 50  = 2.68 ± 0.27 μM). In further studies, 12j-4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j-4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors.

We have previously reported that Agriophyllum oligosaccharides (AOS) significantly enhance glycemic control by increasing the activation of insulin receptor (INS-R), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), peroxisome proliferator-activated receptor (PPAR)-γ, and glucose transporter 4 (Glut4) proteins in hepatic tissues. However, the effect of glucose control by AOS on the regulation of pancreatic tissues in db/db mice and MIN6 cells remains to be determined. An oral dose of AOS (380 or 750 mg/kg) was administered to type-2 diabetic db/db mice for 8 weeks to determine whether AOS regulates glucose by the INS-R/IRS/Glut4-mediated insulin pathway. Meanwhile, the effects of AOS on glucose uptake and its related signaling pathway in MIN6 cells were also investigated. The results showed that the random blood glucose (RBG) level in the AOS-treated group was lower than that in the control group. AOS reduced the levels of glycated hemoglobin (HbA1c) and free fatty acid (FFA) and significantly improved the pathological changes in the pancreatic tissues in db/db mice. Moreover, immunohistochemical analysis revealed that the expression of INS-R, IRS-1, IRS-2, and Glut4 was increased in the AOS-treated group than in the model group. Further, in vitro experiments using MIN6 cells showed that AOS regulated INS-R, IRS-1, IRS-2, and Glut4 protein and mRNA levels and attenuated insulin resistance and cell apoptosis. The results of both in vitro and in vivo experiments were comparable. Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometric analysis of AOS with precolumn derivatization with 3-amino-9-ethylcarbazole (AEC) tentatively identified five types of sugars: glucose, lactose, rutinose, glucuronic acid, and maltotriose. Our present study clearly showed that AOS is efficacious in preventing hyperglycemia, possibly by increasing insulin sensitivity and improving IR by regulating the INS-R/IRS/Glut4 insulin signal pathway. Therefore, AOS may be considered as a potential drug for diabetes treatment.

Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus . Establishment of hepatotoxicity model of APAP in vitro and in vivo . In vitro , HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo , C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1β and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils’ damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1.

The current study was designed to investigate the anti-inflammatory effect of salidroside (SDS) and the underlying mechanism by using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro and a mouse model of binge drinking-induced liver injury in vivo. SDS downregulated protein expression of toll-like receptor 4 (TLR4) and CD14. SDS inhibited LPS-triggered phosphorylation of LPS-activated kinase 1 (TAK1), p38, c-Jun terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Degradation of IκB-α and nuclear translocation of nuclear factor (NF)-κB were effectively blocked by SDS. SDS concentration-dependently suppressed LPS mediated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels, as well as their downstream products, NO. SDS significantly inhibited protein secretion and mRNA expression of of interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Additionally C57BL/6 mice were orally administrated SDS for continuous 5 days, followed by three gavages of ethanol every 30 min. Alcohol binge drinking caused the increasing of hepatic lipid accumulation and serum transaminases levels. SDS pretreatment significantly alleviated liver inflammatory changes and serum transaminases levels. Further investigation indicated that SDS markedly decreased protein level of IL-1β in serum. Taken together, these data implied that SDS inhibits liver inflammation both in vitro and in vivo, and may be a promising candidate for the treatment of inflammatory liver injury.

Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber–DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro , AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.