RESUMO
Hedscandines A-C (1-3), three undescribed indole alkaloids were isolated from Hedyotis scandens Roxb, a traditional Chinese medicine widely used in the treatment of respiratory ailments. Their structures were elucidated by extensive spectroscopic data and electronic circular dichroism calculation. Hedscandine A (1), possessed a unique carbon skeleton with a 1,4-oxazonin-2(3H)-one core system and displayed a rapid bactericidal activity against MRSA with a MIC value of 16 µg/mL. Mechanistic studies showed that compound 1 could disrupt the integrity of bacterial cell membranes and thus lead to bacterial death.
Assuntos
Hedyotis , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/química , Testes de Sensibilidade Microbiana , Alcaloides Indólicos/químicaRESUMO
Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.
Assuntos
Dislipidemias , Transdução de Sinais , Humanos , Olanzapina/farmacologia , Estudos de Casos e Controles , Estresse do Retículo Endoplasmático , Dislipidemias/induzido quimicamente , Lipídeos , eIF-2 Quinase/metabolismo , ApoptoseRESUMO
This study aimed to investigate the chemical constituents in the water extract of the whole herb of Hedyotis scandens by silica gel, ODS, and MCI column chromatographies together with preparative high-performance liquid chromatography(HPLC). The structures of isolated constituents were identified by NMR, HR-ESI-MS, etc. Thirteen compounds were isolated and identified as methyl 4-benzoyloxy-3-methoxybenzeneacetate(1), 4-benzoyloxy-3-methoxybenzeneacetic acid(2), 3-(4-hydroxy-3-methoxyphenyl)-propanoic acid(3), salicylic acid(4), 3-hydroxy-4-methoxypyridine(5), syringic acid(6), hydroxycinnamic acid(7),(R)-6-methyl-4,6-bis(4-methylpent-3-enyl)cyclohexa-1,3-dienecarbaldehyde(8), 1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol(9), 1H-indole-3-carboxaldehyde(10), isoscopoletin(11), syringaresinol(12), and pinoresinol(13). Among them, compounds 1 and 2 were new phenolic acid compounds, compounds 3-5, 8-11, and 13 were isolated from this genus for the first time, and compounds 6, 7, and 12 were obtained from H. scandens for the first time. The activity test showed that compounds 1 and 10 had a certain inhibitory effect on Mycobacterium smegmatis, with MIC_(50) values of 58.5 and 33.3 µg·mL~(-1), respectively.
Assuntos
Medicamentos de Ervas Chinesas , Hedyotis , Hedyotis/química , Medicamentos de Ervas Chinesas/química , Espectroscopia de Ressonância Magnética , Ácido SalicílicoRESUMO
Lipid droplets (LDs) targeting probes are important for investigating the biological functions of LDs. The interplay between LDs and some other organelles can help to further understand the biological functions of these organelles. However, it is still a challenge to design functional probes that can specifically target LDs and are responsive to some other organelles. Herein, a multifunctional aggregation-induced emission luminogen (AIEgen), namely the TPA-CN, was prepared by the simple aldimine condensation reaction for lipid droplet-specific imaging and tracing. TPA-CN can be sensitively responsive to the acid environment of lysosomes due to the pH-response detachable connector in TPA-CN. With the assistance of this characteristic, it can be concluded from the fluorescence imaging and co-localization analysis results that the internalization of TPA-CN and the targeting of LDs does not involve the lysosome and the lysosomal escape process. At last, the TPA-CN was successfully used for the high-sensitivity imaging of dynamic information of LDs.
Assuntos
Gotículas Lipídicas , Lisossomos , Imagem Óptica , Concentração de Íons de Hidrogênio , Corantes FluorescentesRESUMO
Long-term olanzapine treatment has been associated with serious metabolism disorders, such as abnormal body weight gain, hyperglycemia, and dyslipidemia. Recently, accumulated evidence points to a link between the metabolic disorders caused by olanzapine and thermogenetic impairment. Fibroblast growth factor 21 (FGF21), a pleiotropic protein, is a potent stimulator of thermogenesis in brown adipose tissue (BAT). However, the relationship between autocrine FGF21 in BAT and thermogenetic impairment induced by olanzapine has not been investigated. In this study, C57BL/6 mice and C3H10T1/2 (a brown adipocyte cell line) were used to investigate the role of FGF21 in modulating thermogenetic impairments caused by olanzapine. Our data found a fall in BAT temperature, with a decrease in the protein levels of uncoupling protein 1 (UCP1) and FGF21 in olanzapine-treatment mice. Olanzapine-induced deficits of mitochondrial activity and the expression of UCP1 and related thermogenetic factors could be improved by FGF21-overexpression in brown adipocytes. Furthermore, ChIP-sequencing showed the H3K9me3 modification in Fgf21 was dramatically increased in BAT of mice with olanzapine treatment. Lysine-specific demethylase 4a (KDM4a), a histone demethylase responsible for site-specific erasure of H3K9me3, was decreased in olanzapine-treated C3H10T1/2 cells, whereas FGF21 and UCP1 expression and thermogenesis were upregulated in KMD2a-overexpressing brown adipocyte. We concluded that FGF21 was a crucial regulator mediating UCP1-dependent thermogenetic impairments by olanzapine-modulating histone methylations. Our results also provide novel insights into identifying a new therapeutic target for treating metabolic side effects caused by the antipsychotic drug.
Assuntos
Tecido Adiposo Marrom , Histonas , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , Olanzapina/farmacologia , Histonas/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Canais Iônicos/metabolismo , Canais Iônicos/farmacologia , Camundongos Endogâmicos C57BL , Termogênese , Camundongos KnockoutRESUMO
The emergence of drug-resistant fungal pathogens poses great threats to an increasing number of vulnerable populations worldwide, and the need for novel antifungal agents is imperative. In this work, a series of lipo-γ-AA peptides were synthesized and evaluated for their biological activities. One lead, MW5, exhibited potent and broad-spectrum antifungal activity. In addition, MW5 potently boosted the efficacy of fluconazole against clinical azole-resistant Candida isolates. Mechanistic investigation showed that the lead compound disrupted the cell membrane, significantly boosted the production of reactive oxygen species, and undermined the function of the efflux pump, thus resensitizing drug-resistant Candida albicans to fluconazole. Notably, coadministration of MW5 and fluconazole exhibited potent in vivo antifungal activity in a murine model of mucocutaneous candidiasis. Our results demonstrated that lipo-γ-AA peptides have great promise for use alone or in combination to combat drug-resistant Candida infections.
Assuntos
Antifúngicos , Candidíase , Animais , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
Two new polyketides, lasobutone A(1) and lasobutone B(2), along with three known compounds, guignardianone C(3), guignardic acid(4), and 4-hydroxy-17R-methylincisterol(5), were isolated from the endophytic fungi Xylaria sp. by silica gel, MCI, and preparative HPLC, which was separated from the Chinese medicinal material Coptis chinensis and cultivated through solid fermentation with rice. Their structures were elucidated on the basis of spectroscopic methods, such as MS, NMR, IR, UV, and ECD. Compounds 2 and 4 showed inhibitory activities against the nitric oxide(NO) production in the LPS-induced macrophage RAW264.7 with IC_(50) values of 58.7 and 42.5 µmol·L~(-1) respectively, while compound 5 exhibited cytotoxic activities against HT-29 with IC_(50) value of 14.3 µmol·L~(-1).
Assuntos
Antineoplásicos , Policetídeos , Coptis chinensis , Endófitos/química , Fungos , Policetídeos/químicaRESUMO
A new polyketide, coptaspin A(1), along with two known compounds 4-acetyl-3,4-dihydro-6,8-dihydroxy-3-methoxy-5-methylisocoumarin(2), and cytochalasin Z_(12)(3), was isolated from the endophytic fungi Aspergillus sp. ZJ-58, which was isolated from the genuine medicinal plant Coptis chinensis in Chongqing after solid-state fermentation on rice and silica gel, MCI, and HPLC-based separation. Their structures were elucidated by MS, NMR, IR, UV, and ECD. The newly isolated compound 1 showed moderate inhibitory activities against LPS-induced NO production in RAW264.7 macrophages with the IC_(50) value of 58.7 µmol·L~(-1), suggesting its potential anti-inflammatory activity.
Assuntos
Plantas Medicinais , Policetídeos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Aspergillus/química , Coptis chinensis , Policetídeos/farmacologiaRESUMO
Evidential reasoning (ER) rule has been widely used in dealing with uncertainty. As an important parameter to measure the inherent property of evidence, the evidence reliability makes the ER rule constitute a generalized reasoning framework. In current research of the ER rule, the evidence reliability tends to be expressed in the form of quantitative value by certain methods or expert knowledge. The single quantitative value lacks the ability to describe the statistical property of reliability, which leads to unreasonable results. In this article, a new ER rule with continuous probability distribution of reliability denoted by ERr-CR is proposed. The combination of two pieces of evidence is discussed in detail, where the reliability is profiled as random variables with specific probability distribution. To characterize the output of ERr-CR, a novel concept of expectation of the expected utility is proposed. In addition, the ERr-CR is expanded to multiple pieces of evidence to show its universality. Further, the basic performances of the ERr-CR are explored to illustrate the rationality. Moreover, a case study of safety assessment of natural gas storage tanks (NGSTs) is conducted to show the potential applications of ERr-CR, which makes the proposed method more practical.
Assuntos
Projetos de Pesquisa , Probabilidade , Reprodutibilidade dos TestesRESUMO
In current studies of safety assessment for complex systems with the evidential reasoning (ER) rule, the evidence reliability is generally given by experts, which makes the observation data by sensors ignored. However, sensors are inevitably affected by such various uncertainties as perturbations in engineering practice, which can reduce their quality and tracking ability. As such, the observation data may become unreliable, and the modeling accuracy of the ER rule is decreased. In this article, a new ER rule-based safety assessment method with sensor reliability for complex systems is proposed, where sensor reliability and perturbation are considered. The coefficient of the variation-based weighting (CVBW) method is employed to obtain sensor weight. The sensor reliability is calculated by static reliability and dynamic reliability, which are determined by experts and the distance-based method, respectively. The perturbation is quantified as a bounded parameter defined as the perturbation factor, which is used to describe uncertainties and aggregate static reliability and dynamic reliability. The performance analysis of safety assessment is conducted to demonstrate the rationality of perturbation and position poor sensors, followed by a safety assessment algorithm. A case study is carried out to validate the effectiveness of the proposed method.
Assuntos
Algoritmos , Reprodutibilidade dos TestesRESUMO
Penispidins A-C (1-3), new aromatic sesquiterpenoids with two classes of rare carbon skeletons, were isolated from the endophytic fungus Penicillium virgatum HL-110. 1 represents the first example of a dunniane-type aromatic sesquiterpenoid, possessing a novel 4/6/6 tricyclic system, while (±)-2 and 3 have a 7,12-cyclized bisabolene skeleton, featuring a 3,4-benzo-fused 2-oxabicyclo[3.3.1]nonane central framework. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, and ECD calculations. 1 inhibited hepatic lipid accumulation in HepG2 cells.
Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Penicillium/química , Sesquiterpenos/farmacologia , China , Células Hep G2 , Humanos , Estrutura Molecular , Sesquiterpenos/isolamento & purificação , Triglicerídeos/metabolismoRESUMO
Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 28 days with aripiprazole (1.0 mg· kg-1· d-1) or olanzapine (1.0 mg· kg-1· d-1) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and ß-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRß expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg-1· d-1) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg-1· d-1, ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Síndrome Metabólica/etiologia , Quinolonas/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Tiofenos/efeitos adversos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Insulina/metabolismo , Resistência à Insulina/fisiologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Liraglutida/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , RatosRESUMO
Two new 14-membered resorcylic acid lactone derivatives, ascarpins A (1) and B (2), together with three related known compounds (3-5) were isolated from the fungus Aspergillus sp. ZJ-65, obtaining from the intestine of grass carp. These structures were elucidated on the basis of extensive spectroscopic methods, chemical conversion, and comparison with literature. All isolates were tested for their inhibitory activity against LPS-induced NO production in RAW 264.7 macrophages. Among them, compounds 1-4 exhibited potential anti-inflammatory activity with IC50 values ranging from 7.6 to 48.3 µM.
Assuntos
Anti-Inflamatórios/farmacologia , Aspergillus/química , Carpas/microbiologia , Lactonas/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , China , Lactonas/isolamento & purificação , Camundongos , Estrutura Molecular , Óxido Nítrico , Células RAW 264.7RESUMO
As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of progression of cancer, especially in metastasis and proliferation. However, the precise role of Ghrelin in tumorigenesis of gastric cancer (GC) is still poorly understood. In this study, we extensively investigated the roles and mechanisms of Ghrelin in human gastric cancer. Ghrelin levels in cancer tissues and cell lines were analyzed by immunohistochemistry, qRT-PCR, and Western blot. Functional studies were performed after Ghrelin overexpressed or knockdown in AGS cell line. Cell proliferation was evaluated in by MTT and clone formation assays. The wound healing and Transwell system were used to assess the cell migration and invasive ability of GC cells. Cell apoptosis was detected by flow cytometry, and metabolic assays were performed to reveal the function of Warburg effect in the process. Ghrelin was lowly expressed in gastric cancer tissues and cell lines. Overexpression of Ghrelin inhibited gastric cancer cell proliferation, migration, invasion, and promoted apoptosis by activating the AMPK pathway, while D-[lys3]-GHRP-6 (a GHSR agonist) treatment relieved the effect, promoting tumorigenesis. Ghrelin knockdown increased the glucose uptake and lactic acid release, suggesting that Ghrelin elicited an anti-Warburg effect via AMPK pathway to inhibit gastric tumorigenesis. Ghrelin inhibits cell proliferation, migration, and invasion by eliciting an anti-Warburg effect via AMPK signaling pathway in gastric cancer cells.
Assuntos
Adenilato Quinase/metabolismo , Grelina/fisiologia , Transdução de Sinais , Neoplasias Gástricas/patologia , Apoptose/fisiologia , Carcinogênese , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Progressão da Doença , Regulação para Baixo , Grelina/antagonistas & inibidores , Grelina/metabolismo , Glucose/metabolismo , Humanos , Metástase Neoplásica , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated. METHODS: To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O + S), or vehicle (control) for 5 weeks. RESULTS: Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O + S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O + S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by co-treatment with O + B. CONCLUSIONS: Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Antipsicóticos/efeitos adversos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Olanzapina/efeitos adversos , Sinvastatina/uso terapêutico , Tecido Adiposo Marrom/metabolismo , Animais , Glicemia/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Colesterol/sangue , Dislipidemias/induzido quimicamente , Dislipidemias/genética , Dislipidemias/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Triglicerídeos/sangue , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Aumento de Peso/efeitos dos fármacosAssuntos
Anticorpos Antivirais/sangue , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Adulto , Idoso , Betacoronavirus/imunologia , COVID-19 , Teste para COVID-19 , China/epidemiologia , Técnicas de Laboratório Clínico/métodos , Estudos de Coortes , Infecções por Coronavirus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/imunologia , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
Fungal polyketide-nonribosomal peptide (PK-NRP) hybrid macrolactones are a growing family of natural products with biomedical and agricultural activities. One of the most important families is the thermolides, which are produced by extreme thermophilic fungi and exhibit strong nematocidal activity. We show here that the genes ThmABCE from Talaromyces thermophilus NRRL 2155 are critical for thermolide synthesis. Two separate single-module hrPKS (ThmA) and NRPS (ThmB) enzymes collaborate to synthesize the core macrolactone backbone (6 or 7), and the NRPS ThmB-CT domain catalyzes the key macrocyclization step in PK-NRP intermediate release via ester bond formation, representing a novel function of fungal NRPS C domains. We also show that heterologous and engineered expression of the Thm genes in the type strains of Aspergillus nidulans and Escherichia coli not only dramatically enhances the yields of thermolides but also affords different esterified analogues, such as butyryl- (thermolides J and K, 15 and 16), hexanoyl-, and octanyl- derivatives or mixed thermolides. Thermolides L and M (18 and 19), discovered via genome mining-based combinatorial biosynthesis, represent the first l-phenylalanine-based thermolides. Our work shows a unique biosynthetic mechanism of PK-NRP hybrid macrolactones from extremophiles, which led to the discovery of novel compounds and furthers our biosynthetic knowledge.
Assuntos
Antinematódeos/metabolismo , Lactonas/metabolismo , Peptídeos/metabolismo , Policetídeos/metabolismo , Talaromyces/metabolismo , Aspergillus nidulans/genética , Ciclização , Escherichia coli/genética , EsterificaçãoRESUMO
Protoberberine alkaloids belong to the quaternary ammonium isoquinoline alkaloids, and are the main active ingredients in traditional Chinese herbal medicines, like Coptis chinensis. They have been widely used to treat such diseases as gastroenteritis, intestinal infections, and conjunctivitis. Studies have shown that structural modification of the protoberberine alkaloids could produce derivative compounds with new pharmacological effects and biological activities, but the transformation mechanism is not clear yet. This article mainly summarizes the researches on the biotransformation and structure modification of protoberberine alkaloids mainly based on berberine, so as to provide background basis and new ideas for studies relating to the mechanism of protoberberine alkaloids and the pharmacological activity and application of new compounds.
Assuntos
Alcaloides , Alcaloides de Berberina , Berberina , Coptis , BiotransformaçãoRESUMO
Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.
Assuntos
Dislipidemias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Animais , Regulação para Baixo , Dislipidemias/induzido quimicamente , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Feminino , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/patologia , Olanzapina , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.