Exposure to cytarabine causes side effects on adult development and physiology and induces intestinal damage via apoptosis in Drosophila.

Cytarabine (Ara-C) is a widely used drug in acute myeloid leukemia (AML). However, it faces serious challenges in clinical application due to serious side effects such as gastrointestinal disorders and neurologic toxicities. Until now, the mechanism of Ara-C-induced damage is not clear. Here, we used Drosophila melanogaster (fruit fly) as the in vivo model to explore the side effects and mechanism of Ara-C. Our results showed that Ara-C supplementation delayed larval development, reduced lifespan, impaired locomotor capacity, and increased susceptibility to stress response in adult flies. In addition, Ara-C led to the intestinal morphological damage and ROS accumulation in the guts. Moreover, administration of Ara-C promoted gene expressions of Toll pathway, IMD pathway, and apoptotic pathway in the guts. These findings raise the prospects of using Drosophila as in vivo model to rapidly assess chemotherapy-mediated toxicity and efficiently screen the protective drugs.

Using Drosophila melanogaster as a suitable platform for drug discovery from natural products in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and life-treating inflammatory disease that can occur in multiple parts of the human intestine and has become a worldwide problem with a continually increasing incidence. Because of its mild early symptoms, most of them will not attract people's attention and may cause more serious consequences. There is an urgent need for new therapeutics to prevent disease progression. Natural products have a variety of active ingredients, diverse biological activities, and low toxicity or side effects, which are the new options for preventing and treating the intestinal inflammatory diseases. Because of multiple genetic models, less ethical concerns, conserved signaling pathways with mammals, and low maintenance costs, the fruit fly Drosophila melanogaster has become a suitable model for studying mechanism and treatment strategy of IBD. Here, we review the advantages of fly model as screening platform in drug discovery, describe the conserved molecular pathways as therapetic targets for IBD between mammals and flies, dissect the feasibility of Drosophila model in IBD research, and summarize the natural products for IBD treatment using flies. This review comprehensively elaborates that the benefit of flies as a perfact model to evaluate the therapeutic potential of phytochemicals against IBD.

Protective effect of astragalus membranaceus and its bioactive compounds against the intestinal inflammation in Drosophila.

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicines. Astragalus membranaceus (AM), also named Huangqi, is one of the most commonly used fundamental herbs in China. Here, we aimed to investigate mechanism and bioactive compounds of AM on treating sodium dodecyl sulfate (SDS)- induced colitis in Drosophila flies. Our data showed that AM extract (AME) supplementation had no toxic effect in flies, and protected flies against SDS-induced lifespan shortening, intestinal morphological damage, and colon length shortening. Moreover, AME supplementation remarkably rescued SDS-induced intestinal stem cell (ISC) overproliferation and increased reactive oxygen species (ROS) level in the intestine. Mechanistically, AME remarkably rescued the altered expression levels of genes and proteins in c-Jun N-terminal kinase (JNK) and JAK-STAT signaling pathways induced by SDS in gut. Additionally, formononetin, isoliquiritigenin, isorhamnetin, astragaloside I, astragaloside III, vanillic acid, and caffeic acid in AM had protection against SDS-induced inflammatory damage in flies. Taken together, AME could ameliorate the intestinal inflammation partially by suppressing oxidative stress-associated JNK signaling and JAK-STAT signaling pathways. AME may provide a theoretical basis for natural medicine toward treating intestinal inflammatory disease in human.

Gastrodin extends the lifespan and protects against neurodegeneration in the Drosophila PINK1 model of Parkinson's disease.

Gastrodin is the main bioactive ingredient of a famous Chinese herb Rhizoma Gastrodiae. Many studies have reported that gastrodin has antioxidative and neuroprotective effects, although its effect on longevity and the mechanism of neuroprotection have not been well studied. Here, we use Drosophila melanogaster as a model to investigate the longevity and neuroprotective effects of gastrodin. Gastrodin significantly extended the lifespan, increased the climbing ability, enhanced the resistance to oxidative stress, increased the enzyme activities of superoxide dismutase (SOD) and catalase (CAT), and promoted the expression of anti-oxidative genes in old flies. The food intake, reproduction and starvation resistance were not affected in flies treated with gastrodin. Moreover, gastrodin delayed the onset of Parkinson-like phenotypes in Pink1B9 mutant flies, including the prolongation of the lifespan, rescue of the climbing ability, rescue of the progressive loss of a cluster of dopaminergic neurons in the protocerebral posterial lateral 1 region, and increase of the dopamine content in the brain. Gastrodin did not ameliorate the tau-induced neurobehavioral deficits in the fly AD model of taupathy. Together, these results indicate that gastrodin could prolong the lifespan by regulating the antioxidant ability, and protect against neurodegeneration in the Pink1B9 model of PD. This suggests that gastrodin can be considered as an ideal therapeutic candidate for drug development towards anti-aging.

[Effects of Radix Angelicae Sinensis on airway mucus hypersecretion and the TNF-α/NF-κB signaling pathway in Yin-deficiency asthmatic mice].

Objective: To investigate the therapeutic effects of Radix Angelicae Sinensis (RADA) on airway mucus hypersecretion and the tumor necrosis factor-α/ nuclear factor- κB (TNF-α/NF-κB) signaling pathway in Yin-deficiency asthma mice. Methods: KM mice were randomly divided into control group, model group, ambroxol group and RADA low, medium and high dose (2, 4 and 8 g/kg) group(n=12). Ovalbumin and the thyroid gland were used to replicate the model of Yin-deficiency asthma. Asthma symptoms in mice , immune globulin E (IgE) , TNF-α , and the expressions of Mucin 5ac (Muc5ac) and NF- κB in lung tissue were observed under the intervention of RADA. Results: RADA at the doses of 2,4 and 8 g/kg could alleviate the asthma symptoms of Yin-deficiency asthma mice significantly, reduce the levels of IgE in serum and TNF-α in bronchoalveolar lavage fluid (BALF), and inhibite the overexpressions of Muc5ac and NF- κB in lung tissue. Conclusion: RADA has significant anti-asthmatic effect. One of its mechanisms is to inhibit TNF-α/NF- κB signaling pathway and to alleviate airway mucus hypersecretion.

[Therapeutic effects of Dunhuang Liaofengxushouruo decoction on chronic heart failure in rats].

OBJECTIVE: To observe the therapeutic effects and mechanism of Dunhuang Liaofengxushouruo decoction (LXD) (Traditional Chinese Medicine) on chronic heart failure(CHF) in rats. METHODS: Forty-eight male Wistar rats were randomly divided into normal group(n=8):model group, captopril group and LXD(Traditional Chinese Medicine) high, medium and low dose group. Except the normal group, the rats were intravenous injected with adriamycin 2.5 mg/kg in one day for 6 weeks, the captopril rats were intragastric administrated by captopril 25 mg/kg, LXD high, medium and low dose groups were intragastric administrated by LXD of 80, 40, 20 g/kg for 6 consecutive weeks. The rats breathing, coat color, activity, body weight(BW) and time of exhaustive swimming were measured; Heart rate, mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximal rate of left ventricular pressure (+dp/dtmax or -dp/dtmax)of each rat were examined by Power Lab. The levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured; The rats were sacrificed and hearts removed for separation of left and right ventricle, the antioxidant activity and ventricular mass index were measured, left ventricular myocardium was administrated by 4% paraformaldehyde, HE staining, morphological changes were observed under microscope. RESULTS: Body weight of each group decreased, and time of exhaustive swimming decreased after modeling (P<0.01). At 28 days after administration, BW in high and middle dose of LXD groups were increased and the swimming time of rats in LXD high dose group was increased (P<0.05).At 42 days, BW in all of LXD groups were increased and the exhaustive swimming time of high and middle dose of LXD were prolonged (P<0.05), MAP was decreased and LVSP, +dp/dtmax or -dp/dtmax were increased in LXD high and middle groups. The LVEDP was decreased in high dose of LXD group(P<0.05,P<0.01). The levels of creatine kinase (CK) and aspartate aminotransferase (AST) in middle and low dose of LXD groups were decreased(P<0.05,P<0.01), and the serum levels of IL-6, TNF-α and malondialdehyde (MDA) in serum in LXD high and middle dose groups were lower. The activities of superoxide dismutase (SOD) in serum were increased in all of LXD groups, and the LVMI and RVMI were decreased in high and middle dose of LXD groups(P<0.05,P<0.01). The pathological results showed that myocardial fiber arrangement and myocardial interstitial edema phenomenon were obviously improved in high dose of LXD group and CMD decreased. CONCLUSIONS: Therapeutic effect of LXD on CHF by doxorubicin-induced in rats is confirmed, the mechanisms are associated with improved hemodynamics and myocardial tissue.

[Preliminary pharmacodynamics study on antiasthmatic action of butylphthalide in guinea pig].

OBJECTIVE: To study the anti-asthmatic effects of butylphthalide in guinea pig. METHODS: This research included isolated tra-cheal smooth muscle and in vivo animal experiments. Antispasmodic effects of butylphthalide at the concentrations of 1, 10, 100 mg/L were observed through spasmodical tracheal smooth muscle of guinea pig induced by acetylcholine or histamine (n=10). After screened, the guinea pigs were divided into control group, model group, dexamethasone(DXM) group, high and low dose butylphthalide groups. The effects of butylphthalide on nitric oxide (NO), endothelin-1 (ET-1) and asthmatic behaviors were observed on the asthmatic guinea pigs that were stimu-lated six times by the excitation fluid (1% ACh:0.05% Hist=1:1). RESULTS: Butylphthalide at the concentrations of 1、10、100 mg/L had an-ti-spasmodic effects on spasmodical tracheal smooth muscle of guinea pig (15.08 ±7.68、42.41 ±13.54、77.56 ±24.82 to acetylcholine, 19.40 ±7.60、56.84 ±11.72、76.35 ±19.40 to histamine), which showed a certain dose-effect relationship. Butylphthalide could prolong asth-matic incubation period (53.3 ±13.2、33.1 ±13.0), improve asthmatic behaviors, reduce NO in serum (78.71 ±19.40、84.75 ±20.97) and ET-1 in bronchoalveolar lavage fluid (24.30 ±5.80、28.50 ±6.31) (P < 0.05, 0.01). CONCLUSIONS: Butylphthalide has some effects of anti-asthma and one of the mechanisms is to relieve abnormal increase of NO and ET-1.

[Effect of Volatile Oil of Radix Angelicae Sinensis on experimental asthma in rats].

OBJECTIVE: To study the effects of Volatile Oil of Radix Angelicae Sinensis (VOA) on experimental asthma in rat model based on abnormal immune functions of Treg cells. METHODS: After grouping, the asthmatic rats were developed through injecting OVA and AI(OH)3 for sensitization and then administering OVA aerosol for challenge, and the respiratory functions, asthmatic behaviors, IL-10 levels in bronchoalveolar lavage fluid (BALF) (ELISA) and Foxp3 expression (immunohistochemistry) in lung of asthmatic rats were observed. RESULTS: VOA at the doses of 40-160 mg/kg could improve the respiratory functions and the asthmatic behaviors, and upgrade IL-10 levels in BALF and Foxp3 expression in lung of asthmatic rats. CONCLUSION: VOA has some effects of anti-asthma and one of the mechanisms is to improving the lower immune functions of Treg cells.

Matrine alters microRNA expression profiles in SGC-7901 human gastric cancer cells.

Matrine, a major alkaloid extracted from Sophora flavescens, has been reported to possess antitumor properties in several types of cancers, including gastric cancer. However, its mechanisms of action on gastric cancer remain poorly understood. Dysregulation of microRNAs, a class of small, non-coding, regulatory RNA molecules involved in gene expression, is strongly correlated with cancer. The aim of the present study was to demonstrate that matrine treatment altered miRNA expression in SGC7901 cells. Using miRCURY™ microarray analysis, we identified 128 miRNAs substantially exhibiting >2-fold expression changes in matrine-treated cells relative to their expression levels in untreated cells. RT-qPCR was used to show that the levels of 8 miRNAs whose target genes were clustered in the cell cycle pathway increased, while levels of 14 miRNAs whose target genes were clustered in the MAPK signaling pathway decreased. These results were consistent with those from the miRNA microarray experiment. Bioinformatical analysis revealed that the majority of 57 identified enrichment pathways were highly involved in tumorigenesis. In conclusion, the results demonstrated that matrine induces considerable changes in the miRNA expression profiles of SGC7901 cells, suggesting miRNA microarray combined with RT-qPCR validation and bioinformatical analysis provide a novel and promising approach to identify anticancer targets and the mechanisms of matrine involved.

[Effect of flavonoids from hedysari radix on pulmonary functions of pulmonary fibrosis rat].

OBJECTIVE: To study the effect of flavonoids from Hedysari Radix on pulmonary functions of pulmonary fibrosis rat and its mechanism. METHODS: 72 Wistar rats were randomly divided into 6 groups: blank control group, model group, prednisone group, Hedysari Radix flavonoids low, medium and high dosage group. The rat model was established by propelling bleomycin into bronchial tree through endotracheal intubation with laryngoscope. The pulmonary fanctions were measured. RESULTS: Hedysari Radix flavonoids could normalize the pulmonary functions of rats with bleomycin-induced pulmonary fibrosis. CONCLUSION: Hedysari Radix flavonoids can inhibit the process of pulmonary fibrosis.