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Fan L.,Shanghai University | Wang Q.,Shanghai Zhabei District Central Hospital | Liu R.,Ningxia Medical University | Zong M.,Shanghai University | And 4 more authors.
Arthritis Research and Therapy | Year: 2012

Introduction: Rheumatoid arthritis (RA) is characterized by synovial lining hyperplasia, in which there may be an imbalance between the growth and death of fibroblast-like synoviocytes (FLSs). Antibodies against citrullinated proteins are proposed to induce RA. This study aimed to investigate the pathogenic role of citrullinated fibronectin (cFn) in RA.Methods: The distribution of fibronectin (Fn) and cFn in synovial tissues from RA and osteoarthritis (OA) patients was examined by immunohistochemical and double immunofluorescence analysis. FLSs were isolated from RA and OA patients and treated with Fn or cFn. Apoptosis was detected by flow cytometry and TUNEL assay. The expression of survivin, caspase-3, cyclin-B1, Bcl-2 and Bax was detected by real-time PCR. The secretion of proinflammatory cytokines was measured by ELISA.Results: Fn formed extracellular aggregates that were specifically citrullinated in synovial tissues of RA patients, but no Fn deposits were observed in those of OA patients. Fn induced the apoptosis of RA and OA FLSs while cFn inhibited the apoptosis of RA and OA FLSs. Fn significantly increased the expression of caspase-3 and decreased the expression of survivin and cyclin-B1 in FLSs from RA and OA patients. cFn significantly increased the expression of survivin in RA FLSs. Furthermore, cFn increased the secretion of TNF-α and IL-1 by FLSs.Conclusions: cFn plays a potential pathophysiologic role in RA by inhibiting apoptosis and increasing proinflammatory cytokine secretion of FLSs. © 2012 Fan et al.; licensee BioMed Central Ltd.

Hua R.,Hua Medicine
Zhonghua wei zhong bing ji jiu yi xue | Year: 2013

To investigate the association of traumatic severity with changes in lymphocyte subsets in the early stage after trauma. Sixty-three male patients admitted within 4 hours after trauma were enrolled. According to injury severity score (ISS), the patients were divided into two groups: mild trauma group (ISS<16, n=35) and severe trauma group (ISS≥16, n=28). At admission, the patients peripheral blood were extracted to detect T lymphocytes subsets, blood routine test, blood biochemical and arterial blood gas analysis which were used to calculate the acute physiology and chronic health evaluation II (APACHEII) scores. The correlation of lymphocyte subsets and ISS score, and the correlation of lymphocyte subsets and APACHEII score were both analyzed statistically. Another 20 cases of healthy male adults were enrolled as the control group. Compared with the healthy control group, CD3(+) T cell contents in blood were decreased obviously in mild trauma group and severe trauma group (0.648±0.112, 0.647±0.110 vs. 0.708±0.082, both P<0.05); CD4(+) T cells contents in severe group were decreased significantly (0.317±0.086 vs. 0.389±0.064, P<0.05), and natural killer (NK) cells were significantly increased (0.217±0.107 vs. 0.158±0.068, P<0.05). B cells content in severe group was decreased significantly than that of mild group (0.114±0.060 vs. 0.155±0.075, P<0.05). There were no significant difference in CD8(+) and CD4/CD8 ratio among the healthy control group, mild trauma group and severe trauma group (CD8(+): 0.260±0.074, 0.260±0.091, 0.271±0.105; CD4/CD8 ratio: 1.69±0.75, 1.56±0.83, 1.34±0.65, all P>0.05). Except that there were negative correlation between CD3(+) T cells and the ISS scores (r=-0.42, P=0.03), the other lymphocyte subsets showed no correlation with the ISS scores and the APACHEII scores (mild trauma group with ISS scores: CD3(+) r=-0.10, CD4(+) r=-0.31, CD8(+) r=0.18, B cells r=0.20, NK cells r=-0.04; mild trauma group with APACHEII scores: CD3(+) r=0.04, CD4(+) r=-0.07, CD8(+) r=0.06, B cells r=-0.10, NK cells r=0.05, severe trauma group with ISS scores: CD4(+) r=-0.12, CD8(+) r=-0.17, B cells r=0.02, NK cells r=0.31,all P>0.05;severe trauma group with APACHEII scores:CD3(+) r=-0.24, CD4(+) r=0.11, CD8(+) r=-0.26, B cells r=0.15, NK cells r=0.08, all P>0.05). CD3(+) and CD4(+) T cells decreased and NK cells increased significantly in blood in the early stage after severe trauma. CD3(+) T cells are independent indexes which reflect body injury. Therefore, it is necessary to monitor the changes of immune cells dynamically after severe trauma.

Wang P.,Yale University | Yang L.,Yale University | Cheng G.,Yale University | Cheng G.,Hua Medicine | And 9 more authors.
Cell Reports | Year: 2013

RNA viruses are sensed by RIG-I-like receptors (RLRs), which signal through a mitochondria-associated adaptor molecule, MAVS, resulting in systemic antiviral immune responses. Although RLR signaling is essential for limiting RNA virus replication, it must be stringently controlled to prevent damage from inflammation. We demonstrate here that among all tested UBX-domain-containing protein family members, UBXN1 exhibits the strongest inhibitory effect on RNA-virus-induced type I interferon response. UBXN1 potently inhibits RLR- and MAVS-induced, but not TLR3-, TLR4-, or DNA-virus-induced innate immune responses. Depletion of UBXN1 enhances virus-induced innate immune responses, including those resulting from RNA viruses such as vesicular stomatitis, Sendai, West Nile, and dengue virus infection, repressing viral replication. Following viral infection, UBXN1 is induced, binds to MAVS, interferes with intracellular MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. These findings underscore a critical role of UBXN1 in the modulation of a major antiviral signaling pathway. © 2013 The Authors.

Zeng J.-P.,Dong - A University | Bi B.,Hua Medicine | Chen L.,Dong - A University | Yang P.,Dong - A University | And 3 more authors.
Journal of Dermatological Science | Year: 2014

Background: Photoaging skin is due to accumulative effect of UV irradiation that mainly imposes its damage on dermal fibroblasts. To mimic the specific cellular responses invoked by long term effect of UVB, it is preferable to develop a photo-damaged model in vitro based on repeated UVB exposure instead of a single exposure. Objective: To develop a photo-damaged model of fibroblasts by repeated UVB exposure allowing for investigation of molecular mechanism underlying premature senescence and testing of potential anti-photoaging compounds. Methods: Mouse dermal fibroblasts (MDFs) at early passages (passages 1-3) were exposed to a series of 4 sub-cytotoxic dose of UVB. The senescent phenotypes were detected at 24 or 48. h after the last irradiation including cell viability, ROS generation, mitochondrial membrane potential, cell cycle, production and degradation of extracellular matrix. Results: Repeated exposure of UVB resulted in remarkable features of senescence. It effectively avoided the disadvantages of single dose such as induction of cell death rather than senescence, inadequate stress resulting in cellular self-rehabilitation. Conclusion: Our work confirms the possibility of detecting cellular machinery that mediates UVB damage to fibroblasts in vitro by repeated exposure, while the potential molecular mechanisms including cell surface receptors, protein kinase signal transduction pathways, and transcription factors remain to be further evaluated. © 2013 Japanese Society for Investigative Dermatology.

Zhu J.,Hua Medicine | Wu L.,Wuhan University of Science and Technology | Kohlmeier M.,University of North Carolina at Chapel Hill | Ye F.,Wuhan University of Science and Technology | Cai W.,Hua Medicine
Molecular Medicine Reports | Year: 2013

Numerous case-control studies on the association between polymorphisms of key genes involved in methionine remethylation [methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS)] and the susceptibility of cervical intraepithelial neoplasia (CIN) and cervical cancer have provided inconclusive results. The aim of the present meta-analysis was to determine the effects of two MTHFR (C677T and A1298C) and one MS gene polymorphism (A2756G) on the risk of CIN II/III or cervical cancer. Relevant data were retrieved following a systematic search in PubMed, Web of Science, MEDLINE and Wanfang Data up to November 2012. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated from eligible studies by meta-analysis with subgroup analyses stratified by ethnicity. A total of 13 studies with 1,936 cases and 2,858 controls were included in the present meta-analysis. An increased risk of cervical cancer was found in Asian women with the MTHFR 677T allele (TT vs. CC: OR=1.41, 95% CI=1.07-1.86, P=0.01; TT vs. CC+CT: OR=1.38, 95% CI=1.08-1.75, P=0.008), while a decreased risk was observed in Caucasian women (TT vs. CC: OR=0.65, 95% CI=0.45-0.93, P=0.02; TT+CT vs. CC: OR=0.7, 95% CI=0.58-0.86, P=0.0005). No effects of MTHFR C677T polymorphism on CIN II/III risk and MTHFR A1298C or MS A2756G polymorphisms on cervical cancer risk were detected. The sensitivity analysis suggested stability of this meta-analysis and no publication bias was detected. The MTHFR 677T allele may enhance the risk of cervical cancer in the Asian female population and play a protective role in Caucasian females. However, limited association is suggested between MTHFR A1298C and MS A2756G polymorphisms with cervical tumorigenesis.

Hua J.,Hua Medicine
Engineering Technology, Engineering Education and Engineering Management - International Conference on Engineering Technology, Engineering Education and Engineering Management, ETEEEM 2014 | Year: 2015

In order to fast transmission and processing of medical images and do not need to install client and plug-ins, the paper designed a kind of medical image reading system based on BS structure. This system improved the existing IWEB in the framework of PACS client image processing, medical image based on the service WEB completion port model. To realize the fast loading images with high concurrency, compared with the traditional WEB PACS, this system has the advantages of no client without plug-in installation, at the same time in the transmission and processing performance image has been greatly improved. © 2015 Taylor & Francis Group, London.

We conducted a long-term follow-up study in patients with rheumatic diseases who were candidates for biologics treatment to evaluate the effects of biologic agents on the risk of tuberculosis infection and the effect of prophylactic treatment on tuberculosis activation. One hundred one patients with rheumatic diseases who were candidates for biologics treatment were recruited, and 57 healthy subjects were recruited as controls. Tuberculin skin test (TST) and the T-SPOT.TB test were performed for all subjects at baseline. Follow-up testing by the T-SPOT.TB assay was performed every 6 months in patients with rheumatic diseases and at 2 years of recruitment in the healthy controls. In patients with rheumatic diseases and healthy controls, the TST-positive (induration, ≥10 mm) rates were 37.6% (38/101) and 34.0% (18/53), respectively (P > 0.05), while the T-SPOT.TB-positive rates were 46.5% (47/101) and 21.1 (12/57), respectively (P = 0.0019). Fifty-two patients were followed up at month 6 with a T-SPOT.TB-positive rate of 40.4%, and 49 were followed up for ≥12 months with a T-SPOT.TB-positive rate of 36.7%, with no significant difference in the positive rate at different time points including baseline (P > 0.05). Long-term follow-up revealed that conversion to T-SPOT.TB positivity occurred only in the biologics treatment group, with a positive conversion rate of 11.2% (4/38). Most importantly, no latent tuberculosis developed into active tuberculosis during follow-up with T-SPOT.TB screening and preemptive treatment with isoniazid. Biologics treatment appears to increase the risk of tuberculosis infection. However, tuberculosis activation could be prevented by preemptive isoniazid treatment in patients with latent tuberculosis infection while receiving biologics therapy.

The present invention relates to a novel process for the preparation of of the formula (I) (I) wherein R^(1 )and R^(2 )are described herein. The compounds prepared by the present invention are useful in the synthesis and manufacture of compounds for treating diseases or conditions associated with inhibiting actin polymerization.

News Article | July 30, 2015

In his quest to create the first original, billion-dollar drug from a Chinese laboratory, Chen Li is zeroing in on one of the world’s fastest-growing patient groups: diabetes sufferers in China. There were 114 million of them at last count, more than double a 2010 estimate. Numbers are surging because of changing diets and lifestyles, and a genetic susceptibility to the metabolic disease. Once the top scientist in China with Swiss drugmaker Roche Holding AG, Chen is developing a new treatment for diabetes, which he says afflicts Chinese when they’re younger and thinner than Caucasians. The unique features of China’s epidemic mean new weapons are needed to fight it, according to Chen. He’s part of a growing wave of so-called sea turtle scientists -- Chinese returning home after years studying and working abroad -- developing medicines specifically for their fellow citizens. “For too long, innovation in China has meant a ‘me too’ drug,” said Chen, who worked at Roche’s New Jersey research labs before returning to his home country in 2004. “China has no choice but to develop novel drugs, and it will need to be for something that attacks the nation in masses like diabetes or cancer.” Chen’s company, Hua Medicine Ltd., has raised $46 million since 2010 from some of the most prominent U.S. and China biotechnology investors. Venture capitalist Robert Nelsen, who is a co-founder and chairman of Hua, said he wants the company to emulate the success of Receptos Inc., a San Diego-based biotechnology startup that Celgene Corp. bought this month for $7.2 billion. Nelsen’s ARCH Venture Partners was one of Receptos’s early investors, he says, and the returns were among his most lucrative. “Receptos is a good comparison to the value that will be created if the drug works in a large market, but we obviously have to wait for the data,” Nelsen said. One of Hua’s most advanced experimental medicines is HMS5552. The so-called oral glucokinase activator aims to regulate blood-sugar by improving glucose sensitivity for sufferers of type-2 diabetes, the obesity-linked form that accounts for 90 percent of diabetes cases in China. Hua licensed the compound from Basel, Switzerland-based Roche, and the Chinese company is now starting mid-stage clinical trials in more than 20 cities across China. Drugs targeting the glucokinase activator mechanism represent a new approach in diabetes, treatments for which Bloomberg Intelligence estimates will reach $55 billion in sales by 2018. Eli Lilly & Co., based in Indianapolis, announced last year a partnership with Shanghai-based Yabao Pharmaceutical Co. to develop its own experimental glucokinase activator in China. “The collaboration with Yabao is one of the important steps in growing our diabetes footprint,” Lilly spokeswoman Teresa A. Shewman said in an e-mail. Yabao declined to comment. Early stage-trials showed Hua’s HMS5552 more effectively controlled blood-glucose over 24 hours and improved glucose sensitivity in Chinese type-2 diabetes patients, better than standard therapy with oral medications, Chen said. Carbohydrate-loaded diets, a growing taste for fatty fast-foods and inherited genetic factors put Chinese at higher risk of diabetes and impaired glucose tolerance than Caucasians, Chen said. Research published in the Journal of the American Medical Association in 2013 found that as many as half of all adults in China may have elevated blood-glucose levels defined as prediabetes. Drugs such as metformin and Sanofi SA’s Lantus, the world’s best selling diabetes drug, are routinely used in North America and Europe. In China, these therapies effectively control the disease in fewer than half of cases, Chen estimates. Large variations in blood-sugar, especially excessive levels after eating, in diabetes patients increase the risk of complications such as stroke, heart attack and damage to the kidneys, eyes and peripheral nerves. If successful in China, Hua would seek to make the drug available across Asia, and as a complementary therapy in North America and Europe, he said. China’s government has invested heavily in biotechnology, and the investments are starting to pay off, said Elizabeth Krutoholow, a biotech analyst at Bloomberg Intelligence in New York. The value of the industry output’s increased 20 percent to 3.16 trillion yuan ($509 billion) in 2014, the official Xinhua News Agency reported last week. Hua’s drug has been granted “green channel” status by China’s Food and Drug Administration, which is similar to the U.S. FDA’s “fast track” designation and beneficial in a market where approval delays are common, said Frank Yu, founder and Chief Executive Officer of health-care investment-focused Ally Bridge Group, which led a financing round into Hua this January. Hua Medicine receives grants from the government to support research and development. “We don’t want to be another Western company opening a China office,” Nelsen said. “The government is very interested in seeing Chinese develop drugs that solve Chinese health problems, and to do that would be a huge victory.”

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