Genetic Inactivation of ZCCHC6 Suppresses Interleukin‐6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice.
ANIMAL experimentation; CARTILAGE; CARTILAGE cells; DACTINOMYCIN; DNA-binding proteins; GENE expression; GENETIC aspects; IN vivo studies; INTERLEUKINS; MICE; MICRORNA; OSTEOARTHRITIS; PREVENTION; SEQUENCE analysis; SEVERITY of illness index; SYNOVITIS; TRANSCRIPTION factors
Objective: Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin‐6 (IL‐6) in patients with osteoarthritis (OA) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme ZCCHC6 (zinc‐finger CCHC domain–containing protein 6; TUT‐7) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in OA pathogenesis is unknown. The present study was undertaken to investigate whether ZCCHC6 directs the expression of IL‐6 and influences OA pathogenesis in vivo. Methods: Human and mouse chondrocytes were stimulated with recombinant IL‐1β. Expression of ZCCHC6 in human chondrocytes was knocked down using small interfering RNAs. IL‐6 transcript stability was determined by actinomycin D chase, and 3′‐uridylation of microRNAs was determined by deep sequencing. Zcchc6−/− mice were produced by gene targeting. OA was surgically induced in the knee joints of mice, and disease severity was scored using a semiquantitative grading system. Results: ZCCHC6 was markedly up‐regulated in damaged cartilage from human OA patients and from wild‐type mice with surgically induced OA. Overexpression of ZCCHC6 induced the expression of IL‐6, and its knockdown reduced IL‐6 transcript stability and IL‐1β–induced IL‐6 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6−/− mouse chondrocytes rescued the IL‐1β–induced IL‐6 expression. Knockdown of ZCCHC6 reduced the population of micro‐RNA 26b (miR‐26b) with 3′‐uridylation by 60%. Zcchc6−/− mice with surgically induced OA produced low levels of IL‐6 and exhibited reduced cartilage damage and synovitis in the joints. Conclusion: These findings indicate that ZCCHC6 enhances IL‐6 expression in chondrocytes through transcript stabilization and by uridylating miR‐26b, which abrogates repression of IL‐6. Inhibition of IL‐6 expression and significantly reduced OA severity in Zcchc6−/− mice identify ZCCHC6 as a novel therapeutic target to inhibit disease pathogenesis. [ABSTRACT FROM AUTHOR]
Ansari Mohammad Y; Khan Nazir M; Ahmad Nashrah; Green Jonathan; Novak Kimberly; Haqqi Tariq M
Arthritis & Rheumatology
2019
2019-04
<a href="http://doi.org/10.1002/art.40751" target="_blank" rel="noreferrer noopener">10.1002/art.40751</a>
Pomegranate Bioactive Constituents Suppress Cell Proliferation and Induce Apoptosis in an Experimental Model of Hepatocellular Carcinoma: Role of Wnt/β-Catenin Signaling Pathway.
Immunohistochemistry; Gene Expression; Apoptosis; Rats; Pomegranate; Post Hoc Analysis; One-Way Analysis of Variance; Structural Equation Modeling; Experimental Studies; Protocols; Carcinoma; Blotting; Western; Hepatocellular; Animal Studies; In Vivo Studies
Bhatia Deepak; Thoppil Roslin J; Mandal Animesh; Samtani Karishma A; Darvesh Altaf S; Bishayee Anupam
Evidence-based Complementary & Alternative Medicine (eCAM)
2013
2013-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2013/371813" target="_blank" rel="noreferrer noopener">10.1155/2013/371813</a>
Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload.
Mice; Gene Expression Profiling; Signal Transduction; Echocardiography; Staining and Labeling; Descriptive Statistics; Funding Source; Post Hoc Analysis; One-Way Analysis of Variance; T-Tests; Blotting; Western; Animal Studies; In Vivo Studies; Vasoconstriction; Phosphorylation – Drug Effects; Aorta – Physiopathology; Heart Diseases – Prevention and Control; Hypertrophy – Prevention and Control; Plant Extracts – Therapeutic Use; Protein Kinases – Antagonists and Inhibitors
Qi Jianyong; Liu Qin; Gong Kaizheng; Yu Juan; Wang Lei; Guo Liheng; Zhou Miao; Wu Jiashin; Zhang Minzhou
Evidence-based Complementary & Alternative Medicine (eCAM)
2014
2014-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2014/769515" target="_blank" rel="noreferrer noopener">10.1155/2014/769515</a>
Chemopreventive and therapeutic potential of tea polyphenols in hepatocellular cancer.
*Anticarcinogenic Agents; Animal; Animals; Anti-Inflammatory Agents; Antioxidants; Biological Availability; Biological Markers; Carcinoma; Catechin/administration & dosage/analogs & derivatives; Chemoprevention; Disease Models; Hepatocellular – Physiopathology; Hepatocellular – Prevention and Control; Hepatocellular – Therapy; Human; Humans; In Vitro Studies; In Vivo Studies; Liver Neoplasms/*drug therapy/*prevention & control; Mice; Neoplasms – Prevention and Control; Nutrition; Outcomes (Health Care); Phenols – Therapeutic Use; Polyphenols/*administration & dosage/pharmacology; Tea – Therapeutic Use; Tea/*chemistry; Xenograft Model Antitumor Assays
The prophylactic and therapeutic properties of tea have been attributed to green tea catechins and black tea theaflavins besides several other polyphenolic compounds. Tea polyphenols possess potent antioxidant and antiinflammatory properties and modulate several signaling pathways. These biochemical facets of tea polyphenols are responsible for its anticancer properties. Several lethal cancers, such as liver cancer, develop within a background of oxidative stress and inflammation. Liver cancer, also known as hepatocellular carcinoma (HCC), has been shown to occur throughout the world including Asia, Africa, Western Europe, and the United States. Phytochemicals, such as tea polyphenols, provide an effective and promising alternative for the chemoprevention and treatment of HCC. In this article, we systematically review, for the first time, the effects of tea polyphenols in the preclinical in vitro and in vivo HCC models. The review also examines, in critical detail, the biochemical mechanisms involved in the chemopreventive and antineoplastic effects of tea polyphenols in hepatic cancer. Finally, we highlight the role of synergy, bioavailability and pharmacokinetics of tea polyphenols, current status of clinical trials, discuss future directions, and comment on the future challenges involved in the effective use of tea polyphenols for the prevention and management of liver cancer.
Darvesh Altaf S; Bishayee Anupam
Nutrition and cancer
2013
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1080/01635581.2013.767367" target="_blank" rel="noreferrer noopener">10.1080/01635581.2013.767367</a>
Salvianolate reduces murine myocardial ischemia and reperfusion injury via ERK1/2 signaling pathways in vivo.
*MAP Kinase Signaling System/drug effects; Animal Studies; Animals; Blotting; Cardiotonic Agents/pharmacology/therapeutic use; Chinese medicine; Descriptive Statistics; extracellular signal-regulated kinase 1/2; Flavonoids/pharmacology; Heart Ventricle; Heart Ventricles/drug effects/pathology; In Vivo Studies; Inbred C57BL; ischemia and reperfusion injury; Left; Male; Mice; Mitogen-Activated Protein Kinase 1/*metabolism; Mitogen-Activated Protein Kinase 3/*metabolism; Molecular Structure; Myocardial Ischemia – Drug Therapy; Myocardial Reperfusion Injury – Drug Therapy; Myocardial Reperfusion Injury/*drug therapy/enzymology/pathology; Organ Size/drug effects; P-Value; Phosphorylation; Phosphorylation/drug effects; Plant Extracts – Administration and Dosage; Plant Extracts/chemistry/pharmacology/*therapeutic use; protein kinase B; Protein Kinase Inhibitors – Administration and Dosage; Protein Kinase Inhibitors/pharmacology; Protein Kinases – Analysis; Protein Kinases – Drug Effects; salvianolate; Signal Transduction; Staining and Labeling; Western
OBJECTIVE: To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury. METHODS: Myocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes. RESULTS: There were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P\textgreater0.05). The SAL and IPC groups had IS of 26.1%+/-1.4% and 22.3%+/-2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5%+/-2.9% of RR, P\textless0.05, P\textless0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P\textless0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively). CONCLUSION: Salvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.
Qi Jianyong; Yu Juan; Huang Dong-Hui; Guo Liheng; Wang Lei; Huang Xin; Huang Hai-Ding; Zhou Miao; Zhang Minzhou; Wu Jiashin
Chinese journal of integrative medicine
2017
2017-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s11655-016-2621-z" target="_blank" rel="noreferrer noopener">10.1007/s11655-016-2621-z</a>