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APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3B is essential for oncogenesis of HCC, and is a potential target for preventive intervention.

Fil: Zhang, Ye. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Yang, Xue. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Yan, Wenchao. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Li, Rui. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Ye, Qian. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: You, Linjun. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Xie, Wenhao. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Mo, Kun. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Fu, Ruifeng. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Yanxiang. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Chen, Yufei. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Di, Qin. Nanjing Sport Institute. School of Sports and Health; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines. Center for New Drug Safety Evaluation and Research; China Abstract: Sepsis, a systemic inflammatory response syndrome (SIRS) caused by infection, is a major public health concern with limited therapeutic options. Infection disturbs the homeostasis of host, resulting in excessive inflammation and immune suppression. This has prompted the clinical use of immunomodulators to balance host response as an alternative therapeutic strategy. Here, we report that Thymopentin (TP5), a synthetic immunomodulator pentapeptide (Arg-Lys-Asp-Val-Tyr) with an excellent safety profile in the clinic, protects mice against cecal ligation and puncture (CLP)-induced sepsis, as shown by improved survival rate, decreased level of pro-inflammatory cytokines and reduced ratios of macrophages and neutrophils in spleen and peritoneum. Regarding mechanism, TP5 changed the characteristics of LPS-stimulated macrophages by increasing the production of 15-deoxy-Δ12,14 -prostaglandin J2 (15-d-PGJ2). In addition, the improved effect of TP5 on survival rates was abolished by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662. Our results uncover the mechanism of the TP5 protective effects on CLP-induced sepsis and shed light on the development of TP5 as a therapeutic strategy for lethal systemic inflammatory disorders.

In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8–AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. Significance: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8–AR axis in CRPC.

Fil: Gao, Xinghua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Gao, Xinghua. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Gao, Xinghua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Cao, Qiuhua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cao, Qiuhua. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cao, Qiuhua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Cheng, Yan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cheng, Yan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cheng, Yan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dandan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhao, Dandan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dandan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Zhuo. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Zhuo. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Zhuo. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Zhuo. Nanjing University of Chinese Medicine. Translational Medicine Center; China Fil: Yang, Hongbao. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Hongbao. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Hongbao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wu, Qijin. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wu, Qijin. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wu, Qijin. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: You, Linjun. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: You, Linjun. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: You, Linjun. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Bian, Jin-Song. National University of Singapore. Yong Loo Lin School of Medicine. Department of Pharmacology; Singapur Fil: Sun, Dongdong. Nanjing University of Chinese Medicine. Translational Medicine Center; China Fil: Kong, Lingyi. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Kong, Lingyi. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Kong, Lingyi. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Yong. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Abstract: Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6-/- mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.

Fil: Cheng, Yan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Xing-Hua, Gao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Xian-Jing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cao, Qiu-Hua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dan-Dan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhou, Jin-Rong. Harvard Medical School. Beth Israel Deaconess Medical Center. Department of Surgery. Nutrition/Metabolism Laboratory; Estados Unidos Fil: Wu, Hong-Xi. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: You, Lin-Jun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Hong-Bao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: He, Yun-Long. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Yong-Ren. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Bian, Jin-Song. National University of Singapore. Yong Loo Lin School of Medicine. Department of Pharmacology; Singapur Fil: Zhu, Qing-Yi. Jiangsu Province Hospital of Traditional Chinese Medicine. Department of Urology; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Abstract: Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.

The ocular pharmacokinetic (PK) of azithromycin in rabbit eye tissues was evaluated following single-dose and multiple-dose administrations of azithromycin. Because of destructive sampling, only the average ocular tissue concentration–time curve could be captured and used to estimate the PK parameters failing to obtain their standard deviations. In the present study, formulas were explained in details to estimate the major PK parameter errors in destructive sampling. The PK parameters were obtained by analyzing average ocular tissue concentration–time curve and their standard deviations were calculated using the formula proposed in this paper. A case study was included to elucidate the potential application of the formulas. F-test for equality of variances and independent-samples t-test were carried out between test formulation and reference formulation in PK parameters. Thus, a new and simple method was proposed to compare PK behavior for these studies using destructive sampling, which can be potentially applied into other cases in the future. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2371–2379, 2013

In this study, we found that pretreatment with low dose of lipopolysaccharide (LPS), also known as lipoglycans and endotoxin, obviously attenuated liver injury caused by diethylnitrosamine (DEN) in mice. This protective effect was described by decreased ALT, TNF-α, and IL-1β and increased TGF-β production. However, Toll-like receptor 4-deficient (TLR4(-/-)) or macrophages depletion abolished this protection in mice, which revealed Kupffer cells (KCs) and TLR4 to be crucial for the prevention of LPS against DEN-induced damage. Further study revealed that LPS pretreatment induced the KCs to M2 polarization and impaired the signaling of MAPKs and NF-κB that mediated the production of inflammatory cytokines. Moreover, T regulatory cells (Tregs) were also recruited to the liver, which may mediate immunosuppression and participate in the prevention of DEN-induced injury. Our results suggested that LPS protected against DEN-induced hepatitis via induction of M2 Kupffer cells and recruitment of Tregs, which contributes to liver tolerance in TLR4-dependent mechanism.

Lidocaine hydrochloride ophthalmic gel is a novel ophthalmic preparation for topical ocular anesthesia. The study is aimed at evaluating the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. Thirty-six rabbits were randomly placed in 12 groups (3 rabbits per group). The rabbits were quickly killed according to their groups at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose and then the ocular tissue and plasma samples were collected. All the samples were analyzed by a validated LC–MS/MS method. The test result showed that the maximum concentration (C max) of lidocaine in different ocular tissues and plasma were all achieved within 20 min after drug administration, and the data of C max were (2,987 ± 1814) μg/g, (44.67 ± 12.91) μg/g, (26.26 ± 7.19) μg/g, (11,046 ± 2,734) ng/mL, and (160.3 ± 61.0) ng/mL for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The data of the elimination half-life in these tissues were 1.5, 3.2, 3.5, 1.9, and 1.7 h for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The intraocular lidocaine levels were significantly higher than that in plasma, and the elimination half-life of lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. The high intraocular penetration, low systemic exposure, and long duration in the ocular tissues suggested lidocaine hydrochloride 3.5 % ophthalmic gel as an effective local anesthetic for ocular anesthesia during ophthalmic procedures.