Summary The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine-H1 receptor (H1R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of H1R complex with doxepin, a first-generation H1R-antagonist. Doxepin sits deep in the ligand binding pocket and directly interacts with the highly conserved Trp4286.48, a key residue in GPCR activation. This well-conserved pocket with mostly hydrophobic nature contributes to low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H1R-antagonists reveals that the unique carboxyl-group present in this class of compounds interacts with Lys1915.39 and/or Lys179ECL2, both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors defining how minor differences in receptor lead to pronounced selectivity differences with small molecules.

The aim of this study was to investigate the role of apelin in the cell proliferation and autophagy of lung adenocarcinoma. The over-expression of APJ in lung adenocarcinoma was detected by immunohistochemistry, while plasma apelin level in lung cancer patients was measured by enzyme-linked immunosorbent assay. Our findings revealed that apelin-13 significantly increased the phosphorylation of ERK1/2, the expression of cyclin D1, microtubule-associated protein 1 light chain 3A/B (LC3A/B), and beclin1, and confirmed that apelin-13 promoted A549 cell proliferation and induced A549 cell autophagy via ERK1/2 signaling. Moreover, there are pores on the surface of human lung adenocarcinoma cell line A549 and apelin-13 causes cell surface smooth and glossy as observed under atomic force microscopy. These results suggested that ERK1/2 signaling pathway mediates apelin-13-induced lung adenocarcinoma cell proliferation and autophagy. Under our experimental condition, autophagy associated with 3-methyladenine was not involved in cell proliferation.

Apelin and Elabela (ELA) are endogenous ligands of angiotensin domain type 1 receptorassociated proteins (APJ). Apelin/ELA-APJ signal is widely distributed in the cardiovascular system of fetuse and adult. The signal is involved in the development of the fetal heart and blood vessels and regulating vascular tension in adults. This review described the effects of apelin/ELA-APJ on fetal (vasculogenesis and angiogenesis) and adult cardiovascular function [vascular smooth muscle cell (VSMC) proliferation, vasodilation, positive myodynamia], and relative diseases [eclampsia, hypertension, pulmonary hypertension, heart failure (HF), myocardial infarction (MI), atherosclerosis, etc.] in detail. The pathways of apelin/ELA-APJ regulating cardiovascular function and cardiovascular-related diseases are summarized. The drugs developed based on apelin and ELA suggests APJ is a prospective strategy for cardiovascular disease therapy.

In the present study artemisinin (ART) was found to have potent anti-inflammatory effects in animal models of sepsis induced by CpG-containing oligodeoxy-nucleotides (CpG ODN), lipopolysaccharide (LPS), heatkilled Escherichia coli 35218 or live E. coli. Furthermore, we found that ART protected mice from a lethal challenge by CpG ODN, LPS, or heat-killed E. coli in a dose-dependent manner and that the protection was related to a reduction in serum tumor necrosis factor alpha (TNF-␣). More significantly, the administration of ART together with ampicillin or unasyn (a complex of ampicillin and sulbactam) decreased mortality from 100 to 66.7% or 33.3%, respectively, in mice subjected to a lethal live E. coli challenge. Together with the observation that ART alone does not inhibit bacterial growth, this result suggests that ART protection is achieved as a result of its anti-inflammatory activity rather than an antimicrobial effect. In RAW264.7 cells, pretreatment with ART potently inhibited TNF-␣ and interleukin-6 release induced by CpG ODN, LPS, or heat-killed E. coli in a dose-and time-dependent manner. Experiments utilizing affinity sensor technology revealed no direct binding of ART with CpG ODN or LPS. Flow cytometry further showed that ART did not alter binding of CpG ODN to cell surfaces or the internalization of CpG ODN. In addition, upregulated levels of TLR9 and TLR4 mRNA were not attenuated by ART treatment. ART treatment did, however, block the NF-B activation induced by CpG ODN, LPS, or heat-killed E. coli. These findings provide compelling evidence that ART may be an important potential drug for sepsis treatment.Sepsis is a potentially lethal condition that results from a harmful or damaging host response to infection (1,3,8,11). Sepsis is triggered by bacteria and bacterial components, such as bacterial DNA (bDNA) and lipopolysaccharide (LPS) (26,28,29). Delivery of CpG-containing oligodeoxy-nucleotides (CpG ODN) can trigger sepsis by mimicking the immunostimulatory effects of bDNA and therefore has provided a useful animal model of the sepsis condition (21,23,26).Recent surveys conducted in the United States and in Europe have indicated that approximately 2 to 11% of all hospital and intensive care unit admissions can be attributed to severe sepsis. Despite improvements in supportive care and the increased availability of effective antibacterial agents, hospital mortality rates from severe sepsis and septic shock (50 to 60%) have not improved over recent decades (1,28). Unfortunately, many experimental inflammatory antagonist-based therapies have failed in sepsis trials, and currently there is only one adjuvant therapy in clinical use, e.g., activated protein C, which targets the coagulation system (28). Thus, it is important to investigate additional inflammatory antagonist-based treatments with the aim of developing a clinically effective antisepsis drug.Antimalarial drugs such as chloroquine (CQ) and artemisinin (ART) are promising candidates for sepsis treatment. CQ has been demonstrated to protec...