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Acta Pharmacologica Sinica

Cuiping Fu, Shengyu Hao, Xiaobo Xu, Jian Zhou, Zilong Liu, Huan Lu, Limin Wang, Weizhong Jin, Shanqun Li
The integrity of the endothelial barrier is a determinant of the prognosis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated whether and how Sirtuin 1 (SIRT1) maintained the vascular integrity during ALI. An experimental model of ALI was established in mice through intratracheal administration of LPS (10 mg/kg). LPS stimulation significantly increased the pulmonary permeability and decreased the expression of SIRT1 and tight junction proteins (TJs), including occludin, claudin-5, tight junction protein 1 and tight junction protein 2...
July 18, 2018: Acta Pharmacologica Sinica
Adrián Viudez-Martínez, María S García-Gutiérrez, Juan Medrano-Relinque, Carmen M Navarrón, Francisco Navarrete, Jorge Manzanares
Recent evidence suggests that cannabidiol (CBD) may be useful for the treatment of different neuropsychiatric disorders. However, some controversy regarding its profile as a drug of abuse hampers the further development of basic and clinical studies. In this study, the behavioral profile of CBD as a potential drug of abuse was evaluated in C57BL/6J mice. Reinforcing properties of CBD (15, 30, and 60 mg/kg; i.p.) were assessed using the conditioned place preference (CPP) paradigm. Spontaneous withdrawal symptoms and motor activity in the open field were examined 12 h after the last CBD administration (30 mg/kg/12 h, i...
July 18, 2018: Acta Pharmacologica Sinica
Yun-He Ding, Yun-Duan Song, Ya-Xian Wu, Hui-Qiong He, Tian-Hong Yu, Yu-Dong Hu, De-Peng Zhang, Hong-Chao Jiang, Kai-Kai Yu, Xiao-Zong Li, Lei Sun, Feng Qian
Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2...
July 16, 2018: Acta Pharmacologica Sinica
Xin-Zhi Wang, Ru-Feng Xue, Shen-Ye Zhang, Ya-Ting Zheng, Lu-Yong Zhang, Zhen-Zhou Jiang
Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers...
July 16, 2018: Acta Pharmacologica Sinica
Wen-Juan Liu, Xiu-Jun Liu, Jian Xu, Liang Li, Yi Li, Sheng-Hua Zhang, Jia-Lin Wang, Qing-Fang Miao, Yong-Su Zhen
Defensins play an essential role in innate immunity. In this study, a novel recombinant β-defensin that targets the epidermal growth factor receptor (EGFR) was designed and prepared. The EGFR-targeting β-defensin consists of an EGF-derived oligopeptide (Ec), a β-defensin-1 peptide (hBD1) and a lidamycin-derived apoprotein (LDP), which serves as the "scaffold" for the fusion protein (Ec-LDP-hBD1). Ec-LDP-hBD1 effectively bound to EGFR highly expressed human epidermoid carcinoma A431 cells. The cytotoxicity of Ec-LDP-hBD1 to EGFR highly expressed A431 cells was more potent than that to EGFR low-expressed human lung carcinoma A549 and H460 cells (the IC50 values in A431, A549, and H460 cells were 1...
July 16, 2018: Acta Pharmacologica Sinica
Guo-Yi Jia, Duo-Lin Wang, Meng-Zhu Xue, Yu-Wei Liu, Yu-Chen Pei, Ying-Qun Yang, Jing-Mei Xu, Yan-Chun Liang, Peng Wang
Circular RNAs (circRNAs) are emerging species of mRNA splicing products with largely unknown functions. Although several computational pipelines for circRNA identification have been developed, these methods strictly rely on uniquely mapped reads overlapping back-splice junctions (BSJs) and lack approaches to model the statistical significance of the identified circRNAs. Here, we reported a systematic computational approach to identify circRNAs by simultaneously utilizing BSJ overlapping reads and discordant BSJ spanning reads to identify circRNAs...
July 16, 2018: Acta Pharmacologica Sinica
Ting Zhang, Xian-Yan Qin, Xi Cao, Wen-Hao Li, Tao Gong, Zhi-Rong Zhang
Thymopentin (TP5) is an effective immunomodulatory agent for autoimmune disease that has been used clinically for decades. However, its application is greatly limited by its extremely short half-life in vivo, poor membrane permeability and extensive metabolism in gastrointestinal tract, resulting in repeated injection and poor patient compliance. In the present study, we developed a TP5-loaded, phospholipid-based phase separation gel (PPSG) to achieve sustained drug release profile and long-lasting therapeutic effects...
July 12, 2018: Acta Pharmacologica Sinica
Xiao Zhu, Hong-Wen Zhang, Hai-Nan Chen, Xiao-Jun Deng, Yi-Xuan Tu, Ampadu O Jackson, Ji-Na Qing, Ai-Ping Wang, Vaibhav Patel, Kai Yin
Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity...
July 12, 2018: Acta Pharmacologica Sinica
Shi-Gang Qiao, Ying Sun, Bo Sun, An Wang, Jia Qiu, Lei Hong, Jian-Zhong An, Chen Wang, Hui-Ling Zhang
Volatile anesthetics improve postischemic cardiac function and reduce infarction even when administered for only a brief time at the onset of reperfusion. A recent study showed that sevoflurane postconditioning (SPC) attenuated myocardial reperfusion injury, but the underlying mechanisms remain unclear. In this study, we examined the effects of sevoflurane on nitric oxide (NO) release and autophagic flux during the myocardial ischemia/reperfusion (I/R) injury in rats in vivo and ex vivo. Male rats were subjected to 30 min ischemia and 2 h reperfusion in the presence or absence of sevoflurane (1...
July 12, 2018: Acta Pharmacologica Sinica
An-Qi Yin, Feng Wang, Xia Zhang
Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism's long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression...
July 12, 2018: Acta Pharmacologica Sinica
Wen-Bin Fu, Wei Eric Wang, Chun-Yu Zeng
Myocardial infarction (MI) is one of the most serious health threats, resulting in huge physical and economic burdens worldwide. Wnt signaling pathways play an important role in developmental processes such as tissue patterning, cell differentiation and cell division. Appropriate regulation of the activities of Wnt signaling pathways is also important for heart development and healing in post-MI heart. Moreover, Wnt pathway inhibitors have been identified as novel antitumor drugs and applied in ongoing clinical trials...
July 12, 2018: Acta Pharmacologica Sinica
Xue-Li Zhang, Yun Shen, Xiao-Jing Ma, Zhi-Gang Lu, Yi-Ting Xu, Qin Xiong, Yu-Qian Bao
Osteocalcin is a newly identified type of cytokine secreted by osteoblasts, which has an endocrine function, mediates energy and glycol-lipid metabolism, and is closely related to cardiovascular diseases. In this study, we investigated the value of serum osteocalcin levels in predicting left ventricular systolic dysfunction and cardiac death. A total of 258 patients in the Department of Cardiology were included. Two-dimensional echocardiography was performed in all the subjects. The cardiac death of subjects occurring with a median follow-up of 4...
July 10, 2018: Acta Pharmacologica Sinica
Jia Wang, Grace Qun Gong, Yan Zhou, Woo-Jeong Lee, Christina Maree Buchanan, William Alexander Denny, Gordon William Rewcastle, Jackie Diane Kendall, James Michael Jeremy Dickson, Jack Urquhart Flanagan, Peter Robin Shepherd, De-Hua Yang, Ming-Wei Wang
The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor...
July 10, 2018: Acta Pharmacologica Sinica
Zhi-Li Ren, Chao-Dong Wang, Tao Wang, Hui Ding, Ming Zhou, Nan Yang, Yan-Yong Liu, Piu Chan
Neuroprotection targeting mitochondrial dysfunction has been proposed as an important therapeutic strategy for Parkinson's disease. Ganoderma lucidum (GL) has emerged as a novel agent that protects neurons from oxidative stress. However, the detailed mechanisms underlying GL-induced neuroprotection have not been documented. In this study, we investigated the neuroprotective effects of GL extract (GLE) and the underlying mechanisms in the classic MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD...
July 10, 2018: Acta Pharmacologica Sinica
Han-Wei Yang, Hui-Ling Hong, Wen-Wei Luo, Chun-Mei Dai, Xin-Yi Chen, Lu-Ping Wang, Qian Li, Zi-Qing Li, Pei-Qing Liu, Zhuo-Ming Li
Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2 O2 -induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs)...
July 10, 2018: Acta Pharmacologica Sinica
Yan-Fen Li, Yue-Ming Zheng, Yong Yu, Yong Gan, Zhao-Bing Gao
Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27...
July 10, 2018: Acta Pharmacologica Sinica
Jiu-Cheng Zhang, Wei-Dong Chen, Jean Bustamante Alvarez, Kelly Jia, Lei Shi, Qiang Wang, Ning Zou, Kai He, Hua Zhu
The immune checkpoint molecules are emerged in the evolution to protect the host from self-attacks by activated T cells. However, cancer cells, as a strategy to survive and expand, can hijack these molecules and mechanisms to suppress T cell-mediated immune responses. Therefore, an idea of blocking the checkpoint molecules to enhance the anti-tumor activities of the host immune system has been developed and applied to the cancer therapy after discovery of the inhibitory T cell co-receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and further enhanced on the identification of PD-1 and its ligands...
July 10, 2018: Acta Pharmacologica Sinica
Alex Perchuk, Sonya M Bierbower, Ana Canseco-Alba, Zoila Mora, Lauren Tyrell, Neal Joshi, Norman Schanz, Georgianna G Gould, Emmanuel S Onaivi
Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1...
July 10, 2018: Acta Pharmacologica Sinica
Lukas Andreas Heger, Mark Kerber, Marcus Hortmann, Samuel Robinson, Maximilian Mauler, Daniela Stallmann, Daniel Duerschmied, Christoph Bode, Christoph Hehrlein, Ingo Ahrens
Anti-ischemic therapy remains a challenge due to the complexity of hypoxia response pathways. Hypoxia-inducible factor (HIF)-1 is a heterodimer transcription factor consisting of 2 subunits, HIF-1α and HIF-1β. Hypoxia-dependent activation of HIF-1α regulates cellular O2 homeostasis. Raynaud syndrome (RS), as a comorbidity of the autoimmune disease systemic sclerosis (SS), is characterized by vasospasms that limit blood flow to the limbs, resulting in hypoxia. A single-center randomized study was conducted to compare prostaglandin E1 (PgE1) therapy with a treatment combining PgE1 and an endothelin-1 blocker, bosentan...
July 10, 2018: Acta Pharmacologica Sinica
Ali Mazhari, Xiao-Yi Zeng, Xiu Zhou, Songpei Li, Jun Xu, Wen Tan, Ross Vlahos, Stephen Robinson, Ji-Ming Ye
The present study investigated the efficacy of the hepatoprotective drug matrine (Mtr) for its new application for hepatosteatosis and associated disorders in glucose homeostasis. The study was performed in two nutritional models of hepatosteatosis in mice with various abnormal glucose homeostasis: (1) high-fructose diet (HFru) induced hepatosteatosis and glucose intolerance from hepatic, and (2) hepatosteatosis and hyperglycemia induced by high-fat (HF) diet in combination with low doses of streptozotocin (STZ)...
July 6, 2018: Acta Pharmacologica Sinica
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