Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Bioactivity of five components of Chinese herbal formula Jiangzhi granules against hepatocellular steatosis

OBJECTIVE： This study aims to evaluate the bioactivity of five components of the traditional Chinese medicine complex prescription Jiangzhi granules against hepatocellular steatosis. METHODS： The five major components, including protopanaxadiol, tanshinone IIA, emodin, chlorogenic acid, and nuciferine, were extracted from Jiangzhi granules. Their cytotoxicity was assessed to determine the safe dose of each component for HepG2 cells. HepG2 cellular steatosis was induced using 1 mmol/L of free fatty acids （FFAs） for 24 h, and then treated with each component at high, intermediate, and low doses （500, 50, and 5 μmol/L）, respectively for another 24 h. The effects on HepG2 steatosis were observed directly under optical phase microscopy, or through oil red O staining and Nile red assays. In addition, the levels of reactive oxygen species （ROS） in the steatotic HepG2 cells with and without high-dose protopanaxadiol treatment were measured using fluorescent dye 2＇,7＇-dichlorodihydrofluorescein diacetate staining. RESULTS： No obvious cytotoxicity was observed in the HepG2 cells incubated with each of the five components at up to 500μmol/L. At 24 h after incubation with FFAs, the HepG2 cells swelled and many lipid droplets accumulated. The lipid content was attenuated after 24 h of incubation with protopanaxadiol, tanshinone IIA, and emodin at 500 or 50 μmol/L （P 〈 0.05）, especially with 500 μmol/L protopanaxadiol （P 〈 0.01）. In addition, the ROS level was elevated in steatotic cells, but decreased after intervention with 500μmol/L protopanaxadiol （P 〈 0.05）. CONCLUSION： Protopanaxadiol, tanshinone IIA, and emodin alleviate hepatocellular steatosis in a dose-dependent manner, and oxidative stress regulation may partially contribute to the effects of protopanaxadiol. ：

Autophagy activation by Jiang Zhi Granule protects against metabolic stress-induced hepatocyte injury

AIM To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule(JZG) in metabolic stress-induced hepatocyte injury.METHODS An in vitro and in vivo approach was used in this study. Hep G2 cells were incubated in culture medium containing palmitate(PA; 0, 0.1, 0.2, 0.3, 0.4 or 0.5 mmol/L) and treated with or without JZG(100 μg/m L) for 24 h or 48 h, and the progression of autophagy was visualized by stable fluorescence-expressing cell lines LC3 and p62. Western blot analyses were performed to examine the expression of LC3-Ⅱ/LC3-Ⅰ, p62, m TOR and PI3 K, while mitochondrial integrity and oxidative stress were observed by fluorescence staining of JC-1 and reactive oxygen species. C57 BL/6 mice were divided into three groups: control group(n = 10), high fat(HF) group(n = 13) and JZG group(n = 13); and, histological staining was carried out to detect inflammation and lipid content in the liver.RESULTS The cell trauma induced by PA was aggravated in a dose-and time-dependent manner, and hepatic function was improved by JZG. PA had dual effects on autophagy by activating autophagy induction and blocking autophagic flux. The PI3 K-AKT-m TOR signaling pathway and the fusion of isolated hepatic autophagosomes and lysosomes were critically involved in this process. JZG activated autophagy progression by either induction of autophagosomes or co-localization of autophagosomes and lysosomes as well as degradation of autolysosomes to protect against PA-induced hepatocyte injury, and protected mitochondrial integrity against oxidative stress in PA-induced mitochondrial dysfunction. In addition, JZG ameliorated lipid droplets and inflammation induced by HF diet in vivo, leading to improved metabolic disorder and associated liver injury in a mouse model of non-alcoholic fatty liver disease(NAFLD).CONCLUSION Metabolic stress-induced hepatocyte injury exhibited dual effects on autophagy and JZG activated the entire process, resulting in beneficial effects in NAFLD.

Drug resistance and new therapies in colorectal cancer

Colorectal cancer(CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo-and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo-and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibodydrug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

Irritable bowel syndrome and functional constipation management with integrative medicine: A systematic review

BACKGROUND Irritable bowel syndrome(IBS)and functional constipation(FC)are two commonly encountered functional gastrointestinal disorders in clinical practice and are usually managed with Western medicines in cooperation with traditional Chinese medicine(TCM)interventions.Although clinical practice guidelines(CPGs)have been developed to assist clinicians with their decisions,there are still gaps in management with regard to integrative medicine(IM)recommendations.AIM To comprehensively review the currently available CPGs and to provide a reference for addressing the gaps in IBS and FC management.METHODS We searched mainstream English and Chinese databases and collected data from January 1990 to January 2019.The search was additionally enriched by manual searches and the use of publicly available resources.Based on the development method,the guidelines were classified into evidence-based(EB)guidelines,consensus-based(CB)guidelines,and consensus-based guidelines with no comprehensive consideration of the EB(CB-EB)guidelines.With regard to the recommendations,the strength of the interventions was uniformly converted to a 4-point grading scale.RESULTS Thirty CPGs met the inclusion criteria and were captured as data extraction sources.Most Western medicine(WM)CPGs were developed as EB guidelines.All TCM CPGs and most IM CPGs were identified as CB guidelines.Only the 2011 IBS and IM CPG was a CB-EB set of guidelines.Antispasmodics and peppermint oil for pain,loperamide for diarrhea,and linaclotide for constipation polyethylene glycol and lactulose as osmotic laxatives,bisacodyl and sodium picosulfate as stimulant laxatives,lubiprostone and linaclotide as prosecretory agents,and prucalopride were strongly recommended or recommended in FC.TCM interventions were suggested based on pattern differentiation,while the recommendation level was considered to be weak or insufficient.CONCLUSION WM CPGs generally provide a comprehensive management algorithm,although there are still some gaps that could be addressed with TCM.Specific high-quality trials are needed to enrich the evidence.

Role of epigenetics in transformation of inflammation into colorectal cancer

Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer(CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.

Qinggan Huoxue Recipe suppresses epithelial-tomesenchymal transition in alcoholic liver fibrosis through TGF-β1/Smad signaling pathway

AIM: To investigate the mechanism by which Qinggan Huoxue Recipe(QGHXR) inhibits epithelial-to-mesenchymal transition(EMT) in rats with alcoholic liver fibrosis(ALF).METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, includingalanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylineosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor(TGF)-β1/Smad signaling pathway, including TGF-β1, Smad3, snail, occludin, ZO-1 and claudin, was also examined.RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels(m RNA: ALF 0.16 ± 0.05 vs control 1.00 ± 0.08; protein: ALF 0.09 ± 0.05 vs control 0.70 ± 0.17, P < 0.01) and an increase in vimentin and fibronectin levels(m RNA: 11.43 ± 0.39 vs 1.00 ± 0.19 and 9.91 ± 0.34 vs 1.00 ± 0.44, respectively, P < 0.01; protein: 1.13 ± 0.42 vs 0.09 ± 0.03 and 1.16 ± 0.43 vs 0.09 ± 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-β1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-β1 and snail levels(m RNA: 1.76 ± 0.12 vs 1.00 ± 0.05 and 6.98 ± 0.41 vs 1.00 ± 0.10, respectively, P < 0.01; protein: 1.43 ± 0.05 vs 0.12 ± 0.03 and 1.07 ± 0.29 vs 0.07 ± 0.02, respectively, P < 0.01) and the decrease in Smad3 levels(m RNA: 0.05 ± 0.01 vs 1.00 ± 0.12, P < 0.01; protein: 0.06 ± 0.05 vs 0.89 ± 0.12, P < 0.01). Furthermore, levels of the tight junction markers occludin, ZO-1 and claudin decreased in ALF rats compared with healthy control rats(m RNA: 0.60 ± 0.09 vs 1.00 ± 0.12, 0.11 ± 0.00 vs 1.00 ± 0.12 and 0.60 ± 0.01 vs 1.00 ± 0.08, respectively, P < 0.01; protein: 0.05 ± 0.01 vs 0.87 ± 0.40, 0.09 ± 0.05 vs 0.89 ± 0.18 and 0.04 ± 0.03 vs 0.95 ± 0.21, respectively, P < 0.01). In ALF rats treated with QGHXR, E-cadherin levels increased(m RNA: QGHXR 0.67 ± 0.04 vs ALF model 0.16 ± 0.05, P < 0.01; protein: QGHXR 0.66 ± 0.21 vs ALF model 0.09 ± 0.05, P < 0.01), and vimentin and fibronectin levels decreased(m RNA: 6.57 ± 1.05 vs 11.43 ± 0.39 and 1.45 ± 1.51 vs 9.91 ± 0.34, respectively, P < 0.01; protein: 0.09 ± 0.03 vs 1.13 ± 0.42 and 0.10 ± 0.01 vs 1.16 ± 0.43, respectively, P < 0.01). In addition, QGHXR inhibited the expression of TGF-β1 and increased the expression of Smad3(m RNA: 1.03 ± 0.11 vs 1.76 ± 0.12, 0.70 ± 0.10 vs 0.05 ± 0.01, respectively, P < 0.05 and P < 0.01; protein: 0.12 ± 0.03 vs 1.43 ± 0.05 and 0.88 ± 0.20 vs 0.06 ± 0.05, respectively, P < 0.01). QGHXR treatment also reduced the levels of the EMT-inducing transcription factor snail(m RNA: 2.28 ± 0.33 vs 6.98 ± 0.41, P < 0.01; protein: 0.08 ± 0.02 vs 1.07 ± 0.29, P < 0.01) and increased the occludin, ZO-1 and claudin levels(m RNA: 0.73 ± 0.05 vs 0.60 ± 0.09, 0.57 ± 0.04 vs 0.11 ± 0.00 and 0.68 ± 0.03 vs 0.60 ± 0.01, respectively, P < 0.01, P < 0.01 and P < 0.05; protein: 0.92 ± 0.50 vs 0.05 ± 0.01, 0.94 ± 0.22 vs 0.09 ± 0.05 and 0.94 ± 0.29 vs 0.04 ± 0.03, respectively, P < 0.01). The effects of QGR and HXR on the TGF-β1/Smad signaling pathway weresimilar to that of QGHXR; however, the QGR- and HXRinduced changes in vimentin m RNA levels, the QGRinduced changes in fibronectin m RNA levels and the HXR-induced changes in snail and TGF-β1 m RNA levels were not significant.CONCLUSION: Qinggan Huoxue Recipe inhibits EMT in ALF rats by modulating the TGF-β1/Smad signaling pathway, suggesting that the mechanism underlying the amelioration of ALF induced by QGHXR is associated with this pathway.

Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor(FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.

Effect of Chinese medicine Qinggan Huoxuefang on inducing HSC apoptosis in alcoholic liver fibrosis rats

瞄准：在老鼠在肝功能和病理的改进上调查 Qinggan Huoxuefang (QGHXF ) 的效果，并且分析机制。方法：Wistar 老鼠在随机被划分成三个组：正常控制组(12 ) ，微数量的四氯化碳组(CCl (4 ))(12 ) 和模型组织 A (60 ) 。模型组 A 与混合被摄取(500 mL/L 酒精， 8 mL/kg 每天；玉蜀黍油， 2 mL/kg 每天；pyrazole， 24 mg/kg 每天) 一次一天和在齐墩果油的 CCl (4 ) 的 250 mL/L 答案的 0.25 mL/kg 的腹膜内注射两次为 12 wk 的一个星期。CCl (4 ) 组仅仅收到了腹膜内注射。在 8 wk 的结束，模型组 A (60 ) 被划分成 5 亚群：模型组， Xiaochaihu Chongji (XCH ) 组， QGHXF 高剂量组，中等剂量组和低剂量分别地组织，并且被给这些药。在 12 wk 的结束，所有老鼠被打死，血样品收集了，以及肝织物。血样品被用于丙氨酸转氨酶(中高音) 的评估， aspartate aminotransferase (著名计算机生产厂商) ，硷性磷酸酯酶(高山) ， gamma-glutamyltransferase (gamma-GT ) 。肝标本为例程被获得他， apoptosis 基因数组和流动血细胞计数分析。结果：一个肝纤维变性动物模型成功地被建立。纤维变性显然在在 CCl (4 ) 组形成的 QGHXF 高剂量组，和没有纤维变性被减少。与模型组相比， QGHXF 组和 XCH 组能显然减少中高音，著名计算机生产厂商，高山，和 GGT (P【0.05 ) 的水平。QGHXF 高剂量组比 XCH 好在中高音(615+/-190 对 867+/-115 ) 的组，和著名计算机生产厂商(1,972+/-366 对 2,777+/-608 ) 。而且， QGHXF 能减少肝发炎，导致纤维变性的肝的星形的房间(HSC ) apoptosis 并且调整 apoptosis 基因表示。QGHXF 组的 HSC apoptosis 率是 22.4+/-3.13， 13.79+/-2.26 和 10.07+/-1.14，比模型组，高 6.58+/-1.04 (P【0.05 ) 。比作模型组， 39 基因是起来调整的， 11 完全表示了并且 17 在高剂量组下面调整。结论：QGHXF 能改进肝纤维变性和 induce HSC apoptosis。

Progress on haptoglobin and metabolic diseases

Haptoglobin(Hp)is an acidic glycoprotein,existing in the serum and other body fluids of human beings and a variety of mammals.Hp is produced in the liver,white adipose tissue,and the kidney.The genetic polymorphisms and different phenotypes of Hp have different biological functions.Hp has antibacterial,antioxidant,and angiogenic effects and is associated with multiple diseases including simple obesity,vascular complications of diabetes mellitus,nonalcoholic fatty liver disease,hypertension,blood diseases,autoimmune diseases,and malignant tumors.Hp also participates in many life activities,indicating the importance of Hp in further studies.Previously,we found that the expression of serum Hp changed after treatment of simple obesity patients in clinical trials.However,the specific mechanism of Hp in patients with simple obesity is still unclear.The purpose of this article is to introduce recent research progress on Hp,emphasizing the relationship between Hp and the development of metabolic disease,which will improve the understanding of the functions of Hp underlying metabolic diseases and discuss future research directions.

Chinese medicine formulas for nonalcoholic fatty liver disease: Overview of systematic reviews

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)affects more than one-quarter of the global population.Due to the lack of approved chemical agents,many patients seek treatment from traditional Chinese medicine(TCM)formulas.A variety of systematic reviews have been published regarding the effectiveness and safety of TCM formulas for NAFLD.AIM To critically appraise available systematic reviews and sort out the high-quality evidence on TCM formulas for the management of NAFLD.METHODS Seven databases were systematically searched from their inception to 28 February 2020.The search terms included“non-alcoholic fatty liver disease,”“Chinese medicines,”“systematic review,”and their synonyms.Systematic reviews involving TCM formulas alone or in combination with conventional medications were included.The methodological quality and risk of bias of eligible systematic reviews were evaluated by using A Measure Tool to Assess Systematic Reviews 2(AMSTAR 2)and Risk of Bias in Systematic Review(ROBIS).The quality of outcomes was assessed by the Grading of Recommendations Assessment,Development and Evaluation(GRADE)system.RESULTS Seven systematic reviews were ultimately included.All systematic reviews were conducted based on randomized controlled trials and published in the last decade.According to the AMSTAR 2 tool,one systematic review was judged as having a moderate confidence level,whereas the other studies were rated as having a low or extremely low level of confidence.The ROBIS tool showed that the included systematic reviews all had a high risk of bias due to insufficient consideration of identified concerns.According to the GRADE system,only two outcomes were determined as high quality;namely,TCM formulas with the HuoXueHuaYu principle were better than conventional medications in ultrasound improvement,and TCM formulas were superior to antioxidants in alanine aminotransferase normalization.Other outcomes were downgraded to lower levels,mainly because of heterogeneity among studies,not meeting optimal information sample size,and inclusion of excessive numbers of small sample studies.Nevertheless,the evidence quality of extracted outcomes should be further downgraded when applying to clinical practice due to indirectness.CONCLUSION The quality of available systematic reviews was not satisfactory.Researchers should avoid repeatedly conducting systematic reviews in this area and focus on designing rigorous randomized controlled trials to support TCM formula applications.

CircRNA_0084927 promotes colorectal cancer progression by regulating miRNA-20b-3p/glutathione S-transferase mu 5 axis

BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related death worldwide.The 5-year survival rate of patients with early-stage CRC could reach 90%,but it is very low in patients with advanced-stage CRC.Recent studies have shown that circular RNAs play important roles in regulating the migration and invasion of CRC cells.AIM To elucidate the role of circRNA_0084927(circ_0084927)in the migration and invasion of CRC cells and its underlying mechanism.METHODS Clinical tissue samples and cells were collected,and the expression of circ_0084927 was detected by quantitative polymerase chain reaction(qPCR).The diagnostic performance of circ_0084927 was assessed by receiver operating characteristic curve analysis.The role of circ_0084927 in CRC cell proliferation,migration,and invasion was determined using cell counting kit-8 assay,wound healing assay,and transwell assay,respectively.The regulatory relationship among circ_0084927,miRNA-20b-3p(miR-20b-3p),and glutathione S-transferase mu 5(GSTM5)was identified using databases,luciferase reporter assay,qPCR,and Western blot analysis.AKT-mTOR signaling was also verified after circ_0084927 knockdown or miR-20b-3p mimic treatment.RESULTS The expression of circ_0084927 was significantly increased in CRC tissues and cells,and it was higher in advanced-stage CRC compared with early-stage CRC.The area under the curve(AUC)of circ_0084927 was 0.806[95%confidence interval(CI):0.683-0.896].In addition,the AUC was 0.874(95%CI:0.738-0.956)in patients with advanced-stage CRC and 0.713(95%CI:0.555-0.840)in those with early-stage CRC.Knockdown of circ_0084927 inhibited the migration and invasion of HCT116 cells.Moreover,circ_0084927 was found to act as a sponge of miR-20b-3p.MiR-20b-3p activation reduced the circ_0084927 level,whereas miR-20b-3p inhibition increased the circ_0084927 level.But the effect was not found after circ_0084927 mutation.In addition,miR-20b-3p expression in CRC patients was also reduced and negatively correlated with circ_0084927 expression.The function of circ_0084927 in HCT116 cells with circ_0084927 knockdown was rescued by miR-20b-3p.Moreover,GSTM5 expression was significantly decreased after overexpressing miR-20b-3p or inhibiting circ_0084927,but its expression was rescued when circ_0084927 and miR-20b-3p were both inhibited.Finally,AKTmTOR signaling was markedly regulated by circ_0084927 and miR-20b-3p.CONCLUSION The expression of circ_0084927 is significantly increased in CRC and higher in advanced-stage CRC than in early-stage CRC.Moreover,circ_0084927 potentially regulates CRC cell migration and invasion via the miR-20b-3p/GSTM5/AKT/mTOR pathway.

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients.To date,vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D,and its expression can be induced by fatty acids,and insulin.It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation.Thus,the multiplicity of VDR ligands,together with the cell type-specificity of VDR activation,must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.To this end,we have evaluated the relationship between VDR activation and various contributing factors,such as gut microbiota,bile acid,fatty acids,and insulin,in addition to vitamin D,with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.

Natural products that target macrophages in treating non-alcoholic steatohepatitis

Nonalcoholic steatohepatitis(NASH)is the progressive subtype of non-alcoholic fatty liver disease and potentiates risks for both hepatic and metabolic diseases.Although the pathophysiology of NASH is not completely understood,recent studies have revealed that macrophage activation is a major contributing factor for the disease progression.Macrophages integrate the immune response and metabolic process and have become promising targets for NASH therapy.Natural products are potential candidates for NASH treatment and have multifactorial underlying mechanisms.Macrophage involvement in the development of steatosis and inflammation in NASH has been widely investigated.In this review,we assess the evidence for natural products or their active ingredients in the modulation of macrophage activation,recruitment,and polarization,as well as the metabolic status of macrophages.Our work may highlight the possible natural products that target macrophages as potential treatment options for NASH.

Management of non-alcoholic fatty liver disease patients with sleep apnea syndrome

Nonalcoholic fatty liver disease(NAFLD)is strongly associated with sleep apnea syndrome(SAS).Many NAFLD patients have SAS,and obstructive sleep apnea hypopnea syndrome is also considered to be an independent risk factor for NAFLD,as it contributes to the progression of NAFLD via oxidative stress,lipid peroxidation,inflammation,and insulin resistance.This review aims to provide some recommendations for the management of NAFLD patients with SAS,including diet,exercise,weight loss,and continuous positive airway pressure.This review also highlights the importance of effective strategies in NAFLD prevention and treatment.

Vitamin E Therapy in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is closely related to oxidative stress. Vitamin E (VE) is an effective antioxidant, which could relieve NAFLD symptoms by improving the balance of oxidation and anti-oxidation. However, recent researches indicate that the functional mechanisms of VE are not only limited to anti-oxidation, but also include adjusting the metabolism disorders of glucose and lipid. Furthermore, the efficacy of VE remains controversial in the treatment of NAFLD by far, and the suitable condition of patient, drug dosage, drug safety and course of treatment during clinical application still need to be discussed. Therefore, this paper reviewed the recent study progresses of clinical application of VE alone and VE and other drugs.

曲线钢箱梁节段划分及架设方案分析

本文根据互通内曲线钢箱梁桥跨越连霍高速施工实际情况,结合钢箱梁制造、运输、吊装等条件,分析探讨了钢箱梁安装节段划分、架设、焊接等方面的内容,可对类似工程有借鉴,以提升工程质量。

RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and potential biomarkers

BACKGROUND Colorectal cancer(CRC)is a commonly diagnosed cancer of the digestive system worldwide.Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment,drug resistance is a problem that cannot be ignored and needs to be solved.AIM To explore the relationship between circular RNA(circRNA)and CRC drug resistance.circRNA plays a key role in the occurrence and development of cancers,but its function in the process of drug resistance has not been widely revealed.METHODS To explore the role of circRNA in 5-fluorouracil(5-Fu)resistance,we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing.RESULTS We validated the differentially expressed circRNAs in other two paired CRC cells,confirmed that circ_0002813 and circ_0000236 could have a potential competitive endogenous RNA mechanism and be involved in the formation of 5-Fu resistance.And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA.CONCLUSION Our study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.

Macrophages play a role in inflammatory transformation of colorectal cancer

Colorectal cancer(CRC)is one of the most common and fatal cancers worldwide,and it is also a typical inflammatory cancer.The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation.Here,we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages.Furthermore,the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized.In addition,in the era of tumor immunotherapy,CRC currently has a limited response rate to immune checkpoint inhibitors,and we summarize potential therapeutic strategies for targeting tumorassociated macrophages.

Advances in Research on the Role of Chemokines in Occurrence and Development of Autoimmune Thyroid Disease

Chemokines can be divided into four categories: α, β, γ, and δ. Chemokine α is related to neutrophil chemotaxis. Chemokine β is correlated with adsorption of monocytes,basophils, and eosinophils. Chemokine γ is mainly a lymphocyte chemokine. Function of chemokine δ remains unclear. Chemokines α and β are primarily related to occurrence and development of autoimmune thyroid disease. This study reviews chemokines and their receptors that are related to Graves’ disease and Hashimoto’s thyroiditis.