Mechanism of Qingke Pingchuan Granule in Treatment of Acute and Chronic Bronchitis Complicated with Chronic Obstructive Pulmonary Disease： An Exploration Based on Network Pharmacology / 中国实验方剂学杂志

Objective:To explore the potential mechanism of Qingke Pingchuan granule in treating acute and chronic bronchitis complicated with chronic obstructive pulmonary disease （COPD） by network pharmacology. Method:The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） was retrieved to collect the active components of Qingke Pingchuan granule and predict the action targets， followed by the construction of component-target network using Cytoscape 3.8. GeneCards， Online Mendelian Inheritance in Man（OMIM）， and DrugBank were used to harvest disease targets， whose names were put into UniProt for standardization. The treatment targets of Qingke Pingchuan Granule against the two diseases were obtained based on Venn diagram， which were then imported into the STRING platform for constructing the protein-protein interaction （PPI） network. Following the gene ontology（GO） and Kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment analysis based on MetaScape， the active component-common target-signaling pathway network of Qingke Pingchuan granule against acute and chronic bronchitis complicated with COPD was finally constructed. The accuracy of the target was confirmed by literature. Result:A total of 165 active components， 374 related targets， 512 disease-related targets， and 130 common targets were obtained. Among them， the 14 core therapeutic targets were further subjected to GO enrichment analysis， which yielded 390 biological processes， nine cell components， and 23 molecular functions. The KEGG pathway analysis revealed 22 signaling pathways. Conclusion:Qingke Pingchuan granule alleviates the diseases possibly by regulating such targets as vascular endothelial growth factor receptor 2（KDR）， transforming growth factor beta-1 （TGF-<italic>β</italic>₁）， caveolin 1（CAV1）， hypoxia-inducible factor-1alpha（HIF-1<italic>α</italic>）， and interleukin-2（IL-2）， affecting the synthesis and transport of regulatory factors in cytoplasm， and controlling the cell proliferation and apoptosis.

TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain.

Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund's adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

Dynamic oxidative stress and DNA damage induced by oestrogen deficiency and protective effects of puerarin and 17ß-oestradiol in ovariectomized rats.

Oxidative stress plays an essential role in the pathogenesis of cardiovascular diseases and osteoporosis resulting from oestrogen deficiency in the postmenopausal period. In this report, we observed a dynamic change of oxidative stress and DNA damage after ovariectomy in female rats. We then compared phytoestrogen puerarin and 17ß-oestradiol (E2) in their effects on oestrogen deficiency-induced oxidative stress and DNA damage. Serum total antioxidant capacity (TAC), malondialdehyde (MDA) and lymphocytes DNA damage (comet%) were measured. There was a gradual increase in oxidative stress in the ovariectomized (OVX) rats over time after ovariectomy, as compared to rats receiving sham operation. OVX rats that were on puerarin and E2 showed increased TAC and decreased MDA in the serum, as well as decreased lymphocytes comet%. Puerarin appeared to have a more powerful protective effect on DNA oxidative damage than E2. The study indicates that postmenopausal women may benefit from phytoestrogen puerarin.

Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G).

Phenolic acids are found in abundance throughout the plant kingdom. Consumption of wine or other rich sources of phenolic acids, such as the "Mediterranean diet," has been associated with a lower risk of cardiovascular disease. The underlying mechanism(s), however, has remained unclear. Here, we show that many phenolic acids, including those from the hydroxybenzoic and hydroxycinnamic acid classes, can bind and activate GPR109A (HM74a/PUMA-G), the receptor for the antidyslipidemic agent nicotinic acid. In keeping with this activity, treatment with a number of phenolic acids, including cinnamic acid, reduces lipolysis in cultured human adipocytes and in fat pats isolated from wild-type mice but not from mice deficient of GPR109A. Oral administration of cinnamic acid significantly reduces plasma levels of FFA in the wild type but not in mice deficient of GPR109A. Activation of GPR109A by phenolic acids may thus contribute to a cardiovascular benefit of these plant-derived products.

Tea drinking and the risk of biliary tract cancers and biliary stones: a population-based case-control study in Shanghai, China.

Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Apart from gallstones, etiologic factors for biliary tract cancer are not clearly defined. Several epidemiologic studies have suggested that consumption of tea, especially green tea, is protective against a variety of cancers, including gastrointestinal malignancies. As part of a large population-based case-control study of biliary tract disease in Shanghai, China, we evaluated the effects of tea consumption on the risk of biliary tract cancers and biliary stones. The study included 627 incident cases with biliary tract cancer, 1,037 cases with biliary stones and 959 randomly selected controls. Study subjects were interviewed to ascertain data on demographic, medical and dietary factors, including tea consumption. Forty-one percent of the controls were ever tea drinkers, defined as those who consumed at least 1 cup of tea per day for at least 6 months. After adjustment for age, education and body mass index, among women, ever tea drinkers had significantly reduced risks of biliary stones (OR = 0.73, 95% CI = 0.54-0.98) and gallbladder cancer (OR = 0.56, 95% CI = 0.38-0.83). The inverse relationship between tea consumption and gallbladder cancer risk was independent of gallstone disease. Among men, tea drinkers were more likely to be cigarette smokers, and the risk estimates were generally below 1.0, but were not statistically significant. Further studies are needed to confirm these results in other populations and clarify the hormonal and other mechanisms that may be involved.

Total synthesis of methyl protodioscin: a potent agent with antitumor activity.

Methyl protodioscin (1), otherwise known as 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-beta-d-glucopyranosyl]-26-O-[beta-D-glucopyranosyl]-22-methoxy-25(R)-furost-5-ene-3 beta,26-diol, has been synthesized for the first time from diosgenin through nine steps in an overall yield of 7.8%.