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INTRODUCTION: Hepatocellular carcinoma (HCC) is a global health problem with increasing morbidity and mortality, and exploring the diagnosis and treatment of HCC at the gene level has been a research hotspot in recent years. METHODS: In this paper, a series of differentially expressed genes were found from the biochip related to HCC by bioinformatic analysis, then CNDP1 was finally selected for in-depth study according to the function and research progress of each gene. As the rate-limiting enzyme of carnosine hydrolysis, CNDP1 participates in the progress of many diseases, but its function has not been revealed in HCC. In the follow-up study, the low expression of CNDP1 in liver cancer tissues and cells was verified, then the pcDNA3.1-CNDP1 was used to improve the expression level of CNDP1 in HCC cell lines. Furthermore, this paper found that CNDP1 overexpression could significantly suppress cell prolifer-ation, migration, and invasion of HCC cell lines. RESULTS: Mechanismly, the GeneMANIA database predicted that CNDP1 could interact with various proteins that regulate the PI3K-AKT-mTOR signaling pathway, which is overactivated in HCC. And this study showed that CNDP1 overexpression could effectively inhibit the activation of PI3K-AKT-mTOR signaling pathways, more significantly, inhibition of PI3K-AKT-mTOR signaling pathway could disrupt the anti-cancer effect of CNDP1 on HCC. CONCLUSION: In conclusion, we confirmed that CNDP1 was lowly expressed in HCC tissues and cells, and had potential anti-cancer activity. This discovery will lay a cytological foundation for expanding the biological function of CNDP1 and the diagnosis and treatment of HCC in the future.

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Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

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Background: Blood eosinophilia is often associated with various dermatoses, such as atopic eczema, urticaria, drug eruption, bullous pemphigoid, and hypereosinophilic syndrome (HES). Differential diagnosis is very challenging due to the similarities of clinical and pathological characteristics. Purpose: To investigate and analyze the clinical characteristics of dermatoses associated with blood eosinophilia (DABE) to further optimize disease management. Patients and Methods: We conducted a retrospective analysis on 397 DABE patients with blood absolute eosinophil count (AEC) greater than or equal to 0.5×109/L. Clinical characteristics, laboratory values, treatment course, and associated diagnoses were evaluated. All DABE patients were grouped based on the severity of eosinophilia as mild group (0.5 ≤ AEC×109/L < 1.5), moderate group (1.5 ≤ AEC×109/L < 3), and severe group (AEC×109/L ≥ 3). Results: Our study revealed three distinct patterns: (1) Mild eosinophilia associated with localized skin lesions, atopic history, mildly elevated total serum IgE level, diagnosed with eczema/dermatitis, and frequent antihistamines use. (2) Moderate eosinophilia has the characteristics of both mild group and severe group. (3) The severe eosinophilia group had a high proportion of elderly people without atopic history, but with acute onset, generalized skin lesions, and high level of lactate dehydrogenase, and the majority of them were diagnosed with systemic diseases (HES or tumor). Conclusion: We summarize the clinical rules of dermatoses associated with blood eosinophilia, hoping to facilitate the diagnosis and treatment for patients.

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Alcoholic liver disease is one of the leading causes of liver-related morbidity and mortality worldwide, but effective treatments are still lacking. Honokiol, a lignin-type natural compound isolated from the leaves and bark of Magnolia plants, has been widely studied for its beneficial effects on several chronic diseases. Accumulating studies have revealed that honokiol displays a potential therapeutic effect on alcoholic liver disease. In this study, the protective activity of honokiol on alcoholic liver disease was confirmed due to its significant inhibitory activity on the expression levels of inflammatory cytokines (such as tumor necrosis factor-alpha, interleukin-6, and interleukin-1ß) in EtOH-fed mice and in EtOH-induced AML-12 cells. Meanwhile, the expression of the lipid metabolic parameter sterol regulatory element-binding protein-1c was also reduced. However, peroxisome proliferator-activated receptor α was increased in animal and cell experiments, which indicates that the activity of honokiol was related to its regulated activity on lipid metabolism. The result showed that honokiol significantly inhibited the expression level of p38α in vivo and in vitro. Blocking p38α inhibited the expression levels of tumor necrosis factor-alpha, interleukin-6, interleukin-1ß, and sterol regulatory element-binding protein-1c but promoted the expression level of peroxisome proliferator-activated receptor α compared with the honokiol-treated group. Moreover, the forced expression level of p38α further produced the opposite effect on inflammatory cytokines and lipid metabolism indicators. Furthermore, p38α has been related to the activation of the nuclear factor kappa B signaling pathway. In our study, honokiol significantly inhibited the activation of the nuclear factor kappa B signaling pathway mediated by p38α. In conclusion, the results suggest that honokiol might be an effective regulator of p38α by downregulating the nuclear factor kappa B signaling pathway, thereby reducing the inflammatory response and lipid metabolism disorder in alcoholic liver disease.

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Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

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BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease with unknown etiology, associated with increasing morbidity and pessimistic prognosis. Pulmonary fibroblasts (PFbs) are the key effector cells of PF, in which abnormal activation and proliferation is an important pathogenesis of PF. Ring finger protein 2 (RNF2), is identified as the catalytic subunit of poly-comb repressive complex 1, which is closely related to occurrence and development of lung cancer, but its function in PF has not been revealed. In this paper, we sought to identify the regulatory role of RNF2 in lung fibrogenesis and its underlying mechanisms. METHODS: The expression of RNF2 in lung fibrosis tissue (human and Bleomycin-induced mouse) and cell model (TGF-ß1-induced HFL1 cells) was examined by immunoblotting analysis and immunofluorescence. Western blot, qRT-PCR were performed to evaluate the expression of pro-fibrogenic cytokines (including α-SMA, ECM and MMPs/ TIMPs) induced by TGF-ß1 in HFL1 cells. Cell proliferation, cycle progression and apoptosis were examined by fow cytometric. Molecular interactions were tested by Co-IP assays. RESULTS: RNF2 expression was elevated in PF tissues compared to normal adjacent tissues and in PFbs (HFL1) induced by TGF-ß1. Furthermore, knockdown of RNF2 could evidently inhibit the abnormal expression of pro-fibrogenic cytokines (including α-SMA, ECM and MMPs/TIMPs) induced by TGF-ß1 in HFL1 cells. Functionally, RNF2 silencing could significantly suppress TGF-ß1-induced anomalous proliferation, cell cycle progression, apoptosis and autophagy in HFL1 cells. Mechanistically, RNF2 deficiency could effectively inhibit the abnormal activation of mTOR signaling pathway in TGF-ß1-induced HFL1 cells, and mTOR pathway had feedback regulation on the expression of RNF2. Further studies RNF2 could regulate the phosphorylation level of RB1 through interacting with p16 to destroy the binding of p16 and CDK4 competitively. Simultaneously, overexpression of RNF2 could show the opposite results. CONCLUSIONS: These results indicated that RNF2 is a potent pro-fibrogenic molecule for PFbs activation and proliferation through mTOR and p16-CDK4-Rb signaling pathways, and RNF2 inhibition will be a potential therapeutic avenue for treating PF.

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BACKGROUND: Zinc has shown promise in the treatment of patients with viral warts in several clinical trials, but there is no consensus on its effectiveness. OBJECTIVE: To investigate the efficacy of various formulations of zinc on cutaneous warts. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials, EMBASE, PUBMED, and Web of Science without publishing-time restriction. Trials examining zinc in the treatment of warts were collected. RESULTS: Out of 265 articles, a total of 16 met inclusion criteria. Six clinical trials investigated the clinical effectiveness of oral zinc supplementation alone in treating viral warts, two trials evaluated the efficacy of oral zinc in combination with other therapy, five trials investigated the efficacy of intralesional zinc sulfate, and three trials investigated topical zinc treatment efficacy. Zinc therapy was found to be beneficial in 13 of 16 studies evaluating its effects on warts. CONCLUSIONS: The use of zinc is a simple, safe, and cost-effective treatment in viral warts based on some preliminary evidence. However, more well-designed studies need to be performed to further evaluate the effect of zinc on warts.

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Inflammasomes are large multimolecular complexes best recognized because of their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-18 (IL-18) and interleukin-1 ß (IL-1ß). IL-1ß was originally identified as a pro-inflammatory cytokine, capable of inducing local and systemic inflammation as well as a fever response reaction in response to infection or injury. Excessive production of IL-1ß is related to inflammatory and autoimmune diseases. Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterized by excessive inflammatory response. For SARS, there is no correlation between viral load and worsening symptoms. However, there is no specific medicine which is available to treat the disease. As an important part of medical practice, TCM showed an obvious therapeutic effect in SARS-CoV-infected patients. In this article, we summarize the current applications of TCM in the treatment of COVID-19 patients. Herein, we also offer an insight into the underlying mechanisms of the therapeutic effects of TCM, as well as introduce new naturally occurring compounds with anti-coronavirus activity, in order to provide a new and potential drug development strategy for the treatment of COVID-19.

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The therapeutic approach of liver fibrosis is still an unsolved clinical problem worldwide. Notably, the accumulation of extracellular matrix (ECM) in the liver is mediated by the production of cytokines and growth factors, such as transforming growth factor-ß1 (TGF-ß1) in hepatic stellate cells (HSCs). Ring finger protein 2 (RNF2) was identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), mediating the monoubiquitination of histone H2A. In recent years, a growing amount of evidence suggests that RNF2 may play an important role in multiple pathological processes involved in cancer. Here, we explored the role of RNF2 in liver fibrogenesis and its potential mechanisms. The results showed that RNF2 was up-regulated in human fibrotic liver tissue. Knockdown of RNF2 led to a decreasing expression of collagen1 and α-smooth muscle actin (α-SMA) in LX-2 cells, which was upregulated by RNF2 overexpression. Moreover, RNF2 overexpression significantly promoted TGF-ß1-induced LX-2 cell proliferation but decreased apoptosis. Furthermore, knockdown of RNF2 inhibited the activation of ERK/p38 signaling pathways induced by TGF-ß1. These data suggested that RNF2 is an effective pro-fibrogenic factor for HSC activation via ERK/p38 signaling pathway. RNF2 inhibition might be a promising therapeutic target for liver fibrosis.

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Circular RNAs (circRNAs) are endogenous noncoding RNAs with unique cyclic structures. Although they were previously considered as nonfunctional transcription byproducts, numerous studies have demonstrated that circRNAs regulate gene transcription and expression via different mechanisms. Reproductive health influences the quality of life and affects offspring propagation in women. CircRNAs have been found to modify pregnancy-related diseases, gynecologic cancers, polycystic ovary syndrome, aging, gamete, and embryo development. It's promising for circRNAs to be the novel diagnostic and therapeutic targets for multiple reproductive diseases. With the widespread application of assisted reproduction technology (ART), it has been revealed that circRNA identification contributes to estimating the quality of gametes and embryos, reflecting the success rate of ART. CRISPR-Cas9 gene editing technology has enabled the discovery of new roles of circRNAs. So far, the roles of circRNAs in the reproductive system remain poorly defined. In this review, we describe the classification and functions of circRNAs in embryogenesis and the female reproductive system diseases, revealing potential roles of circRNAs physiologically and pathologically. In so-doing, we provide ideas for developing circRNA-based therapeutic treatment and clinical application of various female reproductive system diseases.

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Transmembrane protein 88 (TMEM88) is a potential 2-transmembrane-type protein that interacts with the PDZ domain of Dishevelled-1 (DVL-1), a crucial component of Wnt signalling pathway through its C-terminal Val-Trp-Val (VWV) motif in Xenopus embryo cells. Since the significant function of ß-catenin in liver fibrosis, it is urgent to study the TMEM88 mechanism in liver fibrosis. The current research was for evaluating the function of TMEM88 in the process of the liver fibrosis and clarifying the inherent mechanism. The study found that TMEM88 is decreased in human fibrotic liver tissues. Functionally, TMEM88 significantly reduced the expression levels of α-smooth muscle actin (α-SMA) and collagen type I (Col.I) and repressed extracellular matrix (ECM) accumulation by restoring the balance between matrix metalloproteinases (MMPs) and TIMPs (tissue inhibitor of metalloproteinases). TMEM88 inhibited HSCs proliferation and evaluated the apoptosis of activated LX-2 cells by regulating Wnt3a, Wnt2b and ß-catenin of Wnt/ß-catenin signalling pathway. Moreover, we demonstrated that miR-708 particularly targeted TMEM88 3'-UTR regions and down-regulated the expression level of TMEM88 in TGF-ß1-stimulated LX-2 cells. MiR-708 promoted the generation of ECM and cell activation in activated LX-2 cells. These results determined that miR-708 could promote HSCs activation and enhance ECM accumulation via direct targeting TMEM88 by Wnt/ß-catenin signalling pathway. This will provide a potential target for future research in the process of liver fibrosis.

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Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide that afflicts human health. With the in-depth study of the disease, its pathogenesis has gradually become clear. Although great breakthroughs have been made in the research of ALD, the research and development of drugs related to ALD has lagged behind seriously. However, natural products have always inspired the development of drugs. Meanwhile, there is evidence that some natural products can also play a certain role in the treatment of ALD. Thus, we reviewed the natural products, extracts and formulations with potential anti-ALD activities by consulting the relevant data in the databases of PubMed, Web of Science and CNKI databases, in order to elucidate the regulated mechanism of these natural products. Sum up, the insights provided in present review will be needed for further exploration of botanical drugs in the development of ALD therapy.

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Recent studies have shown that Transmembrane protein 100 (TMEM100) is a gene at locus 17q32 encoding a 134-amino acid protein with two hypothetical transmembrane domainsa, and first identified as a transcript from the mouse genome. As a downstream target gene of bone morphogenetic protein (BMP)-activin receptor-like kinase 1 (ALK1) signaling, it was activated to participate in inducing arterial endothelium differentiation, maintaining vascular integrity, promoting cell apoptosis, inhibiting metastasis and proliferation of cancer cells. However, evidence for the function of TMEM100 in inflammation is still limited. In this study, we explore the role of TMEM100 in inflammatory cytokine secretion and the role of MAPK signaling pathways in tumor necrosis factor-alpha (TNF-α)-induced TMEM100 expression in LX-2 cells. We found that the expression of TMEM100 was decreased markedly in human liver fibrosis tissues, and its expression was also inhibited in LX-2 cells induced by TNF-α, suggesting that it might be associated with the development of inflammation. Therefore, we demonstrated that overexpression of TMEM100 by transfecting pEGFP-C2-TMEM100 could lead to the down-regulation of IL-1ß and IL-6 secretion. Moreover, we found that expression changes of TMEM100 could be involved in inhibition or activation of MAPK signaling pathways accompanied with regulating phosphorylation levels of ERK and JNK protein in response to TNF-α. These results suggested that TMEM100 might play an important role in the secretion of inflammatory cytokines (IL-1ß and IL-6) of LX-2 cells induced by TNF-α, and MAPK (ERK and JNK) signaling pathways might participate in its induction of expression.

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Recent data have shown that Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane, interacts with the PDZ domain of disheveled-1 (Dvl-1) in Xenopus embryos. Indeed, TMEM88 might inhibit the canonical Wnt/ß-catenin signaling pathway by competing with LRP5/6 for interaction with Dvl-1. TMEM88 plays a crucial role in regulating human stem cell differentiation and embryonic development. Until recently, the function of TMEM88 has been a matter of debate. In this study, we explore the role of TMEM88 in cytokine secretion and the role of the MAPK and Wnt/ß-catenin signaling pathway in tumor necrosis factor-alpha (TNF-α)-induced TMEM88 expression in LX-2 cells. We demonstrated that overexpression of TMEM88 results in an upregulation of IL-6 and IL-1ß secretion. On the other hand, knockdown of TMEM88 by transfecting siRNA decreased IL-6 and IL-1ß secretion in LX-2 cells. Meanwhile, the results showed that TMEM88 silencing could increase the expression levels of canonical Wnt/ß-catenin accompanied with upregulated phosphorylation of wnt3a, wnt10b and ß-catenin protein levels in response to TNF-α. In conclusion, these results indicated that TMEM88 plays a significant role in TNF-α-enhanced cytokine (IL-6 and IL-1ß) secretion of LX-2 cells via regulating JNK/P38 and canonical Wnt/ß-catenin signaling pathway.

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Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane. Recent studies showed that TMEM88 was involved in the regulation of several types of cancer. TMEM88 was expressed at significantly higher levels in breast cancer (BC) cell line than in normal breast cell line with co-localized with Dishevelled (DVL) in the cytoplasm of BC cell line. TMEM88 silencing in the ovarian cancer cell line CP70 resulted in significant upregulation of Wnt downstream genes (c-Myc, cyclin-D1) and other Wnt target genes including JUN, PTIX2, CTNNB1 (ß-catenin), further supporting that TMEM88 inhibits canonical Wnt signaling pathway. Wnt signaling pathway has been known to play important roles in many diseases, especially in cancer. For instance, hepatocellular carcinoma (HCC) has become one of the most common tumors harboring mutations in the Wnt signaling pathway. As the inhibitor of Wnt signaling, TMEM88 has been considered to act as an oncogene or a tumor suppressor. Up-regulated TMEM88 or gene therapy approaches could be an effective therapeutic approach against tumor as TMEM88 inhibits Wnt signaling through direct interaction with DVL. Here, we review the current knowledge on the functional role and potential clinical application of TMEM88 in the control of various cancers. Highlights Wnt signaling displays an important role in several pathogenesis of cancer. Wnt signaling pathway is activated during cancer development. TMEM88 has an impact on cancer by inhibiting canonical Wnt signaling. We discuss the importance and new applications of TMEM88 in cancer therapy.

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During the liver fibrosis recovery stage tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can effectively induce apoptosis of activated hepatic stellate cells (HSCs). Normal hepatic stellate cells are resistant to TRAIL cytotoxicity. Therefore, enhancing the sensitivity of TRAIL-induced apoptosis of HSCs may be useful to treat hepatic fibrogenesis. Here, we demonstrated that miR-145 and TRAIL were down-regulated in both liver fibrosis tissue samples and transforming growth factor-ß1 induced HSCs, concomitant with increased the expression of ZEB2. In addition, we found that mimics-mediated over-expression of miR-145 led to resistance to the ZEB2 expression and up-regulation of the TRAIL-induced apoptosis after treatment of LX-2 cells with TRAIL. Furthermore, ZEB2-siRNA transfected LX-2 cells showed the increased sensitivity to TRAIL-induced apoptosis. Whereas, opposite results were obtained in miR-145-inhibitor group or ZEB2 plasmid group. Moreover, miR-145 regulated ZEB2 gene expression by specifically interacting with the 3'-UTR of ZEB2 mRNA to inhibit the expression of ZEB2. Further studies showed that the over-expression of ZEB2 could inhibit TRAIL-induced apoptosis via inhibiting nuclear factor-κB (NF-κB) signaling pathway in LX-2 cells. Collectively, our data suggest that up-regulation of miR-145 can down-regulate ZEB2 expression, consequently promoting TRAIL-induced apoptosis in LX-2 cells through NF-κB signaling pathway, which facilitates the resolution of liver fibrosis.