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OBJECTIVE Cisplatin is a formidable chemotherapy agent widely applying in antineoplastic treatments, but its side effects often limit the clinical usage. Metabolic disorders are one of the side effects induced by cisplatin, which closely relate to the onset of chemotherapy-induced anorexia (CIA) in cancer patients but lacks effective controls. Liujunzi decoction (LJZD) is a traditional Chinese formula that has a promising effect in treating CIA. However, whether LJZD ameliorates CIA through adjusting cisplatin-induced metabolic disorders remain unknow. The present study evalu?ated the mechanism of cisplatin-induced metabolic disorders, and the effect of LJZD in ameliorating these disturbances. METHODS 42 male Sprague-Dawley (SD) rats (180-220 g) were randomly divided into 3 groups:normal control group (distilled water+saline), model group (distilled water+cisplatin), LJZD group (4.8 g·kg-1 Liujunzi decoction ingredients+cisplatin). Intragastrical administered each drug twice a day (7:00-19:00) since day 0 for 4 d, animals were intraperito?neal injected with cisplatin 6 mg·kg-11 h after administration while normal control groups were injected with same volume of saline. On day 3, each group was anesthetized with pentobarbital sodium 45 mg · kg-1 (ip), and blood samples were collected from aorta abdominalis. Then the samples were analyzed using an LC-ESI-MS/MS system. Significantly regu?lated metabolites between groups were determined by VIP≥1 and absolute Log2FC (fold change)≥1. Identified metabo?lites were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Metaboanalyst 5.0 (https://www.metaboanalyst.ca/). RESULTS A total of 133, 77 and 32 differential metabolites were filtrated in control vs model, control vs LJZD and model vs LJZD groups respectively. Comparing to control, the levels of hexadecanoic acid (Log2FC=6.3153), linoleic acid (Log2FC=5.3478), and 8, 11-icosadienoic acid (Log2FC=5.2342) significantly increased, and the levels of N-acetyl-L-tyrosine (Log2FC = -2.6283), cinnamic acid (Log2FC = -2.3381), N-acetylphenylalanine (Log2FC = -2.2501) significantly decreased in model group. The KEGG pathway enrichments of these metabolites indi?cated that, cisplatin-induced metabolic disorders by disturbing metabolism pathways such as linoleic acid metabolism, biosynthesis of unsaturated fatty acids, and phenylalanine metabolism, which suggested that the onset of CIA was partly associated with the metabolic disorders of linoleic acid, unsaturated fatty acids, and phenylalanine. Compared to control, treatment of LJZD significantly increased the levels of 4-hydroxytryptamine (Log2FC =12.0186), hexadecanoic acid (Log2FC = 5.7412), linoleic acid (Log2FC = 5.1877) and significantly decreased the levels of N-acetylmethionine (Log2FC=-1.7317), 2-aminoethanesulfinic acid (Log2FC=-1.6578), N-acetyl-L-tyrosine (Log2FC=-1.5355). And com?paring to the model group, 4-hydroxytryptamine (Log2FC = 12.0186), 7, 12-diketocholic acid (Log2FC = 2.0998), N-acetylneuraminic acid (Log2FC = 2.0560) markedly increased, and 3-hydroxy-3-methylpentane-1 (Log2FC = -1.9202), 5-dioic acid (Log2FC = -1.7166), N-isovaleroylglycine, hexanoyl glycine (Log2FC = -1.4958) markedly decreased in LJZD group. It was worth noting that, there were 23 differential metabolites filtrated both in control vs model and model vs LJZD groups, which were the key metabolites of LJZD in treating CIA. Among these 23 common metabolites, there were 16 metabolites excluding the control vs LJZD group, that was, LJZD had no effect in normal rats while being able to ameliorated cisplatin-induced metabolic disorders by regulating these 16 metabolites. Cisplatin-induced downregula?tion of 11 metabolites such as hydrocinnamic acid, (±)12(13)epoxy-9Z-octadecenoic acid, cinnamic acid were upregulated after LJZD treatment, and cisplatin-induced upregulation of imidazoleacetic acid, 2'-deoxycytidine-5'-monophosphate and other 5 metabolites were downregulated by LJZD. The KEGG pathway analysis indicated that the linoleic acid metabolism, histidine metabolism, and pyrimidine metabolism were the most enriched metabolic pathway. Thus, cisplatin-induced metabolic disturbances mainly by disturbing linoleic acid metabolism, histidine metabolism, and pyrimidine metabolism, and LJZD interacted with these metabolic pathways to reduce metabolic disorders and thus ameliorated CIA. CONCLUSION Cisplatin-induced anorexia was closely related to the metabolic disorders of linoleic acid metabo?lism, biosynthesis of unsaturated fatty acids, and phenylalanine metabolism. The mechanism of LJZD in ameliorating CIA was in concerned with the metabolic adjustments, relating to the regulation of linoleic acid metabolism, histidine metabolism, and pyrimidine metabolism.
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Objective:To observe the effect of forsythiaside A on gastrointestinal motility disorder induced by chemotherapy in mice， and explore the mechanism of forsythiaside A regulating gastrointestinal motility. Method:The 60 KM mice were randomly divided into normal group， model group， metoclopramide group （5 mg·kg-1） and forsythiaside A low， medium and high-dose groups （30， 60， 120 mg·kg-1）， 10 for each group， which include half male and half female. The above dose was given once a day for 4 consecutive days， which the intragastric volume was 10 mL·kg-1. One hour after 1rd day administration， equal volume of saline was intraperitoneally injected to the normal group， 2 mg·kg-1 cisplatin was intraperitoneally injected to the other groups with daily for 4 consecutive days. Observing the effects of forsythiaside A on gastric emptying and small intestinal propulsion on mice models， serum gastrin （GAS） and somatostatin （SS）， motilin （MTL）， vasoactive intestinal peptide （VIP） levels were examined by enzyme-linked immunosorbent assay （ELISA）. Activities of acetylcholinesterase （AChE） and total nitric oxide synthase （tNOS） in gastric antrum and ileum were detected by ELISA. The expression of AChE and inducible nitric oxide synthase （iNOS） in gastric antrum and ileum were detected by Western blot. Result:Compared with normal group， the gastric retention rate and small intestinal propulsion rate of the model group were significantly increased （P<0.01）， serum levels of MTL， GAS， SS and VIP， the AChE activity in the homogenate of ileum in the model group were significantly reduced （P<0.05，P<0.01）， while the tNOS activities in gastric antrum and ileum were significantly increased （P<0.05，P<0.01）. Protein expression of AChE in gastric antrum and ileum were significantly decreased （P<0.05）， and the expression level of iNOS protein was significantly increased in the model group （P<0.05）. Compared with model group， different doses of forsythiaside A can reduce the gastric residual rate and small intestinal propulsion rate of mice to varying degrees. Meanwhile forsythiaside A can increase the serum levels of MTL， GAS， SS， and VIP， and the AChE activity and protein expression levels in gastric antrum and ileum tissues were also increased， while tNOS activity and iNOS protein expression were decreased in gastric antrum and ileum （P<0.05，P<0.01）. Conclusion:Forsythiaside A can significantly ameliorate the delayed gastric emptying and small intestine hyperfunction induced by cisplatin in mice. Its mechanism to ameliorate gastrointestinal dysfunction caused by chemotherapy is related to the regulation of gastrointestinal AChE and NOS activity in gastric antrum and ileum and the regulation of gastrointestinal hormone levels.
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Objective::To explore the mechanism of Xiao Banxiatang in preventing and treating chemotherapy-induced nausea and vomiting by using network pharmacology. Method::The targets of chemotherapy-related nausea and vomiting were collected by therapeutic target database (TTD), Drugbank database and DisGeNET database. The target genes were normalized by Uniprot database. The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was selected according to oral bioavailabilityc (OB) ≥ 30%, drug-likeness (DL) ≥ 0.14 and the literature research. The active constituents of pinellia ternata and ginger were collected through the PubChem database, the ALOGPS2.1 database and the Swiss Target Prediction database, and the target of ginger was collected and standardized through the Uniprot database, the molecular inverse docking of the important component 6-gingerol was carried out through the DRAR-CPI database, gene ontology (GO) analysis and kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed through DAVID 6.8 database, and relationship diagrams were drawn by Cytoscape 3.2.1 software and network topology parameters were analyzed, GO and KEGG bubble maps were drawn by ImageGP tool. Result::A total of 148 targets for chemotherapeutic nausea and vomiting, and 27 active ingredients of Xiao Banxiatang were collected, including 22 associated with chemotherapeutic nausea and vomiting, 38 control targets, 67 biological processes based on GO analysis, 11 cell components, 18 molecular functions, 21 KEGG pathways, involving cyclic Adenosine monophosphate (cAMP) signaling pathway, calcium signaling pathway, Rap1 signaling pathway. Conclusion::Based on network pharmacology, chemotherapy-related nausea and vomiting and Xiao Banxiatang were analyzed to provide ideas for the prevention and treatment of chemotherapy-induced nausea and vomiting.
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The 2017 China (Lianyungang) International Medical Technology Conference was held in Lianyungang,Jiangsu Province during November 15-17,2017.During this conference,the Division for Traditional Chinese Medicine and Natural Products Pharmacology of Chinese Pharmacological Society (CNPHARS) and Jiangsu Kanion Pharmaceutical Co. Ltd.jointly held the Forum on R&D and Interna-tionalization of New Drugs and Health Products of Traditional Chinese Medicine.The forum was co-chaired by Professor ZHANG Yong-xiang, President of CNPHARS, Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS,and Chair of the Natural Product Section of Inter-national Union of Basic&Clinical Pharmacology(IUPHAR), Professor DU Guan-hua,former President of CNPHARS and Vice-Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS,and Dr.XIAO Wei,Chairman of the Board of Jiangsu Kanion Pharmaceutical Co. Ltd. And Vice-Chair of Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS. More than 70 scholars attended the forum, including four foreign experts [Michael SPEDDING, Secretary-General of IUPHAR; Professor Valérie B. SCHINI-KERTH, Vice-Chair of the Natural Product Section of IUPHAR; Professor Cherry WAINWRGHT, Director of Centre for Natural Product Drugs of Robert Gordon University; Professor InKyeom KIM, Director of the Korean Society of Pharmacology], members of the Division for Traditional Chinese Medicine and Natural Products Pharmacology of CNPHARS and leading researchers at Jiangsu Kanion Pharmaceutical Co.,Ltd.GU Jin-hui,Director of the Division of National Science and Technology Major Project for Drug Innovation,Department of Health Science,Technology and Education,National Health and Family Planning Commission of the People's Republic of China was also invited to attend the forum. Representatives discussed the R&D and internationalization of new drugs and health products of traditional Chinese medicine.The summary of views and advice of some experts was published here for the purpose of promoting domestic and overseas academic exchange, and playing an active role in improving the level of R&D and internationalization of new drugs and health products of traditional Chinese medicine in China.
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Aim To investigate the effects of astragalus polysaccharide ( APS ) on depressive behaviors and hippocampal NF-κB signaling in rats with depression. Methods Wistar rats were randomly divided into con-trol group, depressive group, APS-low (200 mg·kg-1 ·d-1 ) group and APS-high ( 400 mg · kg-1 · d-1 ) group. Depressive behaviors were induced by chronic unpredictable mild stress ( CUMS) in rats. After trea-ted with APS, depressive behaviors were valuated by open field test, forced swim test and sucrose preference test. Levels of NF-κB p65, phosphorylated NF-κB p65 ( p-NF-κB p65 ) , phosphorylated IκBα ( p-IκBα) , NF-κB p65 DNA binding activity, TNF-α, IL-1β and IL-6 were measured to assess the activity of NF-κB sig-naling pathways. Results Compared to control group, rats in depressive group had less sucrose intake in su-crose preference and longer immobility time in forced swim test, as well as increased hippocampal NF-κB signaling activity. However, APS treatment dose-de-pendently alleviated depressive-like behaviors and in-hibited the activation of NF-κB signaling induced by UCMS. Conclusion The antidepressant effects of APS might be associated with the inhibition of hipp-ocampal NF-κB signaling pathway.
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Aim To investigate the effects of astragalus polysaccharide (APS) on renal TGF-β1/Smads signa-ling pathway in rats with diabetes mellitus(DM). Methods Wistar rats were randomly divided into nor-mal group,DM group,APS low dose (APS-low) group and APS high dose (APS-high) group. Rats in APS-low group and APS-high group respectively received 200 and 400 mg·kg-1·d-1APS for 8 weeks. Con-centrations of fasting blood-glucose(FBG),blood urea nitrogen and creatinine,as well as urinary kidney injury molecule-1 (KIM-1) and osteopontin (OPN) were measured. Levels of TGF-β1,Smad2,phosphorylated Smad2 (p-Smad2),Smad3,phosphorylated Smad3 (p-Smad3),Smad7,matrix metalloproteinase (MMP) 2,MMP-9,tissue inhibitor of matrix metalloproteinases (TIMP)-1 and TIMP-2 were investigated. Results Compared to control group,DM group had higher levels of FBG,blood urea nitrogen,creatinine KIM-1,OPN, TGF-β1,Smad2,p-Smad2,Smad3,p-Smad3,TIMP-1 and TIMP-2,but lower levels of Smad7,MMP-2 and MMP-9. APS significantly decreased the levels of FBG,blood urea nitrogen,creatinine KIM-1 and OPN, as well as inhibited the activity of TGF-β1/Smads sig-naling pathway. Conclusion The renoprotective effects of APS might be associated with the inhibition of TGF-β1/Smads signaling pathway.
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Skin reaction or dermatological toxicities induced by immunotherapy is common. It usually manifests skin rash or erythema and can be cured by skin lotion or steroid. Nivolumab, a human IgG4 programmed cell death protein 1 (PD-1) inhibitor, blocks T cells activation preventing signal and allows the immune system to clear cancer cells. Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA, with less than 10% unusual skin reaction, like sensory neuropathy, peeling skin, erythema multiforme, vitiligo, and psoriasis. Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity. The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies, but the risk of side effects may be high. We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy. The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events. Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.
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<p><b>OBJECTIVE</b>To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC).</p><p><b>METHODS</b>In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival.</p><p><b>RESULTS</b>The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75; P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48; 95% confidence interval, 0.35-0.68; P<0.001). The main adverse effect of sorafenib was rash and acne of the skin (in 51.7% patients). The incidences of severe rash, diarrhea, and dry skin were 5.6%, 5.6%, and 2.2% in the sorafenib group. One patient reached partial response in the sorafenib group.</p><p><b>CONCLUSIONS</b>Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.</p>
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Antineoplastic Agents , Therapeutic Uses , Carcinoma, Hepatocellular , Drug Therapy , Mortality , Pathology , Cross-Over Studies , Disease-Free Survival , Kaplan-Meier Estimate , Liver Function Tests , Liver Neoplasms , Drug Therapy , Mortality , Pathology , Neoplasm Invasiveness , Neoplasm Staging , Niacinamide , Therapeutic Uses , Phenylurea Compounds , Therapeutic Uses , Treatment OutcomeABSTRACT
<p><b>OBJECTIVE</b>To study contractility of guinea pig ileum in vitro,and analyze the mechanism of anti-emetic effects of Lianqiao.</p><p><b>METHOD</b>Using emesis-relating agonists as drugs, the inhibitory effects of Lianqiao on guinea pig ileum contractility in vitro were observed in organ bath.</p><p><b>RESULT</b>Lianqiao could inhibit guinea pig ileum spontaneous contractions, reducing the tone of contractions dose-dependently. Acetylcholine (Ach), histamine (His), 5-hydroxytryptamine (5-HT) stimulated contractions of the guinea pig ileum, enhanced the tone and amplitude. All the three doses (10, 5, 2 g x L(-1)) of Lianqiao could suppress the contractility, significantly reduced the tone and amplitude of ileum contractions stimulated by drugs but not the frequency. Dopamine could inhibit the spontaneous contraction tone and amplitude of ileum; Both the large doses (10, 5 g x L(-1)) of Lianqiao could antagonise the inhibitory effect of DA, enhance the tone and amplitude. Small dose(2 g x L(-1)) had additive effects on tone of ileum contractions with DA,but enhanced the amplitude not the frequency.</p><p><b>CONCLUSION</b>Lianqiao have an inhibitory effect on guinea pig ileum contractions,the mechanism might be blocking M receptor, H1 receptor, 5-HT receptor and D2 receptor or directly suppressed ileum smooth muscle. The mechanisms of anti-emetic effect of Lianqiao needs further study.</p>
Subject(s)
Animals , Male , Antiemetics , Pharmacology , Dopamine , Pharmacology , Forsythia , Guinea Pigs , Ileum , Physiology , Muscle Contraction , PhytotherapyABSTRACT
Objective: To observe the anti-tumor effect of Phellinus Linteus and Coriolus Versicolor Capsules (PLCVC) in S180 sarcoma and H22 hepatoma animal models in mice. Methods: The sarcoma S1180 and hepatoma H22 models were established in mice. After 12 days of treatment, the animals were killed, and the subcutaneous sarcoma were separated and weighted. The levels of vascular endothelial growth factor(VEGF), CD4 and CD8 of S180 tumor tissue were investigated by immunohistochemical method. KM mice were intraperitoneal injected with H22 hepatoma cells, and treated with different experimental drugs. The survival time was observed and recorded, and life-prolongation rate was calculated. Result: PLCVC could inhibit the growth of S180 and H22 tumor, and inhibit the expression of VEGF, improve the expression of CD4 and CD8. The survival time of the mice treated by PLCVC were significantly longer than the untreated group. Conclusion: PLCVC can inhibit the growth of tumour, the mechanism is partially related to inhibiting angiogenesis and improving the immunological function.
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BACKGROUND: It has reported that nicotinamide is capable of protecting intervertebral disc (IVD) against interleukin-1β (IL-1β) or tumor necrosis factor-alpha (TNF-α) induced degeneration. However, the protective mechanism of nicotinamide on IVD cells apoptosis and proliferation remains unclear.OBJECTIVE: To investigate regulatory effects of nicotinamide on rabbit nucleus pulposus cell apoptosis and proliferation in vitro.DESIGN, TIME AND SETTING: Randomized control grouping design, which was carried out in the Laboratory of Orthopaedics and Stem Cell Center, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from April to October 2007.MATERIALS: Ten Japanese white rabbits (aged 2-3 months weighing 1.5-2.0 kg) were used in this study. Furthermore, nucleus pulposus cells obtained from L1-6 lumbar spine were harvested and cultured for further experiments.METHODS: The NP cells were divided into 6 groups, including control group (without any drug as control), nicotinamide group (0.5 g/L nicotinamide), IL-1β group (10 μg/L IL-1β), IL-1β + caspase group (10 μg/L IL-1β and non-specific caspase inhibitor Z-VAD-FMK), IL-1β + small-dose nicotinamide group (10 μg/L IL-1β and 0.05 g/L nicotinamide), and IL-1β + large-dose nicotinamide group (10 μg/L IL-1β and 0.5 g/L nicotinamide). After 3 days of culture, the cells were examined with Annexin V-PI staining, caspase-3, 8 and 9 activity staining and MTT assay.MAIN OUTCOME MEASURES: The apoptotic rates, the positive rates of caspase-3, 8 and 9 activity staining and the absorbance of MTT assay of each group.RESULTS: ① As compared to IL-1β group, the apoptotic rates were decreased in the IL-1β + caspase group and IL-1β + large-dose nicotinamide group (P < 0.01). ②As compared to IL-1β group, the positive rates of caspase-3, 8 and 9 activity staining were decreased in the IL-1β + caspase group, IL-1β + large-dose and small-dose nicotinamide groups (P < 0.01 or P < 0.01). ③As compared to IL-1β group, the absorbance was increased in the IL-1β + caspase group and IL-1β + large-dose nicotinamide group (P < 0.01).CONCLUSION: Nicotinamide is capable of promoting cell proliferation and inhibiting IL-1β induced apoptosis of nucleus pulposus cells in vitro. The inhibition of apoptosis mainly acts via inhibition of the mitochondrial pathway.
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AIM To establish radioligand binding assay of gastrin receptor in rat gastric parietal cell. METHODS Using 125 I labeled [Leu 15 ] gastrin 17 I as the radioligand, rat gastric parietal cells as the receptor preparations. RESULTS In the range of the study, a Scatchard plot of the binding was made by Ligand program with an equilibrium K d of approximately 1 249?10 -10 mol?L -1 and a maximum binding capacity of 4 4604?10 -12 mol?L -1 . The amount of gastrin binding was strongly associated with the cell concentration of rat gastric parietal cell preparations ranged from 0 25?10 9 to 2?10 9 cells?L -1 . The variant coefficent of the binding assay was 7 04% within the same sample. The competitive inhibiting analyses showed that 125 I gastrin was bound to gastric parietal cell preparations with a high specificity. CONCLUSION The radioligand binding assay of gastrin receptor in rat gastric parietal cell preparations meets the criteria for establishing receptor binding assay.
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Only limited species of animals with vomiting reflex are available for the vomiting animal models. From 1980s some new vomiting models have been developed, such as in ferret, which is convinced its vomiting behavior is closest to human being; Suncus murinus(house musk shrew)is the smallest mammal used in vomiting model and the most sensitive animal to motion sickness; rat, although without vomiting reflex, but consuming non-nutritive substance such as kaolin(pica) can be considered to be an index of nausea and vomiting; mink, from the same genus as ferret, can be a substitute of ferret in vomiting model. It should be noted that the sensitivity profile to different emetic stimuli is species-dependent.