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ATG10S is a newly discovered subtype of the autophagy protein ATG10. It promotes complete macroautophagy/autophagy, degrades multiple viral proteins, and increases the expression of type III interferons. Here, we aimed to investigate the mechanism of ATG10S cooperation with IFNL1 to degrade viral proteins from different viruses. Using western blot, immunoprecipitation (IP), tandem sensor RFP-GFP-LC3B and in situ proximity ligation assays, we showed that exogenous recombinant ATG10S protein (rHsATG10S) could enter into cells through clathrin, and ATG10S combined with ATG7 with IFNL1 assistance to facilitate ATG12-ATG5 conjugation, thereby contributing to the autophagosome formation in multiple cell lines containing different virions or viral proteins. The results of DNA IP and luciferase assays also showed that ATG10S was able to directly bind to a core motif (CAAGGG) within a binding site of transcription factor ZNF460 on the IFNL1 promoter, by which IFNL1 transcription was activated. These results clarified that ATG10S promoted autophagosome formation with the assistance of IFNL1 to ensure autophagy flux and autophagic degradation of multiple viral proteins and that ATG10S could also act as a novel transcription factor to promote IFNL1 gene expression. Importantly, this study further explored the antiviral mechanism of ATG10S interaction with type III interferon and provided a theoretical basis for the development of ATG10S into a new broad-spectrum antiviral protein drug. Abbreviation : ATG: autophagy related; ATG10S: the shorter isoform of autophagy-related 10; CC50: half cytotoxicity concentration; CCV: clathrin-coated transport vesicle; CLTC: clathrin heavy chain; CM: core motif; co-IP: co-immunoprecipitation; CPZ: chlorpromazine; ER: endoplasmic reticulum; HCV: hepatitis C virus; HBV: hepatitis B virus; HsCoV-OC43: Human coronavirus OC43; IFN: interferon; PLA: proximity ligation assay; rHsATG10S: recombinant human ATG10S protein; RLU: relative light unit; SQSTM1: sequestosome 1; ZNF: zinc finger protein.

Abnormal cell adhesion between leukocytes and endothelial cells is closely associated with the development of numerous inflammation-related diseases, with adhesion molecules playing a crucial role. The disruption of cell adhesion directly or indirectly inhibits excessive cell adhesion and thus produces a therapeutic effect. However, there are only a few clinically available antagonists of cell adhesion. One of the biggest challenges is the development of novel and efficient cell adhesion inhibitors. Recently, the anti-inflammatory pharmacological activity of natural products of microbial origin has also received increasing attention. Here, we obtained a potential cell adhesion inhibitor isoechinulin B, an indole diketopiperazine derivative, from the Antarctic fungus Aspergillus sp. CPCC 401072, which is active against cell adhesion. Isoechinulin B decreased the expression of vascular endothelial adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) by inhibiting the activation of the NF-κB signaling pathway, thereby inhibiting cell adhesion between leukocytes and endothelial cells to reduce macrophage infiltration in the liver and significantly attenuate lipopolysaccharide-induced acute liver injury in mice. CONCLUSION: Isoechinulin B is a novel cell adhesion inhibitor derived from fungi found in extreme environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo . Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Na Zhang reports was provided by Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Medicinal Biotechnology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of Bacteroides thetaiotaomicron ( B. theta ) and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of B. theta to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, B. theta did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, B. theta regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with B. theta increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that B. theta ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of B. theta as a potential probiotic for NAFLD.

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic and a major public health problem, with a prevalence of approximately 25%. The pathogenesis of NAFLD is complex and may be affected by the environment and susceptible genetic factors, resulting in a highly variable disease course and no approved drugs in the clinic. Notably, 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), which belongs to the 17β-hydroxysteroid dehydrogenase superfamily (HSD17Bs), is closely related to the clinical outcome of liver disease. HSD17Bs consists of fifteen members, most related to steroid and lipid metabolism, and may have the same biological function as HSD17B13. In this review, we highlight recent advances in basic research on the functional activities, major substrates, and key roles of HSD17Bs in the progression of NAFLD to develop innovative anti-NAFLD drugs targeting HSD17Bs., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The naturally high background value region of Cd derived from the weathering of carbonate has received wide attention. Due to the significant difference in soil physicochemical properties, soil Cd content, and bioavailability of different parent materials in the karst area, there are certain limitations in using the total soil Cd content to classify the environmental quality of cultivated land. In this study, surface soil and maize samples of eluvium and alluvial parent material in typical karst areas were collected systematically; the contents of maize Cd, soil Cd, pH, and oxides were analyzed, the Cd geochemical characteristics of different parent soils and the influencing factors of their bioavailability were revealed, and scientific and effective arable land use zoning suggestions based on the prediction model were suggested. The results showed that the physicochemical properties of different parent material soils in the karst area were obviously different. The alluvial parent material soil had low Cd content but high bioavailability, and the maize Cd exceeding rate was high. The maize Cd bioaccumulation factor was significantly negatively correlated with soil CaO, pH, Mn, and TC, and the correlation coefficients were -0.385, -0.620, -0.484, and -0.384, respectively. Compared with the multiple linear regression prediction model, using the random forest model to predict the maize Cd enrichment coefficient had higher accuracy and precision. Furthermore, a new scheme for the safe utilization of cultivated land at the plot scale based on soil Cd and predicted crop Cd content was proposed in this study, making full use of arable land resources to ensure crop safety.

The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wang, Li, Tang, Li, Lei, Li, Jiang, Li, Dong, Jiang and Peng.)

Background: Diffuse large B-cell lymphoma (DLBCL) is a non-Hodgkin lymphoma with high mortality rates. Small nucleolar RNAs (snoRNAs) are tumor-specific biological markers, but there are few studies on the role of snoRNAs in DLBCL., Materials and Methods: Survival-related snoRNAs were selected to construct a specific snoRNA-based signature via computational analyses (Cox regression and independent prognostic analyses) to predict the prognosis of DLBCL patients. To assist in clinical applications, a nomogram was built by combining the risk model and other independent prognostic factors. Pathway analysis, gene ontology analysis, transcription factor enrichment, protein-protein interactions, and single nucleotide variant analysis were used to explore the potential biological mechanisms of co-expressed genes., Results: Twelve prognosis-correlated snoRNAs were selected from the DLBCL patient cohort of microarray profiles, and a three-snoRNA signature consisting of SNORD1A, SNORA60, and SNORA66 was constructed. DLBCL patients could be divided into high-risk and low-risk cohorts using the risk model, and the high-risk group and activated B cell-like (ABC) type DLBCL were linked with disappointing survival. In addition, SNORD1A co-expressed genes were inseparably linked to the biological functions of the ribosome and mitochondria. Potential transcriptional regulatory networks have also been identified. MYC and RPL10A were the most mutated SNORD1A co-expressed genes in DLBCL., Conclusion: Put together, our findings explored the potential biological effects of snoRNAs in DLBCL, and provided a new predictor for DLBCL prediction., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Rationale: Extranodal nature killer/T-cell lymphoma (ENKTL) failing in asparaginase-containing treatments is fatal, it has a higher mortality rate when accompanied by secondary hemophagocytic lymphohistiocytosis (HLH). The study reported 2 ENKTL-related HLH patients., Patient Concerns: Patient 1 visited for nasal congestion and runny nose for 6 months then got a fever and serious myelosuppression after P-GEP (pegaspargase, gemcitabine, etoposide, and methylprednisolone) chemotherapy. Patient 2 complained of painless lymphadenectasis in the right neck for 4 months and experienced recurrent fever and poor performance status after 3 cycles of P-Gemox (pegaspargase, gemcitabine, and oxaliplatin) chemotherapy., Diagnoses: Patient 1 and patient 2 were diagnosed as ENKTL failing in asparaginase-based chemotherapy and involving secondary HLH., Interventions: The dose of chidamide was 20 mg twice a week for 2 weeks and sintilimab was 200 mg once every 3 weeks., Outcomes: ENKTL was relieved and the HLH was resolved after the therapy of sintilimab and chidamide. The patients had achieved durable survival without immune-related adverse events., Lessons: ENKTL-related HLH needs early diagnosis and treatment. The combined strategy of sintilimab plus chidamide help deal with HLH and solve ENKTL, it may be a useful treatment option for ENKTL-related HLH., Competing Interests: All authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Primary ovarian lymphoma has been difficult to diagnose clinically and pathologically due to its rare incidence and non-specific clinical symptoms., Case Presentation: A 75-year-old female patient was reported in this study. The patient had a six-month history of changes in bowel habits, with occasional black feces and paroxysmal pain in the abdomen. The computed tomography scan of the pelvic cavity illustrated that rectal cancer and sigmoid colon adenocarcinoma invaded the lower part of the right-side ureter. The patient was once treated with excision of part of small intestine, fallopian tube and ovary, and uterus. The pathological examination of these excised tissues, combined with the immunohistochemistry, confirmed that the female patient suffered from primary ovarian diffuse large B-cell lymphoma (DLBCL), and the lymphoma had invaded the entire right-side ovary tissues, serous membranes on the posterior surface of the uterus, and the wall of small intestine., Conclusion: Few reports were available regarding the primary ovarian DLBCL. The initial symptom of the patient was the changes in bowel habits, which had not been reported beforehand. Hopefully, this case could helpfully render the early diagnosis possible, and increase clinical understanding of primary ovarian DLBCL, which would thereby reduce the chance of misdiagnosis., (© 2022. The Author(s).)

Nonalcoholic fatty liver disease (NAFLD) is becoming an increasingly serious disease worldwide. Unfortunately, no specific drug has been approved to treat NAFLD. Accumulating evidence suggests that lipotoxicity, which is induced by an excess of intracellular triacylglycerols (TAGs), is a potential mechanism underlying the ill-defined progression of NAFLD. Under physiological conditions, a balance is maintained between TAGs and free fatty acids (FFAs) in the liver. TAGs are catabolized to FFAs through neutral lipolysis and/or lipophagy, while FFAs can be anabolized to TAGs through an esterification reaction. However, in the livers of patients with NAFLD, lipophagy appears to fail. Reversing this abnormal state through several lipophagic molecules (mTORC1, AMPK, PLIN, etc.) facilitates NAFLD amelioration; therefore, restoring failed lipophagy may be a highly efficient therapeutic strategy for NAFLD. Here, we outline the lipophagy phases with the relevant important proteins and discuss the roles of lipophagy in the progression of NAFLD. Additionally, the potential candidate drugs with therapeutic value targeting these proteins are discussed to show novel strategies for future treatment of NAFLD., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl 4 . The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and β-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion : Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Li, Dong, Wang, Tan, Wang, Jiang, Lei, Li, Sun, Jiang and Peng.)

Cancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy., (© 2021. The Author(s).)

Background: Esophageal cancer is a common malignant tumor and its 5-year survival rate is much lower than 30% due to its invasiveness and pronounced metastasis ability, as well as the difficulty in early diagnosis. This study aimed to elucidate the molecular mechanism of ubiquitin conjugating enzyme E2 C (UBE2C) in esophageal squamous cell carcinoma (ESCC)., Methods: In this study, we conducted a comprehensive evaluation of the UBE2C expression in ESCC by collecting the protein and mRNA expression data (including in-house RNA-seq, in-hosue immunohistochemistry, TCGA-GTEx RNA-seq and tissue microarray) to calculate a combined standardized mean difference (SMD) and summary receiver operating characteristic curve (sROC). Kaplan-Meier (K-M) method was used for survival analysis. We also explored the mechanism of UBE2C in ESCC by combing the differentially expressed genes (DEGs) of ESCC, related-genes of UBE2C in ESCC and the putative miRNAs and lncRNAs which may regulate UBE2C., Results: UBE2C protein and mRNA were highly expressed in ESCC tissues (including 772 ESCC tissue samples and 1837 non-cancerous tissue control samples). The pooled SMD of UBE2C expression values was 1.98 (95% CI: 1.51-2.45, p < 0.001), and the the area under the curve (AUC) of the sROC was 0.93 (95% CI: 0.90-0.95). The results of survival analysis suggested that UBE2C is likely to play different roles in different stages of the ESCC. Pathway anaylsis showed that UBE2C mainly influenced the biological function of esophageal cancer by synergistic effects with CDK1, PTTG1 and SKP2. We also constructed a potential UBE2C-related ceRNA network for ESCC (HCP5/has-miR-139-5p/UBE2C)., Conclusion: UBE2C mRNA and protein level were highly expressed in ESCC and UBE2C was likely to play different roles in different stages of the ESCC., (© 2021. The Author(s).)

Objective: To analyze gene expression profile of T cell lymphoma Jurkat cell line treated with paclitaxel by computational biology based on next generation sequencing and to explore the possible molecular mechanism of paclitaxel resistance to T cell lymphoma at gene level., Methods: IC50 of paclitaxel on Jurkat cell line was determined by CCK-8 assay. Gene expression profile of Jurkat cells treated with paclitaxel was acquired by next generation sequencing technology. Gene microarray data related to human T cell lymphoma were screened from Gene Expression Omnibus (GEO) database (including 720 cases of T cell lymphoma and 153 cases of normal tissues). Combined with the sequencing data, differential expression genes (DEGs) were intersected and screened. DAVID database was used for enrichment analysis of GO function and KEGG pathway to determine and visualize functional entries of DEGs, and protein-protein interactions network of DEGs was drawn. The levels of gene expression were detected and verified by RT-qPCR., Results: CCK-8 results showed that the proliferation of Jurkat cells was inhibited by paclitaxel depended on the concentration apparently. Treated by paclitaxel for 48 h, P<0.05 and |log2(FC)|≥1 were used as filter criteria on the results of RNA Sequencing (RNA-Seq) and GeoChip, 351 DEGs were found from Jurkat cells, including 323 up-regulated genes and 28 down-regulated genes. The GO functional annotation and KEGG pathway enrichment analysis showed that the role of paclitaxel was mainly concentrated in protein heterodimerization activity, nucleosome assembly and transcriptional dysregulation in cancer, etc. The results of RT-qPCR were consistent with those of the sequencing analysis, which verified the reliability of this sequencing., Conclusion: Paclitaxel can affect the proliferation and apoptosis of T-cell lymphoma by up-regulating JUN gene, orphan nuclear receptor NR4A family genes and histone family genes.

Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang and Peng.)

Transforming growth factor beta (TGF-β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-β isoforms, including TGF-β1, TGF-β2 and TGF-β3, remain unclear. Here, we demonstrated that all of the three TGF-β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-β/SMAD signalling pathway-dependent and TGF-β/SMAD signalling pathway-independent manners. TGF-β isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-β1 and TGF-β2, not TGF-β3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-β isoforms in the HCV-related liver disease progression., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: To investigate the imaging features of hemangiomas in long tabular bones for better diagnosis., Methods: Twenty-four patients with long bone hemangiomas confirmed by pathology were enrolled. Nineteen patients had plain radiography, fourteen patients had computed tomography (CT) and eleven had magnetic resonance imaging (MRI). The hemangioma was divided into medullary [13], periosteal [6] and intracortical type [5]., Results: Among 19 patients with plain radiography, eleven patients were medullary, three periosteal, and five intracortical. In the medullary type, the lesion was primarily osteolytic, including five cases with irregular and unclear rims and one lesion having osteosclerotic and unclear rims. In three patients with the periosteal type, the lesion had clear rims with involvement of the cortical bone in the form of bone defect, including two cases with local thickened bone periosteum and one case having expansile periosteum. Five intracortical hemangiomas had intracortical osteolytic lesions with clear margins. Among 14 patients with CT imaging, 8 cases were medullary, three periosteal, and three intracortical. Among 8 medullary hemangiomas, one had ground glass opacity, and seven had osteolytic, expansile lesions like soft tissue density with no calcification. In three periosteal cases, the lesion was osteolytic with thickened periosteum and narrowed medullary cavity. In three intracortical hemangiomas, the lesion was of even soft tissue density with no calcification. Among 11 patients with MRI imaging, seven were medullary, two periosteal, and two intracortical. Among 7 medullary lesions, six were of hypointense signal on T1WI and hyperintensesignal on T2 WI. In two periosteal cases, the periosteum was thickened, with one case being of equal signal, and the other having no signal. Two intracortical hemangiomas were both of slightly low signal on T1WI but hyperintense signal on T2WI., Conclusions: The long bone hemangiomas had characteristic cystic honeycomb-like presentations in plain radiograph. CT and MRI imagings are helpful for diagnosis of hemangiomas in long bone.

Objective: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic without effective therapeutic agents in the clinic. This meta-analysis aimed to assess the efficacy of the marketed hepatoprotectant bicyclol at improving blood biomarkers in patients with NAFLD., Design: Electronic databases were searched for randomised controlled trials (RCTs) published up to August 2020 using bicyclol to treat NAFLD. The risk of bias, quality of evidence and publication bias were evaluated. Blood biomarkers, including alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), triglyceride (TG) and total cholesterol (TC), were analysed using Review Manager V.5.3 software. Outcomes with significant heterogeneity (I 2 ≥75%) were divided into the bicyclol monotherapy subgroup and combination treatment subgroup., Results: Twelve RCTs involving 1008 patients were finally included. No serious adverse events were reported in the bicyclol-treated groups. The total effective rate of bicyclol intervention for NAFLD was significantly higher than that of the control group. The decreases in the levels of AST (mean difference (MD) = -15.20; 95% CI -20.51 to -9.90; I 2 =74%), TBIL (MD = -1.72; 95% CI -2.72 to -0.72; I 2 =0%) and TC (MD = -0.52; 95% CI -0.70 to -0.34; I 2 =67%) treated by bicyclol were significantly higher than those in the control group. When a high heterogeneity existed (I 2 ≥75%), subgroup analyses were conducted and revealed significantly decreased ALT levels (MD = -34.07; 95% CI -36.70 to -31.43; I 2 =0%) merely in the bicyclol monotherapy subgroup, while TG level (MD = -0.39; 95% CI -0.45 to -0.33; I 2 =0%) was decreased in the bicyclol combination therapy subgroup., Conclusions: The study presents the evidence of bicyclol monotherapy and/or combination therapy for improving liver function and blood lipid biomarkers in patients with NAFLD. This preliminary study predicts that bicyclol might be an alternative drug for NAFLD therapy in the future., Competing Interests: Competing interests: None declared, (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aloperine, a natural alkaloid isolated from the Chinese traditional herb Sophora alopecuroides, is a broad-spectrum antiviral agent with anti-inflammatory activity. Here, we found that aloperine effectively inhibited hepatitis C virus (HCV) propagation in Huh7.5 cells and primary human hepatocytes without cytotoxicity, and it blocked HCV cell-to-cell viral transmission. The antiviral mechanism evidence demonstrated that aloperine inhibits HCV internalisation from endocytosis to the membrane fusion process, and the target may be associated with host factors. Aloperine additively inhibited HCV propagation with direct-acting antivirals (DAAs) and was effective against HCV variants resistant to known DAAs. Therefore, aloperine might be a natural lead compound for the development of innovative antivirals, and the combined use of aloperine with DAAs might contribute to eliminating liver diseases caused by HCV infection., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aimed to create prognostic signatures to predict AML patients' survival using alternative splicing (AS) events. The AS data, RNA sequencing data, and the survival statistics of 136 AML patients were obtained from The Cancer Genome Atlas (TCGA) and TCGA SpliceSeq databases. Total 34,984 AS events generated from 8,656 genes, 2,583 of which were survival-associated AS events, were identified using univariate Cox regression. The prognostic models constructed using independent survival-associated AS events revealed that low-risk splicing better predicted patients' survival. ROC analysis indicated that the predictive efficacy of the alternate terminator model was best in the area under the curve at 0.781. Enrichment analysis revealed several important genes (TP53, BCL2, AURKB, PPP2R1B, FOS, and BIRC5) and pathways, such as the protein processing pathway in the endoplasmic reticulum, RNA transport pathway, and HTLV-I infection pathway. The splicing network of splicing events and factors revealed interesting interactions, such as the positive correlation between HNRNPH3 and CALHM2-13010-AT, which may indicate the potential splicing regulatory mechanism. Taken together, survival-associated splicing events and the prognostic signatures for predicting survival can help provide an overview of splicing in AML patients and facilitate clinical practice. The splicing regulatory network may improve the understanding of spliceosomes in AML.

Interferon lambda-2 (IL28A) has a wide antiviral effect with fewer side-effects. Autophagy is a host mechanism to maintain intracellular homeostasis and defends invasion of pathogenic microorganisms. HCV NS5A can disable host defense systems to support HCV replication. Thus, molecular mechanism of interaction among interferon lambda, autophagy, and HCV was concerned and explored in this study. We report that HCV NS5A activated an incomplete autophagy by promoting the autophagic ubiquitylation-like enzymes ATG3, ATG5, ATG7, ATG10, and autophagosome maker LC3B, but blocked autophagy flux; IL28A bound to NS5A at NS5A-ISDR region, and degraded HCV-NS5A by promoting autolysosome formations in HepG2 cells. A software prediction of IL28A protein conformation indicated a potential structure of IL28A homotetramer; the first α-helix of IL28A locates in the interfaces among the four IL28A chains to maintain IL28A homotetrameric conformation. Co-IP and cell immunofluorescence experiments with sequential deletion mutants demonstrate that IL28A preferred a homotetramer conformation to a monomer in the cells; the IL28A homotetramer is positively correlated with autolysosomal degradation of HCV NS5A and the other HCV proteins. Summarily, the first α-helix of IL28A protein is the key domain for maintaining IL28A homotetramer which is required for promoting formation of autolysosomes and degradation of HCV proteins in vitro.

Objective: To investigate the expression level and potential mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in patients with myelodysplastic syndromes (MDS)., Methods: Immunohistochemistry (IHC) techniques were used to examine the protein expression of HIF-1α in paraffin-embedded myeloid tissues from 82 patients with MDS and 33 controls (patients with lymphoma that is not invading myeloid tissues). In addition, the associations between the protein expression of HIF-1α and clinical parameters were examined. To further investigate the significance of HIF-1α expression in MDS patients, the researchers not only extracted the data about HIF-1α expression from MDS-related microarrays but also analyzed the correlation between the level of HIF-1α expression and MDS. The microRNA (miRNA) targeting HIF-1α was predicted and verified with a dual luciferase experiment., Results: Immunohistochemistry revealed that the positive expression rate of HIF-1α in the bone marrow of patients with MDS was 90.24%. This rate was remarkably higher than that of the controls (72.73%) and was statistically significant (P < .05), which indicated that HIF-1α was upregulated in the myeloid tissues of MDS patients. For the GSE2779, GSE18366, GSE41130, and GSE61853 microarrays, the average expression of HIF-1α in MDS patients was higher than in the controls. Particularly for the GSE18366 microarray, HIF-1α expression was considerably higher in MDS patients than in the controls (P < .05). It was predicted that miR-93-5p had a site for binding with HIF-1α, and a dual luciferase experiment confirmed that miR-93-5p could bind with HIF-1α., Conclusion: The upregulated expression of HIF-1α was examined in the myeloid tissues of MDS patients. The presence of HIF-1α (+) suggested an unsatisfactory prognosis for patients, which could assist in the diagnosis of MDS. In addition, miR-93-5p could bind to HIF-1α by targeting, showing its potential to be the target of HIF-1α in MDS., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective : To enquire into the clinical significance and potential molecular mechanism of microRNA (miRNA)-196b-5p in hepatocellular carcinoma (HCC). Methods : Quantitative reverse transcription and polymerase chain reaction (qRT-PCR) were utilized to examine miR-196b-5p expression level in 67 HCC paraffin embedded tissues and corresponding adjacent tissues. Correlations of miR-196b-5p expression level with clinicopathological characteristics were analyzed in our study. The expression level and clinical significance of miR-196b-5p in HCC were also evaluated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We made predictions of the target genes of miR-196b-5p by twelve online software and then selected genes predicted by at least 5 software. Subsequently, in order to obtain the potential target genes of miR-196b-5p, we overlapped the predicted target genes and down-regulated mRNAs in HCC based on TCGA database. Then, we performed the Gene Ontology (GO) and the Disease Ontology (DO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network construction of those miR-196b-5p potential target genes. Results : Higher expression level of miR-196b-5p was seen in HCC tissues than in the corresponding adjacent tissues based on qRT-PCR ( P = 0.0007). The expression level of miR-196b-5p was linked with tumor size ( P = 0.03), tumor node ( P = 0.024), vascular invasion ( P = 0.029) and capsular invasion ( P = 0.026) in HCC patients. Comprehensive meta-analysis of miR-196b-5p expression based on TCGA, GEO and qRT-PCR verified that higher expression level of miR-196b-5p was observed in HCC tissues than in normal control liver tissues (SMD = 0.56, 95%CI: 0.39-0.72, P heterogeneity = 0.275, I 2 = 18.3%). GO annotation revealed that the top terms in biological process, cellular component and molecular function were single-organism catabolic process, neuronal cell body and transmembrane receptor protein kinase activity, respectively. The most relevant disease in DO annotation was arteriosclerosis. The tryptophan metabolism pathway ranked first in KEGG pathway enrichment analysis. The PPI network showed that IGF1, FOXO1, AR and FOS were mostly likely to become the core genes of miR-196b-5p potential target genes, which however required further experiments for validation. Conclusion : The miR-196b-5p was observed to show higher expression in HCC tissues than in normal control liver tissues. Moreover, the miR-196b-5p expression level had correlations with the clinicopathological parameters such as vascular invasion of HCC, but the molecular mechanisms of miR-196b-5p in HCC still need further elucidation and verification., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alternative splicing in tumor cells may be used as a molecular marker for the differential diagnosis of certain tumor types and assessment of prognosis. The aim of the present study was to investigate the associations among alternative splicing events, splicing factors, and the survival of patients with hepatocellular carcinoma (HCC). The alternative splicing event profiles of 371 patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) SpliceSeq data, and the percent‑splice‑in value for each splicing event was calculated. The association between alternative splicing events and overall survival was evaluated. The most significant prognosis‑related splicing events were used to build up a prognostic index (PI). A total of 3,082 survival‑associated alternative splicing events were detected in HCC. The final PI based on all of the most significant candidate alternative splicing events exhibited better performance in distinguishing good or poor survival in patients compared to the PI based on a single type of splicing event. Receiver operating characteristic curves confirmed the high efficiency of the PI in predicting the survival of HCC patients, with an area under the curve of 0.914. The overexpression of 32 prognosis‑related splicing factor genes could also predict poor prognosis in patients with HCC. In conclusion, the constructed computational prognostic model based on HCC‑specific alternative splicing events may be used as a molecular marker for the prognosis of HCC.

Alternative splicing (AS) has been widely reported to play an important role in cancers, including esophageal carcinoma (ESCA). However, no study has comprehensively investigated the clinical use of combination of prognostic AS events and clinicopathological parameters. Therefore, we collected 165 ESCA patients including 83 esophageal adenocarcinoma (EAC) and 82 esophageal squamous cell carcinoma (ESCC) patients from The Cancer Genome Atlas to explore the survival rate associated with seven types of AS events. Prognostic predictors for the clinical outcomes of ESCA patients were built. Predictive prognosis models of the alternative acceptor site in ESCA (area under the curve [AUC] = 0.83), alternative donor site in EAC (AUC = 0.99), and alternative terminator site in ESCC (AUC = 0.974) showed the best predictive efficacy. A novel combined prognostic model of AS events and clinicopathological parameters in ESCA was also constructed. Combined prognostic models of ESCA all showed better predictive efficacy than independent AS models or clinicopathological parameters model. Through constructing splicing regulatory network, the expression of AS factor was found to be negatively correlated with the most favorable AS events. Moreover, gene amplification, mutation, and copy number variation of AS genes were commonly observed, which may indicate the molecular mechanism of how the AS events influence survival. Conclusively, the constructed prognostic models based on AS events, especially the combined prognostic models of AS signatures and clinicopathological parameters could be used to predict the outcome of ESCA patients. Moreover, the splicing regulatory network and genomic alteration in ESCA could be used for illuminating the potential molecular mechanism., Competing Interests: None.

Farnesoid X receptor (FXR) agonists play important regulatory roles in bile acid, lipid and glucose metabolism in vitro and in vivo. Thus, FXR agonists exhibit potential therapeutic effects on metabolism-related diseases that are associated with extrahepatic manifestations induced by hepatitis C virus (HCV) infection. This study investigated the effect and mechanism of FXR agonist GW4064 against HCV in vitro to explore the potential application of FXR agonists. Results showed that GW4064 and other FXR agonists have potent antiviral activity against HCV in Huh7.5 cells. GW4064 down-regulated the expression of scavenger receptor class B type I protein via FXR and thereby indirectly inhibited HCV entry into cells, leading to interruption of HCV life cycle. GW4064 also exhibited synergistic anti-HCV effect with known direct-acting antiviral agents (DAAs) used in the clinic and remained sensitive to DAA-resistant HCV mutations. Therefore, FXR agonists are also a kind of antiviral agent, and might be helpful in treatment of HCV-induced hepatic and extrahepatic manifestations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Depressive symptoms worsen asthma outcomes; however, the mechanism remains largely unexplored., Objective: This study aimed to determine whether depressive symptom-associated immune inflammation correlates with impaired bronchodilator response (BDR) and airway inflammatory phenotypes., Methods: Eligible adults with asthma (n = 198) underwent clinical assessment, sputum induction and blood sampling. Depressive symptoms were defined by scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Pre- and post-bronchodilator spirometry was performed for BDR. Airway inflammatory phenotypes were defined by sputum cell counts. CRP, IL-1β, IL-5, IL-6, IL-8, TNF-α, IFN-γ, CCL17 and CCL22 in serum and sputum were detected., Results: Compared with the non-depressive group (n = 174), the depressive group (n = 24) exhibited impaired BDR (P = 0.032) and increased sputum neutrophils (P = 0.023), which correlated with the HADS-D scores (P = 0.027 and P = 0.029). Levels of IL-1β, TNF-α and IFN-γ in the serum and those of IL-1β and IFN-γ in the sputum were elevated in the depressive group compared to those in the non-depressive group (all P < 0.05). Multiple regression models indicated that TNF-α in the sputum and IL-1β, IL-6 and IFN-γ in both the serum and sputum were inversely associated with BDR; TNF-α in the sputum and IL-1β in both the serum and sputum were positively correlated with sputum neutrophils. Mediation analyses revealed that IL-1β and TNF-α in the sputum and IL-1β in both the serum and sputum mediate the correlations of the HADS-D scores with BDR and sputum neutrophils, respectively., Conclusions and Clinical Relevance: Asthma patients with depressive symptoms present worse asthma control, which is most likely explained by impaired BDR and neutrophilic airway inflammation. IL-1β and TNF-α, which are two key pro-inflammatory cytokines that mediate the correlation of depressive symptoms with impaired BDR and neutrophilic airway inflammation, may serve as targeted biomarkers in the neuropsychological phenotype of asthma; however, this result needs to be further validated., (© 2019 John Wiley & Sons Ltd.)

Objective: To explore the clinical significance and potential molecular mechanism of endothelin receptor type B (EDNRB) in hepatocellular carcinoma (HCC)., Methods: Immunohistochemistry was used to detect EDNRB protein expression level in 67 HCC paraffin embedded tissues and adjacent tissues. Correlations between EDNRB expression level and clinicopathologic parameters were analyzed in our study. The expression level and clinical significance of EDNRB in HCC were also evaluated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The cBioPortal for Cancer Genomics was employed to analyze the EDNRB related genes, and Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network were conducted for those EDNRB related genes., Results: Lower expression level of EDNRB in HCC was verified by immunohistochemistry than adjacent tissues (P < 0.0001). The expression level of EDNRB in HCC tissues was lower than normal control liver tissues based on TCGA and GEO data (standard mean difference [SMD] = -1.48, 95% [confidence interval] CI: -1.63-(-1.33), P heterogeneity  = 0.116, I 2  = 32.4%). Kaplan-Meier analysis showed that HCC patients with lower EDNRB expression were more prone to poor prognosis (P = .0041). The top terms of GO annotation in biological process, cellular component and molecular function were vasculature development, actin filament and transmembrane receptor protein kinase activity, respectively. The KEGG pathway enrichment analysis confirmed that EDNRB related genes mainly participated in Vascular smooth muscle contraction, cGMP-PKG signaling pathway and Focal adhesion pathways. The result of PPI network construction showed that KDR, VEGFC, FLT1, CDH5 and ADCY4 were possible to become the core genes of EDNRB related genes, which need further experiments to confirm., Conclusion: Our study provides novel findings and insights on the molecular pathogenesis of HCC from EDNRB view., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of mangiferin on proliferation, apoptosis and cycle of FLT3-ITD mutation-positive acute myeloid leukemia cells and its mechanism., Methods: The effects of different concentration of mangiferin on proliferation of MV4-11 cells were detected by CCK8 method. Apoptosis, cell cycle and FLT3 transmembrane protein expression were detected by flow cytometry. FLT3 mRNA expression was detected by real-time fluorescent quantitative polymerase chain reaction (PCR) ., Results: Mangiferin obviously inhibited MV4-11 proliferation in a concentration and time dependent manner (48 h，r=0.922；72 h，r=0.959；96 h，r=0.973). The ratio of G0/G1 phase in cell cycle increased with the enhancement of concentration of mangiferin in MV4-11 cells for 48 h, and the ratio of S phase decreased with enhasment of concentration. The increase of apoptosis was more obvious. The expression of FLT3 transmembrane protein significantly decreased after the actior of IC50 concentration of mangiferin in MV4-11 cells for 48 h. The results of qRT-PCR showed that the expression of FLT3 mRNA significantly decreased after treatment of MN4-11 cells with mangiferin (P＜0.05)., Conclusion: Mangiferin inhibits MV4-11 cell proliferation, arrests cell cycle progression and promotes apoptosis, which may be related with the inhibition of FLT3 activity by mangiferin and the subsequent signaling pathways involved in apoptosis and proliferation of cells.

Several studies have indicated that microRNAs (miRs) mediate multiple pathways associated with tumorigenesis and progression. Our preliminary study experimentally verified that miR‑146a‑5p has a role in the biological behavior of non‑small cell lung cancer (NSCLC) cells. To perform further investigation of miR‑146a‑5p, the present study evaluated miR‑146a‑5p by targeting its downstream gene tumor collagenase stimulatory factor (TCSF) to influence cell viability, proliferation and apoptosis in NSCLC. Online sequence prediction, a thorough search of the open source database The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC) of TCSF in clinical lung cancer tissues, and a dual‑luciferase assay, as well as assays to test viability, proliferation and apoptosis in vitro, were conducted to explain the targeted regulation association between miR‑146a‑5p and TCSF in NSCLC. The miRanda and TargetScanHuman database revealed that TCSF and miR‑146a‑5p had target binding sites. A luciferase reporter assay demonstrated that miR‑146a‑5p and TCSF did have complementary sequences (P<0.05). From the TCGA database, TCSF was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues when compared with normal lung tissues (P<0.05). Furthermore, the protein level of TCSF in cancerous lung tissues was determined by IHC, and it was concluded that TCSF protein was also upregulated in NSCLC tissues (P<0.001). A significant difference was identified following in vitro experiments for the NSCLC cell line A549, which revealed that miR‑146a‑5p and TCSF regulated cell viability, proliferation and apoptosis. In conclusion, the present study verified the target action association between TCSF and miR‑146a‑5p with high throughput data analysis and experimental results in NSCLC.

A new species of Nemacheilidae, Triplophysa sanduensis sp. nov., is described here based on specimens collected from a small cave in Dengguang Village, Zhonghe Town, Sandu County, Guizhou Province, China. The new species can be distinguished from its congeners by the following combination of characters: branched dorsal-fin rays 8-9; branched pectoral-fin rays 8-9; branched pelvic-fin rays 5; branched anal-fin rays 5; vertebrae 4+37; snout length 45.5-50.1% of head length; postdorsal length 39.0-42.8% of standard length; caudal-peduncle depth/caudal-peduncle length range from 56.4% to 71.9%; the posterior chamber of the gas bladder degenerated; body elongated, covered by scattered scales; eyes present and normal in size, not reduced or absent; and a complete lateral line. A phylogenetic analysis based on the mitochondrial cytochrome oxidase subunit 1 (COI) gene resolved Triplophysa sanduensis as sister to Triplophysa longliensis. Kimura's 2-parameter genetic distance of the COI gene sequences between these two species was 1.9%.

In the current study, we proposed to explore the potential role and related signaling pathways of Homobox A10 (HOXA10) in non-small cell lung cancer (NSCLC). HOXA10 levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were detected by qRT-PCR and the expression of HOXA10 was significantly up-regulated in the NSCLC tissue of all 55 pairs (P = 0.037). Overexpression of HOXA10 was closely correlated with the clinical stage of LUSC (P = 0.011). HOXA10 expression in RNA sequencing data based on 1, 077 cases exhibited concordant significant up-regulation in NSCLC, LUAD and LUSC (P < 0.001). In NSCLC, HOXA10 expression was closely correlated to patient T stage (P = 0.006). In LUAD, HOXA10 expression was compactly correlated to patient N stage (P = 0.02). Some of the microarrays from Gene Expression Omnibus (GEO) and ArrayExpress showed consistent over-expression of HOXA10 levels in NSCLCs. More importantly, the combined SMD value was 0.052 (95% CI: 0.29-0.75, P < 0.001) generated by meta-analysis from 47 datasets based on 4, 616 cases of NSCLC. The area under the curve (AUC) of SROC supported the over-expression of HOXA10 in NSCLC as being 0.88 (95% CI: 0.81-0.93), with sensitivity and specificity of 0.88 (95% CI: 0.81-0.93) and 0.56 (95% CI: 0.44-0.66), respectively. In addition, 111 co-expressed genes were collected from cBioPortal and enriched in "cell cycle", "cell adhesion molecules", "p53 signaling", and "adherens junction". Interestingly, an up-regulation trend of HOXA10 protein expression was also observed in NSCLC through tissue chips and immunohistochemistry. In conclusion, the overexpression of HOXA10 may play a pivotal role in the tumorigenesis of NSCLC, and this effect is observed more obviously in LUSC than in LUAD., Competing Interests: None.

Background: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated., Methods: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia., Results: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL)., Conclusions: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.

Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest.

Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C. We investigated the anti-inflammatory effects and mechanisms of bicyclol in HCV-infected hepatocytes and further confirmed the putative results in a mouse hepatitis model induced by the coinjection of polyinosinic-polycytidylic acid [poly (I:C)] and D-galactosamine (D-GalN). The results showed that the activation of nuclear factor kappa B (NF-κB) and the subsequent increase of inflammatory factors were directly induced by HCV infection and were persistent after clearance of the virus in Huh7.5 cells. Bicyclol decreased the activation of NF-κB and the levels of inflammatory factors in HCV-infected hepatocytes by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and the effect was synergistic with DAAs in HCV-infected hepatocytes. Bicyclol attenuated the ROS-MAPK-NF-κB axis via recovering mitochondrial function without a dependence on dihydronicotinamide adenine dinucleotide phosphate oxidase and superoxide dismutases. The anti-inflammatory effects and mechanism of bicyclol were verified in mouse hepatitis induced by the coinjection of poly(I:C)/D-GalN. Bicyclol directly ameliorates the chronic inflammation caused by HCV infection and might be used with DAAs or after DAA therapy for ultimately curing chronic hepatitis C.

Diffuse large B-cell lymphoma (DLBCL) is the most main subtype in non-Hodgkin lymphoma. After chemotherapy, about 30% of patients with DLBCL develop resistance and relapse. This study was to identify potential therapeutic drugs for DLBCL using the bioinformatics method. The differentially expressed genes (DEGs) between DLBCL and non-cancer samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. The R software package (SubpathwayMiner) was used to perform pathway analysis on DEGs affected by drugs found in the Connectivity Map (CMap) database. Protein-protein interaction (PPI) networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes online database and Cytoscape software. In order to identify potential novel drugs for DLBCL, the DLBCL-related pathways and drug-affected pathways were integrated. The results showed that 1927 DEGs were identified from TCGA and GEO. We found 54 significant pathways of DLBCL using KEGG pathway analysis. By integrating pathways, we identified five overlapping pathways and 47 drugs that affected these pathways. The PPI network analysis results showed that the CDK2 is closely associated with three overlapping pathways (cell cycle, p53 signaling pathway, and small cell lung cancer). The further literature verification results showed that etoposide, rinotecan, methotrexate, resveratrol, and irinotecan have been used as classic clinical drugs for DLBCL. Anisomycin, naproxen, gossypol, vorinostat, emetine, mycophenolic acid and daunorubicin also act on DLBCL. It was found through bioinformatics analysis that paclitaxel in the drug-pathway network can be used as a potential novel drug for DLBCL., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: The specific expression level and clinical significance of miR-375-3p in HNSCC had not been fully stated, as well as the overall biological function and molecular mechanisms. Therefore, we purpose to carry out a comprehensive meta-analysis to further explore the clinical significance and potential function mechanism of miR-375-3p in HNSCC., Methods: HNSCC-related data was gained from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and peer-reviewed journals. A meta-analysis was carried out to comprehensively explore the relationship between miR-375-3p expression level and clinicopathological features of HNSCC. And summary receiver operating characteristic (SROC) curve analysis was applied for evaluating disease diagnosis value of miR-375-3p. In addition, a biological pathway analysis was also performed to assess the possible molecular mechanism of miR-375-3p in HNSCC., Results: A total of 24 available records and references were added into analysis. The overall pooled meta-analysis outcome revealed a relatively lower expression level of miR-375-3p in HNSCC specimens than that in non-cancerous controls (P < 0.001). And SROC curve analysis showed that the pooled area under the SROC curve (AUC) was 0.90 (95%CI: 0.88-0.93). In addition, biological pathway analysis indicated that LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 maybe the latent target genes of miR-375-3p, which were greatly enriched in the pathways of beta3 integrin cell surface interactions and the binding of RNA via the insulin-like growth factor-2 mRNA-binding protein (IGF2BPs/IMPs/VICKZs)., Conclusion: MiR-375-3p expression clearly decreased in HNSCC samples compared with non-cancerous controls. Meanwhile, miR-375-3p may serve as a tumor suppressor via regulating tumor-related genes LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 in HNSCC., (Copyright © 2018 Elsevier GmbH. All rights reserved.)