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Hepatocellular carcinoma (HCC) is one of the most deadly malignancies in the world, with strong invasiveness, low cure rate, high metastasis rate and poor prognosis. Sorafenib is the most important and effective first-line drug for the treatment of advanced hepatocellular carcinoma, but its clinical efficacy is severely limited by primary and acquired drug resistance. Mi-crornas ( micrornas) are small non-coding Rnas that play a key regulatory role in the occurrence and development of hepatocellular carcinoma and the progression of sorafenib resistance. This paper summarizes the role of micrornas in the initiation and development of sorafenib resistance in hepatocellular carcinoma, in order to further understand the mechanism of sorafenib anti-hep-atocellular carcinoma, and to provide valuable theoretical basis for clinical targeted therapy and prognosis improvement in hepatocellular carcinoma.
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Objective:To investigate the effect and mechanism of miR-195 regulating FOXK1 gene and PI3K/Akt pathway on stomach adenocarcinoma proliferation, invasion and migration ability.Methods:Public database samples were employed to analyze the expression differences and prognostic significance of miR-195 in stomach adenocarcinoma. After overexpression of mir-195-5p in two cell lines, MGC803 and AGS, altered cell proliferation, invasion, and migration abilities were detected by Alamar Blue, Wound healing, and Transwell assays. The potential target genes and binding sites of miR-195 were predicted by the starBase. Western blot was used to detect the expression levels of foxk1 and phosphorylation sites in the PI3K/Akt pathway of target genes after overexpression of mir-195-5p. A Dual-luciferase reporter assay was used to verify the relationship between mir-195-5p and foxk1. Statistical analyses were performed with IBM SPSS 22 software and R 4.0.3.Results:Our results showed a significant over-expression of miR-195 in the tumor tissues, compared with the paired normal tissues ( P<0.001) , which could inhibit the proliferation and invasion of stomach carcinoma cells and significantly correlated with survival ( P=0.011) . Moreover, our study indicated that miR-195 depressed the expression of FOXK1 and significantly reduced the activation of the PI3K/Akt pathway, which had a negative effect on the proliferation and invasion of stomach carcinoma cells. The phosphorylated Akt (s473 site) expression in the PI3K/Akt pathway was significantly decreased after overexpression of miR-195. Conclusion:Overall, our studies clarify the important function of the miR-195 in the diagnosis and therapy of patients with stomach carcinoma and reveal the FOXK1 and PI3K/Akt pathway regulation by the miR-195, which are of important clinical significance in the differential diagnosis.
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Prostate cancer (PCa) is an epithelial malignancy that occurs in the prostate tissue and is the second most common cancer in men after lung cancer, affecting millions of men worldwide. MicroRNA (miRNA) is a non-coding small RNA of length 20-22nt that regulates gene expression post-transcriptionally. miRNAs are involved in the regulation of almost all important biological life processes such as cell cycle progression, cell proliferation, cell apoptosis, and cell migration. Recently, more and more studies have shown that miRNAs are involved in the occurrence of various human tumors including PCa. This review summarizes the current research progress of PCA-related miRNAs, and analyzes the role of malregulated miRNAs in the pathogenesis, diagnosis and treatment of PCa. In addition, the role of miRNA in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) is emphasized.
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Cholesterol is an important lipid component in the body, which not only participates in the formation of cell membranes, but also is the raw material for the synthesis of bile acids and steroid hormones. Low density lipoprotein receptor (LDLR) is involved in cholesterol metabolism and plays an important role in maintaining the cholesterol homeostasis of organism cells. The expression of LDLR is precisely regulated by transcription, post-transcription and post-translation, and the imbalance of ldlr expression will lead to the occurrence and development of many diseases. In this paper, the molecular regulation mechanism of LDLR, the damage of target organs caused by the imbalance of LDLR expression and the research and development progress of drugs targeting LDLR are reviewed, which provides theoretical basis for further understanding of the progress of diseases related to lipid metabolism disorder and new insights for developing drugs targeting LDLR with more effective and less side effects.
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In recent years, the prevalence of pulmonary fibrosis is increasing worldwide. Due to its complex pathogenesis and different clinical manifestations, the treatment options are limited. The nucleotide-binding oligomerization domain like receptor family pyrin domain-containing protein 3(NLRP3) inflammasome plays an important role in pulmonary fibrotic diseases, and its activation and inhibition can directly affect the process of pulmonary fibrosis. The structure of NLRP3 inflammasome consists of a sensor molecule, NLRP3, apoptosis-associated speck-like protein CARD, and caspase-1. There are three signaling pathways that include canonical pathway, selective or noncanonical pathway, and alternative pathway. Excessive activation of NLRP3 inflammasome can accelerate the development of idiopathic pulmonary fibrosis and pulmonary fibrosis induced by silicosis. Therefore, the NLRP3 inflammasome may serve as a therapeutic target of pulmonary fibrosis. NLRP3 inflammasome activators and inhibitors can mediate the activation and inhibition of NLRP3 inflammasome, and then regulate the occurrence and development of pulmonary fibrosis. Inhibiting the activation of NLRP3 inflammasome can improve pulmonary fibrosis. However, the specific mechanism has not been elucidated. The therapeutic strategies for pulmonary fibrosis need further research on the activation and regulation of NLRP3 inflammasome.
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Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies, which makes its pathogenesis an important target for research. A growing number of studies have shown that non-coding RNA (ncRNA), including microRNA (miRNA) and long non-coding RNA (lncRNA), plays a significant role in tumorigenesis. This review summarizes the roles of miRNA and lncRNA in the progression, diagnosis, and neoadjuvant chemotherapy of TNBC. Aberrantly expressed miRNA and lncRNA are listed according to their roles. Further, it describes the multiple mechanisms that lncRNA shows for regulating gene expression in the nucleus and cytoplasm, and more importantly, describes lncRNA-regulated TNBC progression through complete combining with miRNA at the post-transcriptional level. Focusing on miRNA and lncRNA associated with TNBC can provide new insights for early diagnosis and treatment-they can be targeted in the future as a novel anticancer target of TNBC.
Subject(s)
Female , Humans , Gene Expression Regulation, Neoplastic , MicroRNAs/physiology , Neoadjuvant Therapy , RNA, Long Noncoding/physiology , Triple Negative Breast Neoplasms/pathologyABSTRACT
Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies, which makes its pathogenesis an important target for research. A growing number of studies have shown that non-coding RNA (ncRNA), including microRNA (miRNA) and long non-coding RNA (lncRNA), plays a significant role in tumorigenesis. This review summarizes the roles of miRNA and lncRNA in the progression, diagnosis, and neoadjuvant chemotherapy of TNBC. Aberrantly expressed miRNA and lncRNA are listed according to their roles. Further, it describes the multiple mechanisms that lncRNA shows for regulating gene expression in the nucleus and cytoplasm, and more importantly, describes lncRNA-regulated TNBC progression through complete combining with miRNA at the post-transcriptional level. Focusing on miRNA and lncRNA associated with TNBC can provide new insights for early diagnosis and treatment—they can be targeted in the future as a novel anticancer target of TNBC.
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Huntington's disease (HD) is a monogenic genetic disease of neurodegenerative disorders caused by repeated amplification of CAG trinucleotides in the first exon of the Huntingtin gene (HTT), and there are no treatments which could forestall or slow Huntington's disease. The protein product encoded by HTT is called huntingtin (Htt). The mutated huntingtin protein (mHtt) is easy to form aggregation which is toxic, leading to a series of cytological abnormalities and neuronal dysfunction. MicroRNA (miRNA) plays an important role in the post-transcriptional regulation of genes whose expression is related to the pathological process of Huntington's disease. miRNA is becoming the promising biomarker for the treatment of HD. Recent studies on the regulation of specific miRNAs in HD and the prediction of their target genes may provide a potential role for the treatment of HD. This review highlights the research progress on miRNAs in the occurrence of HD.
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A comprehensive regulation mechanism,as one of the five basic healthcare system components,plays an important role in safeguarding the health and life rights of all nationals of a country.The authors explored the construction of such a mechanism and related reform experiences of the healthcare industry in the context of building a healthy China.On such basis,the paper analyzed in depth the connotation of the comprehensive regulation and the existing challenges,in order to propose countermeasures for the establishment of a proactive,comprehensive and coordinated comprehensive regulation mechanism.
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This paper summarizes research progresses of Chinese scholars in the field of drug metabolism and pharmacokinetics (DMPK) in 2018. Chinese scholars focused on drug metabolizing enzymes and transporters, and carried out studies on the mechanisms of drug metabolism and transport of active molecules. Topics of research included regulatory mechanisms of drug metabolizing enzymes or transporters, and their implications in drug development and disease etiology or progression. Here, we summarized studies on drug toxicity based on drug metabolism or transport, rational drug use in the clinic, drug metabolism mediated by intestinal flora, metabolism of traditional Chinese medicines, and new technologies or models in DMPK. In recent years, the research focus of drug metabolism in China has transformed from serving for new drug discovery and rational use, to innovation driven and mechanism oriented research. The domestic research topics and technology utilization are gradually aligning with the international conventions.
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By reviewing the relevant domestic and foreign literature of organic anion transporters(organic anion transporting polypeptides,OATP),the research on subtypes,regulation mechanisms,distribution,effect and influenc- ing factors of OATP is summarized. OTAP acts as a transporter widely distributed in humans and rodents,and their pro- tein structure is not exactly the same in different species. There are also differences in the distribution of OTAP in various organs in the same species,and the ability of OTAP to transport substances is different. When multiple drugs or foods are taken at the same time,they may interact through OATP,resulting in the decreased efficacy and increased adverse reac- tions of drugs. More research is needed on the exploration of OATP subtypes and mechanisms.
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Glucocorticoids ( GCs) have important regulatory effects on skeletal muscle metabolism. GCs can inhibit skeletal muscle glucose uptake and glycogen synthesis, and improve blood glucose levels by inhibiting Pik3rl expression, inhibiting insulin signaling pathway, or promoting pyruvate dehydrogenase kinase 4 expression; GCs can inhibit skeletal muscle lipid metabolism , causing the accumulation of lipid metabolism intermediates diacylglycerol and ceramides, and inducing skeletal muscle insulin resistance; GCs can induce MuRFl and MAFbx expression by promoting FoxO expression, activating the ubiquitin-proteasome system and autophagy lysosome system, and activating oxidative stress system, or promote the protein decomposi-tion of skeletal muscle by up-regulating C/EBPp expression; GCs can also inhibit the mTOR pathway by promoting myostatin and Pik3rl expression and inhibit skeletal muscle protein synthesis by up-regulating KLF-15 expression. This article explores the effects of GCs on skeletal muscle metabolism and its molecular mechanisms by tracking the latest developments at home and a-broad, which will provide reference for the clinical application of GCs.
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To study the effect of in vitro fertilization-embryo transfer (IVF-ET) on the contractile function of mesenteric vessels in offspring mouse model and its regulatory mechanism. Methods Offspring mouse model of IVF-ET (20 weeks after birth) was built to compare with natural born descendant in vascular regulation. The bodyweight and BMI of mice were measured. Serum levels of cardiovascular related cytokines were tested by ELISA and colorimetric method. Samples of mesenteric vascular were from IVF-ET mice and normal controls. Given the vital function in regulating vascular contraction which Ca2+signaling pathway exhibited , four representative genes (Calm2, Itprl, RyR2, RyR3) were selectedfor study. And the mRNA expression levels of Calm2, Itpr2, RyR2, RyR3 were tested by qPCR. The protein expression levels of Calm2 and Itprl were tested by Western blot. Results Mice born under IVF-ET showed increased bodyweight and abnormal BMI after 20th week, and the serum levels of NO and Ang II were significantly higher than those of control (P < 0. 0 5) . The expression levels of Calm2, Itprl were up-regulated both in molecular and protein levels (P <0. 0 1) , RyR3 was up-regulated in molecular level (P < 0. 01) , while RyR2 was down-regulated in molecular level (P < 0. 0 1) . Conclusions The changes of serological markers and regulatory gene expression level related to vasoconstriction function may be closely related to the increased risk of cardiovascular diseases in IVF-ET offspring.
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OBJECTIVE@#To investigate the expression of cytokine signal suppressor 3 (SOCS3) in colon cancer tissue and the mechanism by which SOCS3 regulates the proliferation and invasion of colon cancer.@*METHODS@#We collected the specimens of tumor tissues and paired adjacent tissues from 80 patients with colon cancer undergoing radical resection in our hospital between July, 2014 and May, 2017, and the expression of SOCS3 in the tissue samples was analyzed using Western blotting. We also transfected colon cancer cell line SW480 with a SOCS3-overexpressing plasmid or a small interference RNA (siRNA) for SOCS3 knockdown, and the changes in the cell proliferation and invasion capacity were evaluated using CCK-8 assay and Transwell assay, respectively. The effect of demethylation and IL-6 treatment on SOCS3 expression and the proliferation and invasion of SW480 cells were observed.@*RESULTS@#Colon cancer tissues showed a lowered expression of SOCS3 compared with the adjacent tissues. Over-expression of SOCS3 significantly inhibited while SOCS3 knockdown obviously promoted the proliferation and invasion of SW480 cells . Demethylation treatment up-regulated SOCS3 expression and inhibited the proliferation and invasion capacity of SW480 cells; IL-6 treatment of the cells caused the reverse changes.@*CONCLUSIONS@#SOCS3 participates in the development and progression of colon cancer and serves as a potential target for colon cancer treatment. In patients with colon cancer, the low expression of SOCS3 possibly as a result of methylation may promote the proliferation and invasion of the cancer cells.
Subject(s)
Humans , Cell Line, Tumor , Cell Proliferation , Colonic Neoplasms , Pathology , Cytokines , Demethylation , Disease Progression , Interleukin-6 , Pharmacology , Neoplasm Invasiveness , Neoplasm Proteins , Metabolism , RNA, Small Interfering , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein , Genetics , Metabolism , TransfectionABSTRACT
Long non-coding RNAs (lncRNAs) are members of RNA that are structurally similar to mRNA. They cannot encode proteins because they do not have a conserved open reading frame. LncRNAs were once regarded as abnormalities or noises or without any biological function after gene transcription. With the further development of research, it has been found that it can participate in normal or abnormal biological processes as an important regulator. LncRNAs are closely related to the development of nervous system function, metabolic disorders and tumors. LncRNAs abnormally expressed in cervical cancer participate in the regulation of various biological processes of cervical cancer by inhibiting or promoting tumors. This article reviews the recent reports on the abnormal regulation, molecular regulation mechanism and potential clinical application of lncRNAs in cervical cancer.
Subject(s)
Female , Humans , RNA, Long Noncoding , RNA, Messenger , Uterine Cervical Neoplasms , GeneticsABSTRACT
MicroRNA (miRNA) is a kind of important gene expression regulatory molecules during biological process, but its regulation mechanism in metabolic process of bone tissues has not been completely clarified. In this review, the regulation of miRNA on osteoblast differentiation in microgravity environment was discussed. The positive and negative regulation of miRNA was summarized, respectively, with focus on introducing the mechanism of different genes. Some miRNA molecules that have important effects on bone metabolism under microgravity were enumerated. MiRNA plays an important role in regulating and controlling bone metabolic diseases in microgravity environment, and its related studies are significant for the prevention and treatment of bone loss induced by weightlessness.
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Objective To address the protective role Huangqi Jianzhong Decoction (HQJZ) against chronic atrophic gastritis (CAG) in rats with metabolites in serum, and illuminate its regulative approaches to the targets. Methods CAG rat model was constructed by alternant administrations of ammonia solution and sodium deoxycholate, combined with the hunger disorder method. Rats were randomly separated into five groups: control group, model group, positive group (teprenone), low-dose group, medium-dose group, and high-dose group of HQJZ for continuous ig administration for four weeks. Body weight, biochemical indexes, and histopathological exam were used to evaluate the efficacy of HQJZ after the model replicated successfully. 1H NMR-based metabonomics was employed to analyze the plasma metabolic features of HQJZ deviated from CAG rats. Partial least square regression analysis (PLS-RA) and MetPA analysis were utilized to explore the relevant pathways and the underlying mechanism involved in HQJZ against CAG. Results The pharmacodynamic results demonstrated that HQJZ possessed beneficial activities in treating CAG, which partially ascribed to the improvement of gastric PA and antioxidant system in vivo. A total of 18 plasma metabolites were selected as the potential biomarkers related to the development of CAG, 10 out of them including 3-hydroxybutyrate, lactate, acetate, succinate, etc. were significantly regulated by HQJZ. Three regulation pathways: arginine and proline metabolism, glycerolipid metabolism, and glycine, serine and threonine metabolism, were recognized to be the most relevant efficacy of HQJZ against CAG based on PLS-RA and MetPA analysis. Conclusion The efficacy of HQJZ against CAG were ascribed to the improvement of the pathological changes due to its regulation to the energy imbalance, excessive oxidative stress, immune disorders, as well as inflammation.
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Ischemic heart disease is a leading cause of morbidity and mortality throughout the world which is a serious threat to human health. Tanshinone IIA is a major lipophilic component extracted from the roots of Salvia miltiorrhiza. Studies have shown that tanshinone IIA has a variety of anti-cardiovascular diseases, and its mechanism is related to the regulation of myocardial cell apoptosis and autophagy. This article discusses the signaling pathways and their correlations related to apoptosis and autophagy in ischemic heart disease. The recent advances about the regulation of apoptosis and autophagy in the treatment to ischemia heart disease by tanshinong IIA were summarized. The mechanism of regulating apoptosis and autophagy to produce cardiovascular protection was discussed. This paper will provide a basis for in-depth study of ischemic heart disease and the development and utilization of drugs.
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Plateau environment has the characteristic of low ox-ygen and low pressure, which leads to a series of physiological changes and affects the process of drug metabolism in the body. Many factors affect the pharmacokinetic parameters, including gastric emptying, blood rheology, cardiopulmonary function, hepatorenal function, cytochrome P450 enzyme and so on. The present study focuses on drug metabolic enzymes, since drug transporter is the key factor that mediates drugs in their entrance to the body through the cell membrane, producing the curative effect. In order to provide the reference to further research on the effect of plateau hypoxia on pharmacokinetics and guide the rational use of drugs, we review in this paper the classification of the transporter, mediated drug substrates, the influence of hypoxia on expression levels of drug transporter substrates and the regulatory mechanism of drug transporter under the condition of hypoxia.
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@#With the development of implant dentistry and biomaterials, dental implants have become the first rehabilitative option proposed for the treatment of missing teeth. Most studies about dental implants and biomaterials currently focus on osteogenesis and the osseointegration of the implant, neglecting the importance of the immune response. In recent years, the development of osteoimmunology has been one of the greatest achievements in bone biomaterials; osteoimmunology has revealed the vital role of immune cells in regulating bone dynamics, implying the value of studies on materials with favorable osteoimmunomodulatory properties. This article reviews the integration between bone tissue and implants and summarizes the effects of the immune response during osseointegration and new bone formation to show the importance of regulating the immune response in this process. The effect of macrophages on osteogenesis and osteoclastogenesis is then reviewed due to the high plasticity and multiple roles of macrophages during this process. Accordingly, the interaction between the implants, the immune systems and the skeletal system is explained, showing the potential value of osteoimmunomodulation as a biological principle for developing bone biomaterials and new types of implants.