摘要：
The beta 1-adrenergic receptor (AR) is the primary beta-AR subtype in the heart and is the target of metoprolol (Met), which is commonly used to treat angina and hypertension. Previous studies have revealed a positive correlation between the methylation levels of the adrenoreceptor beta 1 gene (Adrb1) promoter in the myocardium with the antihypertensive activity of Met in spontaneously hypertensive rats (SHR), which affects beta 1-AR expression in H9C2 cells. The aim of the present study was to investigate the effects of myocardial beta 1-AR downregulation using short-hairpin RNA (shRNA) against Adrb1 on the antihypertensive activity of Met in SHR. Recombinant adeno-associated virus type 9 (rAAV9) vectors carrying Adrb1 shRNA (rAAV9-Adrbl) or a negative control sequence (rAAV9-NC) were generated and used to infect rat hearts via the pericardial cavity. The results of reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting analyses demonstrated that cardiac beta 1-AR expression in the rAAV9-Adrbl group was significantly downregulated when compared with the rAAV9-NC group (P<0.001, P<0.001 and P=0.032, respectively). In addition, a greater reduction in systolic blood pressure (SBP) was observed in the rAAV9-NC group compared with the rAAV9-Adrbl group following Met treatment (P=0.035). Furthermore, downregulation of myocardial beta 1-AR was associated with a significant decrease in SBP (P<0.001). In conclusion, these data suggest that suppression of beta 1-AR expression in the myocardium reduces SBP and sensitivity to Met in SHR.
作者机构：
[Zeng, Bijun; Wang, Chang; Tang, Xueyong; Wang, Haizhen; Shen, Hui; Yang, Zhibo; Liu, Wen] Hunan Univ Chinese Med, Dept Dermatol, Affiliated Hosp 2, Changsha 410005, Hunan, Peoples R China.;[Shen, Hui] Guanxi Univ Chinese Med, Dept Dermatol, Ruikang Hosp, Nanning 530000, Guangxi Provinc, Peoples R China.;[Yang, Zhibo] 233 Caie North Rd, Changsha 410005, Hunan, Peoples R China.
通讯机构：
[Yang, Zhibo] 2;233 Caie North Rd, Changsha 410005, Hunan, Peoples R China.
关键词：
MiR-330;IL-22;CTNNB1;Keratinocyte;Psoriasis
摘要：
Psoriasis is a common chronic inflammatory skin disease which is characterized by hyperproliferation and aberrant differentiation of keratinocytes; however the exact pathogenesis is largely unknown. Interleukin-22 (IL-22) has demonstrated its vital role in T cell-mediated immune response by interacting with keratinocytes in the pathogenesis of psoriasis. The microRNAs (miRNAs) are a class of small noncoding RNA molecules that play important roles in cellular processes by regulating gene expression at the post-transcriptional level. MiR-330 has been reported to inhibit the proliferation and migration of mouse keratinocytes. In the present study, we indicated that miR-330 expression in lesion tissue of psoriasis patients was specifically down-regulated, and could inhibit IL-22-induced proliferation of HaCaT and HKC cell. Wnt/beta-catenin pathway plays an essential role in the pathogenesis of psoriasis. By direct targeting CTNNB1, miR-330 could significantly downregulate IL-22-induced CTNNB1 expression. In addition, we found that the downstream targets of b-catenin, CyclinD1 and Axin2, could be affected by miR-330; miR-330 could suppress CyclinD1 protein expression and rescue Axin2 protein expression. Taken together, we indicated miR-330 inhibits IL-22-induced proliferation of HaCaT and HKC cell by targeting CTNNB1 and subsequently affect the downstream factors, CyclinD1 and Axin2 for the first time, and provide diagnostic markers and a novel target for psoriasis treatment. (C) 2017 Published by Elsevier Masson SAS.
作者机构：
[He, Xiaojuan; Lu, Aiping; Niu, Xuyan; Tan, Yong; Lu, Cheng] China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing, Peoples R China.;[Liu, Xinru; Zhang, Weidong; Zu, Xianpeng] Second Mil Med Univ, Sch Pharm, Shanghai, Peoples R China.;[Zhou, Ke] Hunan Univ Chinese Med, Affiliated Hosp 2, Changsha, Hunan, Peoples R China.;[Lu, Aiping; Zhang, Weidong; Lu, AP; Zhang, Ge; He, Bing; Bian, Zhaoxiang; Xu, Gang] Hong Kong Baptist Univ, Sch Chinese Med, Inst Adv Translat Med Bone & Joint Dis, Hong Kong, Hong Kong, Peoples R China.;[Xiao, Cheng] China Japan Friendship Hosp, Beijing, Peoples R China.
通讯机构：
[Lu, Aiping] C;[Zhang, Weidong; Lu, Aiping] S;[Zhang, G; Lu, AP] H;China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing, Peoples R China.;Second Mil Med Univ, Sch Pharm, Shanghai, Peoples R China.
摘要：
Hyperuricemia (HU) often progresses to combine with non-alcoholic fatty liver disease (NAFLD) in the clinical scenario, which further exacerbates metabolic disorders; early detection of biomarkers, if obtained during the HU progression, may be beneficial for preventing its combination with NAFLD. This study aimed to decipher the biomarkers and mechanisms of the development of steatosis in HU. Four groups of subjects undergoing health screening, including healthy subjects, subjects with HU, subjects with HU combined with NAFLD (HU+NAFLD) and subjects with HU initially and then with HU+NAFLD one year later (HU-->HU+NAFLD), were recruited in this study. The metabolic profiles of all subjects' serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. The metabolomic data from subjects with HU and HU+NAFLD were compared, and the biomarkers for the progression from HU to HU+NAFLD were predicted. The metabolomic data from HU-->HU+NAFLD subjects were collected for further verification. The results showed that the progression was associated with disturbances of phospholipase metabolism, purine nucleotide degradation and Liver X receptor/retinoic X receptor activation as characterized by up-regulated phosphatidic acid, cholesterol ester (18:0) and down-regulated inosine. These metabolic alterations may be at least partially responsible for the development of steatosis in HU. This study provides a new paradigm for better understanding and further prevention of disease progression.
摘要：
The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-kappa B expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-kappa B, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF-kappa B inhibitor CAPE. Hmgb1 knockdown activated, but exogenous Hmgb1 inactivated, p-IGF1R/p-PI3K p-85/p-Akt/p-mTOR signaling. Knockdown of Klotho gene expression significantly decreased apoptosis, increased invasion in melanoma cells, and inhibited xenograft A375 tumor growth. A significantly high percentage of cells stained positive for p-NF-kappa B, but negative for Klotho, in melanoma tissues compared to normal and benign skin tissues. The positive p-NF-kappa B and negative Klotho protein expression correlated with poor prognosis in melanoma patients. Multivariate analysis revealed an independent association between p-NF-kappa B / Klotho protein level and overall survival. In conclusion, Hmgb1 can inhibit Klotho gene expression and malignant phenotype in melanoma cells through activation of NF-kappa B signaling.
摘要：
Malignant melanoma is the most aggressive type of skin cancer. RAB22A, a member of RAS oncogene family, has been found to be significantly upregulated in multiple human cancers. In the present study, we found that RAB22A mRNA expression was significantly upregulated in melanoma tissues (including 60 primary melanomas and 84 metastatic melanomas) compared to benign nevi (n = 20), which were significantly higher in metastatic melanoma tissues than primary tissues. Immunohistochemistry data further showed that the positive immunoreactivity of RAB22A was detected in 66% (95/144) melanoma tissues, but not in benign nevi. Moreover, high expression of RAB22A was significantly associated with advanced clinical stage in melanoma. Furthermore, patients with high RAB22A expression had shorter overall survival compared those with low expression of RAB22A. In-vitro study showed that RAB22A was also upregulated in melanoma cell lines WM35, A375, WM451, and SK-MEL-1, when compared with the normal melanocyte HM cells. Knockdown of RAB22A significantly reduced the proliferation, migration and invasion of melanoma A375 cells, while overexpression of RAB22A significantly promoted these malignant phenotypes. In addition, RAB22A was found to be a target of miR-203, a tumor suppressive miRNA in melanoma. Besides, miR-203 was downregulated in melanoma tissues and cell lines, when compared with benign nevi and HM cells, respectively. Taken these findings together, our study could validate an oncogenic role of RAB22A in melanoma, suggesting that RAB22A may be a potential therapeutic target for melanoma.
摘要：
The present study aimed to investigate the effect of co-culture of fibroblast-like synoviocytes (FLS) with human umbilical cord-mesenchymal stem cells (UC-MSCs) on rheumatoid arthritis (RA) and to understand the mechanisms that mediate the induced changes. FLS and UC-MSCs were isolated and cultured individually, FLS were then cultured with or without UC-MSCs. The phenotype of UC-MSCs was analyzed prior to co-culture. The UC-MSCs were successfully isolated and expanded, and exhibited a fibroblast-like morphology. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to determine the expression levels of interleukin (IL)-1β, IL-6, and chemokine (C-C motif) ligand (CCL)-2. The cell apoptosis rate was determined by flow cytometry. Furthermore, the RNAs of aggrecan and collagen type II were isolated and assessed in a chondrogenesis assay following co-culture for 7, 14, 21 and 28 days. Protein expression levels of apoptosis-related proteins, including B-cell lymphoma (Bcl-2), Bcl-2-associated X protein, p53 and phospho (p)-AKT, and growth differentiation factor-5 were analyzed by western blotting. ELISA and qRT-PCR demonstrated that compared with FLS cultured alone, co-culture with UC-MSCs significantly downregulates the expression levels of IL-1β, IL-6 and CCL-2. Additionally, the percentage of apoptotic cells was significantly increased in the co-cultured cells (P<0.05), and the relative RNAs levels of aggrecan and collagen type II were increased compared with FLS alone. Furthermore, the expression levels of Bcl-2 (P<0.05) and p-AKT (P<0.05) were significantly decreased, whereas, p53 (P=0.001), Bax (P<0.01) and GDF-5 (P<0.01) were increased by co-culture of FLS with UC-MSCs compared with FLS alone. In conclusion, co-culture of FLS with UC-MSCs may be important and clinically useful for the treatment of RA by inhibiting the expression of pro-inflammatory mediators, inducing apoptosis and promoting chondrogenesis.
作者：
Su, Feng;Zhu, Shilin;Ruan, Jinlan;Muftuoglu, Yagmur;Zhang, Longbo*;...
期刊：
Oncotarget,2016年7(4):4142-4154 ISSN：1949-2553
通讯作者：
Yuan, Qianying;Zhang, Longbo
作者机构：
[Su, Feng] Cent S Univ, Xiangya Hosp, Dept Emergency, Changsha, Hunan, Peoples R China.;[Zhu, Shilin] Hunan Univ Chinese Med, Affiliated Hosp 2, Changsha, Hunan, Peoples R China.;[Yuan, Qianying; Ruan, Jinlan] Huazhong Univ Sci & Technol, Dept Pharmacol, Wuhan 430074, Peoples R China.;[Muftuoglu, Yagmur; Yuan, Qianying] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA.;[Zhang, Longbo] Cent S Univ, Xiangya Hosp, Dept Neurosurg, Changsha, Hunan, Peoples R China.
通讯机构：
[Yuan, Qianying] H;[Yuan, Qianying] Y;[Zhang, Longbo] C;Huazhong Univ Sci & Technol, Dept Pharmacol, Wuhan 430074, Peoples R China.;Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA.
关键词：
Notch;RY10-4;breast cancer;resistance
摘要：
RY10-4, a novel protoapigenone analog, shows potent cytotoxicity against human breast cancer cells. However, breast cancer cell lines overexpressing human epidermal growth factor receptor 2 (HER2), SKBR3 and BT474, showed less sensitivity to RY10-4 when compared to breast cancer cells lines expressing lower levels of HER2, such as MDA-MB-231 and MCF-7 cells. This was associated with aberrant hyperactivity in Notch signaling in cells treated with RY10-4, since treatment with RY10-4 causes an increase in Notch activity by 2-to3.5-fold in SKBR3 and BT474 cell lines. The increase in activity was abrogated with a gamma-secretase inhibitor, DAPT, or with Notch1 small-interfering RNA (si-Notch1). Cell proliferation was inhibited more effectively by RY10-4 plus DAPT or si-Notch1 than either agent alone. RY10-4 plus DAPT increases apoptosis in both HER2-overexpressing cell lines by two-fold compared to RY10-4 alone, while DAPT alone has no significant effects on apoptosis. In addition, we previously found RY10-4 could inhibit tumor growth through the PI3K/AKT pathway. Here we report that the combination of RY10-4 and DAPT exhibit additive suppression on AKT phosphorylation, contributing to the anti-cancer effects. In an animal model, this combination therapy inhibits the growth of SKBR3 tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. These results indicate that the aberrant activation of Notch signaling impedes the inhibitory effect of RY10-4 on HER2-amplified cell proliferation. Furthermore, these adverse effects can be prevented by treatment combining RY10-4 with a Notch pathway inhibitor.
摘要：
Objective: The aim of the present study was to investigate the effects of Longdanxiegan formula granule (LDXGFG), a Chinese traditional medicine on Toll-like receptor (TLR) pathway in recurrent genital herpes. Materials and Methods: An experimental recurrent genital herpes model was constructed using herpes guinea pig model. The effect of LDXGFG on expression levels of TLR pathway genes were detected using real-time polymerase chain reaction. Furthermore, the dendritic cells and Langerhans cells were isolated and the TLR pathway genes of these cells were assayed after LDXGFG treatment. Results: The result suggested two different expression patterns of TLR pathway genes in genital herpes and recurrent genital herpes, including upregulated genes and downregulated genes. TLR1, TLR4, TLR6, TLR7, TLR8, TLR9, and TLR10 showed a significant decrease while, TLR2, TLR3, and TLR5 increased in genital herpes and recurrent genital herpes guinea pigs. Meanwhile, the downregulated genes in genital herpes and recurrent genital herpes were stimulated by LDXGFG. By contrast, the upregulated genes decreased significantly after LDXGFG treatment. In both dendritic cells and Langerhans cells, the TLR pathway genes exhibited same pattern: the LDXGFG corrected the abnormal expression of TLR pathway genes. Conclusion: The present results suggest that LDXGFG is an alternative, inexpensive, and lasting-effect medicine for herpes simplex virus 2 infection. Copyright (C) 2016, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC.
摘要：
Numb, an endocytic adaptor, is a known cell fate determinant that participates in asymmetric cell division. The present study aimed to explore the potential roles of Numb in hepatocarcinogenesis. Numb expression was investigated in hepatocellular carcinomas (HCC) with reverse transcription-quantitative polymerase chain reaction and immunohistochemical examination; its association with the prognosis of HCC patients was analyzed. In addition, the effects of Numb deletion on proliferation of HCC cells and its relevant molecules were evaluated in Huh7 and HepG2 cells. Numb overexpression was observed in 62% of adjacent non-tumor tissues and 46% of tumor tissues. Overexpression of Numb in HCC was associated with histological grade, portal vein invasion and the number of tumors (P=0.001, 0.022 and 0.034 respectively). Multivariate analysis revealed that Numb expression was an independent prognostic indicator of HCC patients. Methylation of the Numb promoter contributed to hepatocarcinogenesis. In vitro assays demonstrated that Numb silencing resulted in inhibition of cell proliferation, induction of apoptosis, down-regulation of cyclin-dependent protein kinase 4 (CDK4) and S-phase kinase-associated protein 2 (SKP2), and upregulation of Bcl-2 homologous antagonist/killer (BAK) and cyclin-dependent kinase inhibitor 1 (p21). The present study suggests that downregulation of Numb inhibits colony formation and cell proliferation, induces apoptosis of HCC cells and independently predicts the poor prognosis of HCC patients. Thus, Numb has a potential role in the development and progression of HCC.
摘要：
Introduction: Psoriasis is a common and recurrent disease and difficult to treat. The aim was to develop an evidence-based clinical practice guideline of Chinese herbal medicine (CHM) for psoriasis vulgaris with focus on Chinese medicine pattern differentiation and treatment as well as approved herbal proprietary medicine. Methods: The guideline development group involved in various expertise in contents and methods. Authors searched electronic databases include CNKI, VIP, Sino-Med, Wanfang data, PubMed, the Cochrane Library, EMBASE, as well as checked China State Food and Drug Administration (SFDA) from the inception till March 31, 2013. Systematic reviews and randomized controlled trials of Chinese herbal medicine treating adults with psoriasis vulgaris were evaluated. Risk of bias tool in the Cochrane Handbook and evidence strength developed by the GRADE group were applied for the evaluation, and recommendations were based on the findings incorporating evidence strength. After several rounds of expert consensus, the final guideline was endorsed by relevant professional committees. Results: CHM treatment principle and formulae based on pattern differentiation together with approved patent herbal medicines are the main treatments for psoriasis vulgaris, and the diagnosis and treatment focusing on blood related patterns is the major domain. Conclusion: CHM therapy alone or combined with other conventional treatment reported in clinical studies together with expert consensus were recommended for clinical practice. (C) 2014 Elsevier GmbH. All rights reserved.
期刊：
Experimental and Therapeutic Medicine,2014年8(2):430-434 ISSN：1792-0981
通讯作者：
He, Yong-Heng
作者机构：
[Luo, Min; He, Yong-Heng; Hu, Xiang-Dang; Peng, Tian-Shu; Lu, Hai-Yan] Hunan Univ Chinese Med, Dept Anorectal Dis, Affiliated Hosp 2, Changsha 410005, Hunan, Peoples R China.;[Yi, Jian; Nie, Tian; Shuai, Yun-Fei] Hunan Univ Chinese Med, Affiliated Hosp 1, Dept Blood & Oncol, Changsha 410007, Hunan, Peoples R China.;[He, Yong-Heng] Hunan Univ Chinese Med, Dept Anorectal Dis, Affiliated Hosp 2, 233 Caie North Rd, Changsha 410005, Hunan, Peoples R China.
通讯机构：
[He, Yong-Heng] H;Hunan Univ Chinese Med, Dept Anorectal Dis, Affiliated Hosp 2, 233 Caie North Rd, Changsha 410005, Hunan, Peoples R China.
关键词：
PPM1D;biomarker;colorectal cancer;prognosis
摘要：
Protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) has been associated with carcinogenesis. The present study investigated PPM1D expression as a potential biomarker in colorectal cancer (CRC). PPM1D expression was assessed using immunohistochemistry in 368 patients with CRC. The correlation between PPM1D expression, clinicopathological features and prognosis was analyzed. PPM1D small interfering (si)RNA-induced PPM1D silencing was performed in CRC cell lines to assess the effect of PPM1D on tumor cell proliferation and invasion in vitro. A total of 68.48% (252/368) of the CRC samples displayed high PPM1D expression. By contrast, only 9.24% (34/368) of the matched non-cancerous tissue samples exhibited high PPM1D expression. High PPM1D expression was correlated with node metastasis (P=0.0024), distant metastasis (P<0.001) and TNM stage (P=0.0016). Kaplan-Meier survival analysis revealed that patients with low PPM1D expression had significantly longer survival than those with high PPM1D expression (P=0.012). Moreover, multivariate analyses demonstrated that high PPM1D expression was an independent prognostic factor for overall survival (hazard ratio = 0.24; 95% confidence interval, 0.13-0.86; P=0.004). Furthermore, PPM1D gene silencing was found to significantly reduce the proliferation and invasion of CRC cells in vitro. These findings suggest a role for PPM1D as a prognostic marker and potential therapeutic target in CRC.
