RESUMO
Aspercitrininone A (1), a novel polyketide featuring an unprecedented tetracyclic 6/6/6/5 spiral skeleton, was obtained from the rice fermentation cultures of the fungus Aspergillus cristatus together with five known compounds (2-6). Their structures were determined by HRESIMS data, 1D and 2D NMR spectroscopic analysis, and electronic circular dichroism (ECD) calculations. Aspercitrininone A was revealed as a new type of C/D cycle spiral structure and an unusual addition product of o-quinoid form citrinin with 2-methylterrefuranone. Compounds 1, 4, and 5 exhibited potent antibacterial activities with minimal inhibitory concentration (MIC) values from 13.2 to 67.3 µg/mL against four strains of human pathogenic bacteria in vitro.
Assuntos
Aspergillus , Policetídeos , Humanos , Policetídeos/farmacologia , Policetídeos/química , Estrutura Molecular , Antibacterianos/farmacologia , Antibacterianos/química , EsqueletoRESUMO
Vitellogenins (Vtgs) are essential for female reproduction in oviparous animals, yet the exact roles and mechanisms remain unknown. In the present study, we knocked out vtg1, which is the most abundant Vtg in zebrafish, Danio rerio via the CRISPR/Cas 9 technology. We aimed to identify the roles of Vtg1 and related mechanisms in reproduction and development. We found that, the Vtg1-deficient female zebrafish reduced gonadosomatic index, egg production, yolk granules and mature follicles in ovary compared to the wide type (WT). Moreover, the Vtg1-deficient zebrafish diminished hatching rates, cumulative survival rate, swimming capacity and food intake, but increased malformation rate, and delayed swim bladder development during embryo and early-larval phases. The Vtg1-deficiency in female broodstock inhibited docosahexaenoic acid-enriched phosphatidylcholine (DHA-PC) transportation from liver to ovary, which lowered DHA-PC content in ovary and offspring during larval stage. However, the Vtg1-deficient zebrafish increased gradually the total DHA-PC content via exogeneous food intake, and the differences in swimming capacity and food intake returned to normal as they matured. Furthermore, supplementing Vtg1-deficient zebrafish with dietary PC and DHA partly ameliorated the impaired female reproductive capacity and larval development during early phases. This study indicates that, DHA and PC carried by Vtg1 are crucial for female fecundity, and affect embryo and larval development through maternal-nutrition effects. This is the first study elucidating the nutrient and physiological functions of Vtg1 and the underlying biochemical mechanisms in fish reproduction and development.
Assuntos
Ovário , Peixe-Zebra , Animais , Feminino , Vitelogeninas/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Fígado , Reprodução/fisiologia , LecitinasRESUMO
OBJECTIVE: Our team previously reported the use of antofloxacin-based bismuth quadruple therapy for the eradication of Helicobacter pylori (H. pylori). This study aimed to compare the efficacy and safety of 10 and 14 days of antofloxacin-based versus 14 days of clarithromycin-based bismuth quadruple therapy in the first-line treatment for H. pylori infection. METHODS: 1174 patients with H. pylori infection were randomized into three groups: 10-days and 14-days antofloxacin (ANT10 and ANT14) groups who received 10 and 14 days of antofloxacin-based bismuth quadruple therapy (colloidal bismuth pectin 200 mg t.i.d., esomeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and antofloxacin 200 mg q.d.), 14-days clarithromycin (CLA14) group who received 14 days of clarithromycin-based bismuth quadruple therapy (colloidal bismuth pectin 200 mg t.i.d., esomeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d.). Eradication rate, antibiotic resistance and adverse events were analyzed. RESULTS: The intention-to-treat (ITT) and per-protocol (PP) analyses have showed statistically different eradication rates between ANT14 group and ANT10 group (ITT p = 0.001; PP p < 0.001), but no statistical difference between ANT10 group and CLA14 group (ITT p = 0.340; PP p = 0.092). Treatment regimen, drug resistance and therapy duration were important clinical factors related to H. pylori eradication rates in multivariate logistic analysis. Longer durations had significantly higher eradication rates in patients with antibiotic-resistant strains or antibiotic-susceptible strains. The incidences of nausea and bitter taste were significantly higher in CLA group compared with ANT group (p = 0.002 for nausea; p = 0.002 for bitter taste). The ANT10 and ANT14 group had similar adverse event rates of gastrointestinal reactions. CONCLUSION: The study showed that the H. pylori eradication rate with ANT14 therapy was higher than that with ANT10 and CLA14 therapy without significantly increasing the rates of adverse event. 14 days of antofloxacin-based bismuth quadruple therapy may be a more effective way as the first-line treatment for H. pylori infection.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/uso terapêutico , Claritromicina/farmacologia , Bismuto/uso terapêutico , Bismuto/efeitos adversos , Esomeprazol/uso terapêutico , Quimioterapia Combinada , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/etiologia , Amoxicilina/uso terapêutico , Amoxicilina/farmacologia , Náusea , Pectinas/farmacologia , Pectinas/uso terapêutico , Resultado do Tratamento , Inibidores da Bomba de Prótons/efeitos adversosRESUMO
BACKGROUND: Fish cannot use carbohydrate efficiently and instead utilize protein for energy supply, thus limiting dietary protein storage. Protein deposition is dependent on protein turnover balance, which correlates tightly with cellular energy homeostasis. Mitochondrial fatty acid ß-oxidation (FAO) plays a crucial role in energy metabolism. However, the effect of remodeled energy homeostasis caused by inhibited mitochondrial FAO on protein deposition in fish has not been intensively studied. OBJECTIVES: This study aimed to identify the regulatory role of mitochondrial FAO in energy homeostasis maintenance and protein deposition by studying lipid, glucose, and protein metabolism in fish. METHODS: Carnitine-depleted male Nile tilapia (initial weight: 4.29 ± 0.12 g; 3 mo old) were established by feeding them with mildronate diets (1000 mg/kg/d) for 6 wk. Zebrafish deficient in the carnitine palmitoyltransferase 1b gene (cpt1b) were produced by using CRISPR/Cas9 gene-editing technology, and their males (154 ± 3.52 mg; 3 mo old) were used for experiments. Normal Nile tilapia and wildtype zebrafish were used as controls. We assessed nutrient metabolism and energy homeostasis-related biochemical and molecular parameters, and performed 14C-labeled nutrient tracking and transcriptomic analyses. RESULTS: The mitochondrial FAO decreased by 33.1-88.9% (liver) and 55.6-68.8% (muscle) in carnitine-depleted Nile tilapia and cpt1b-deficient zebrafish compared with their controls (P < 0.05). Notably, glucose oxidation and muscle protein deposition increased by 20.5-24.4% and 6.40-8.54%, respectively, in the 2 fish models compared with their corresponding controls (P < 0.05). Accordingly, the adenosine 5'-monophosphate-activated protein kinase/protein kinase B-mechanistic target of rapamycin (AMPK/AKT-mTOR) signaling was significantly activated in the 2 fish models with inhibited mitochondrial FAO (P < 0.05). CONCLUSIONS: These data show that inhibited mitochondrial FAO in fish induces energy homeostasis remodeling and enhances glucose utilization and protein deposition. Therefore, fish with inhibited mitochondrial FAO could have high potential to utilize carbohydrate. Our results demonstrate a potentially new approach for increasing protein deposition through energy homeostasis regulation in cultured animals.
Assuntos
Ácidos Graxos/metabolismo , Glucose/metabolismo , Metilidrazinas/farmacologia , Mitocôndrias/metabolismo , Proteínas/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Ciclídeos , Citocromos b/genética , Citocromos b/metabolismo , DNA , Metabolismo Energético , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Homeostase , Insulina , Masculino , Mutação , Oxirredução , Peixe-ZebraRESUMO
Energy metabolism plays important roles in stress resistance and immunity in mammals, however, such functions have not been established in fish. In the present study, Nile tilapia (Oreochromis niloticus) was fed with mildronate, an inhibitor of mitochondrial fatty acid (FA) ß-oxidation, for six weeks subsequently challenged with Aeromonas hydrophila and ammonia nitrogen exposure. Mildronate treatment reduced significantly l-carnitine concentration and mitochondrial FA ß-oxidation efficiency, while it increased lipid accumulation in liver. The fish with inhibited hepatic FA catabolism had lower survival rate when exposed to Aeromonas hydrophila and ammonia nitrogen. Moreover, fish fed mildronate supplemented diet had lower immune enzymes activities and anti-inflammatory cytokine genes expressions, but had higher pro-inflammatory cytokine genes expressions. However, the oxidative stress-related biochemical indexes were not significantly affected by mildronate treatment. Taken together, inhibited mitochondrial FA ß-oxidation impaired stress resistance ability in Nile tilapia mainly through inhibiting immune functions and triggering inflammation. This is the first study showing the regulatory effects of lipid catabolism on stress resistance and immune functions in fish.
Assuntos
Ciclídeos , Ácidos Graxos/metabolismo , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Metilidrazinas/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Aeromonas hydrophila/fisiologia , Amônia/metabolismo , Ração Animal , Animais , Carnitina/metabolismo , Ciclídeos/metabolismo , Dieta , Suplementos Nutricionais , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Mitocôndrias/efeitos dos fármacos , Nitrogênio/metabolismo , Oxirredução/efeitos dos fármacos , Distribuição AleatóriaRESUMO
Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Colestase/induzido quimicamente , Suplementos Nutricionais/efeitos adversos , Hepatopatias/epidemiologia , Antibacterianos/efeitos adversos , Antibacterianos/toxicidade , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , China/epidemiologia , Colestase/complicações , Colestase/patologia , Diagnóstico Diferencial , Suplementos Nutricionais/toxicidade , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Guias como Assunto , Humanos , Incidência , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Masculino , Prognóstico , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Peroxisome proliferation activated receptor α (PPARα) is an important transcriptional regulator of lipid metabolism and is activated by high-fat diet (HFD) and fibrates in mammals. However, whether nutritional background affects PPARα activation and the hypolipidemic effects of PPARα ligands have not been investigated in fish. In the present two-phase study of Nile tilapia (Oreochromis niloticus), fish were first fed a HFD (13% fat) or low-fat diet (LFD; 1% fat) diet for 10 weeks, and then fish from the first phase were fed the HFD or LFD supplemented with 200 mg/kg body weight fenofibrate for 4 weeks. The results indicated that the HFD did not activate PPARα or other lipid catabolism-related genes. Hepatic fatty acid ß-oxidation increased significantly in the HFD and LFD groups after the fenofibrate treatment, when exogenous substrates were sufficiently provided. Only in the HFD group, fenofibrate significantly increased hepatic PPARα mRNA and protein expression, and decreased liver and plasma triglyceride concentrations. This is the first study to show that body fat deposition and dietary lipid content affects PPARα activation and the hypolipidemic effects of fenofibrate in fish, and this could be due to differences in substrate availability for lipid catabolism in fish fed with different diets.
Assuntos
Ciclídeos/fisiologia , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Fenômenos Fisiológicos da Nutrição , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Especificidade de Órgãos/genética , Oxirredução , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Excess fat accumulation has been observed widely in farmed fish; therefore, efficient lipid-lowering factors have obtained high attention in the current fish nutrition studies. Dietary L-carnitine can increase fatty acid ß-oxidation in mammals, but has produced contradictory results in different fish species. To date, the mechanisms of metabolic regulation of L-carnitine in fish have not been fully determined. The present study used zebrafish to investigate the systemic regulation of nutrient metabolism by dietary L-carnitine supplementation. L-carnitine significantly decreased the lipid content in liver and muscle, accompanied by increased concentrations of total and free carnitine in tissues. Meanwhile, L-carnitine enhanced mitochondrial ß-oxidation activities and the expression of carnitine palmitoyltransferase 1 mRNA significantly, whereas it depressed the mRNA expression of adipogenesis-related genes. In addition, L-carnitine caused higher glycogen deposition in the fasting state, and increased and decreased the mRNA expressions of gluconeogenesis-related and glycolysis-related genes, respectively. L-carnitine also increased the hepatic expression of mTOR in the feeding state. Taken together, dietary L-carnitine supplementation decreased lipid deposition by increasing mitochondrial fatty acid ß-oxidation, and is likely to promote protein synthesis. However, the L-carnitine-enhanced lipid catabolism would cause a decrease in glucose utilization. Therefore, L-carnitine has comprehensive effects on nutrient metabolism in fish.
Assuntos
Carnitina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Peixe-Zebra/metabolismo , Animais , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Suplementos Nutricionais , Gluconeogênese/genética , Glicogênio/metabolismo , Glicólise/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/metabolismo , Músculos/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Using rare minnow (Gobiocypris rarus) embryos as experimental model, the developmental toxicity of Cu, Zn and Cd were investigated following exposure to 0.001-1.000mg/L for 72h, and the toxicity effects were evaluated by larval malformation rate, heart rate, pericardial area, spontaneous movements, tail length, enzyme activities and biomarker genes. Our results revealed that increased malformation rate provide a gradual dose-response relationship, and the most pronounced morphological alteration was heart and body malformations. Values of 72h EC50 with their 95 percent confidence intervals on G. rarus embryos were 0.103 (0.072-0.149)mg/L for Cu, 0.531 (0.330-1.060)mg/L for Zn, 0.219 (0.147-0.351)mg/L for Cd. Enzyme activities can be regard as a type of low-dose stimulation and high-dose inhibition. Stress and metabolism-related genes (hsp70, cyp1a and mt) were significantly up-regulated, development-related genes (wnt8a, vezf1 and mstn) were significantly down-regulated after the treatment by Cu, Zn and Cd. Overall, the present study points out Cu, Zn and Cd are highly toxic to G. rarus embryos. The information presented in this study will be helpful in fully understanding the toxicity induced by Cu, Zn and Cd in fish embryos.
Assuntos
Cádmio/toxicidade , Cobre/toxicidade , Cyprinidae/embriologia , Embrião não Mamífero/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Zinco/toxicidade , Animais , Cyprinidae/anormalidades , Proteínas de Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Concentração Inibidora 50RESUMO
A new compound, rel-2R,5S,9S,10R,11R,12-trihydroxy-6(7)-spirovetiven-8-one-9- O-ß-D-glucopyranoside (1), along with a known spirovetiven glucoside (2), was isolated from the leaves of Nicotiana rustica L. The structure of compound (1) was elucidated on the basis of spectroscopic data.
Assuntos
Proliferação de Células/efeitos dos fármacos , Glucosídeos/isolamento & purificação , Nicotiana/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Sesquiterpenos/isolamento & purificação , Aspergillus niger/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , China , Escherichia coli/efeitos dos fármacos , Etanol , Glucosídeos/química , Glucosídeos/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
OBJECTIVE: To explore the effects of taurine on the ultrastructure and P2X7 receptor protein expression in brain following traumatic brain injury (TBI) in rats. METHODS: Forty male SD rats, were divided randomly into four groups that were sham-operated group, TBI group, TBI plus low-dose taurine group and TBI plus high-dose taurine group. The TBI model was established by Marmarou's method, the expression of P2X7 receptor protein in parietal cortex and hippocampus was detected by the immunohistochemical method, the ultrastructure of parietal cortex were observed by transmission electron microscope. RESULTS: Compared with sham-operated group, the positive expression cells of P2X7 receptor protein in parietal cortex and hippocampus of TBI group were significantly increased (P < 0.01). Compared with TBI group, the positive expression cells of P2X7 receptor protein in parietal cortex and hippocampus of TBI plus low-dose taurine group and TBI plus high-dose taurine group were significantly decreased (P <0.01 or P <0.05). Compared with TBI plus low-dose taurine group, the positive expression cells of P2X7 receptor protein in parietal cortex and hippocampus of TBI plus high-dose taurine group were significantly decreased (P < 0.05 or P < 0.01). The pathological damage of parietal cortex in the TBI plus high-dose taurine group was obviously lightened. CONCLUSION: Taurine exerts the neuroprotective effect on TBI in rats, the protective mechanism might be associated with down-regulating the expression of P2X7 receptor protein in parietal cortex and hippocampus.