RESUMO
The objective of the study was to evaluate the in vitro and in vivo schistosomicidal activity of sanguinarine (SA) on Schistosoma mansoni and its in silico pharmacokinetic parameters. ADMET parameters and oral bioavailability were evaluated using the PkCSM and SwissADME platforms, respectively. The activity of SA in vitro, at the concentrations of 1.0-25 µM, was analyzed through the parameters of motility, mortality, and cell viability of the worms at intervals of 3-24 h. Mice were infected with cercariae and treated by gavage with SA (5 mg/kg/day, in a single dose or two doses of 2.5 mg/kg every 12 h for 5 consecutive days) on the 1st (skin schistosomula), 14th (pulmonary schistosomula), 28th (young worms), and 45th (adult worms) days after infection. In vitro and in vivo praziquantel was the control. In vitro, SA showed schistosomicidal activity against schistosomula, young worms, and couples; with total mortality and reduced cell viability at low concentrations and incubation time. In a single dose of 5 mg/kg/day, SA reduces the total worm load by 47.6%, 54%, 55.2%, and 27.1%, and female worms at 52.0%, 39.1%, 52.7%, and 20.2%, respectively, results which are similar to the 2.5 mg/kg/day dose. SA reduced the load of eggs in the liver, and in histopathological and histomorphometric analyses, there was a reduction in the number and volume of hepatic granulomas, which exhibited less inflammatory infiltrate. SA has promising in vitro and in vivo schistosomicidal activity against different developmental stages of S. mansoni, in addition to reducing granulomatous liver lesions. Furthermore, in silico, SA showed good predictive pharmacokinetic ADMET profiles.
Assuntos
Alcaloides , Anti-Infecciosos , Isoquinolinas , Esquistossomicidas , Feminino , Animais , Camundongos , Antiparasitários , Schistosoma mansoni , Benzofenantridinas/farmacologia , Alcaloides/farmacologiaRESUMO
Benzophenanthridines belong to the benzylisoquinolic alkaloids, representing one of the main groups of this class. These alkaloids include over 120 different compounds, mostly in plants from the Fumariaceae, Papaveraceae, and Rutaceae families, which confer chemical protection against pathogens and herbivores. Industrial uses of BZD include the production of environmentally friendly agrochemicals and livestock food supplements. However, although mainly considered toxic compounds, plants bearing them have been used in traditional medicine and their medical applications as antimicrobials, antiprotozoals, and cytotoxic agents have been envisioned. The biosynthetic pathways for some BZD have been established in different species, allowing for the isolation of the genes and enzymes involved. This knowledge has resulted in a better understanding of the process controlling their synthesis and an opening of the gates towards their exploitation by applying modern biotechnological approaches, such as synthetic biology. This review presents the new advances on BDZ biosynthesis and physiological roles. Industrial applications, mainly with pharmacological approaches, are also revised.
Assuntos
Benzofenantridinas/biossíntese , Alcaloides/biossíntese , Alcaloides/química , Alcaloides/farmacologia , Benzofenantridinas/química , Benzofenantridinas/farmacologia , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Vias Biossintéticas , Desenvolvimento de Medicamentos , Isoquinolinas/química , Isoquinolinas/farmacologia , Medicina Tradicional , Fenômenos Fisiológicos Vegetais , Relação Estrutura-AtividadeRESUMO
We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia-reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions of the highly diffusible cell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rat hearts, after 20 min of stabilization, were assigned to the following groups: (1) Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of global ischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of 100 µM was administered for 10 min before the onset of ischemia and then during the first 10 min of reperfusion. In additional groups, ETZ was administered in the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, a protein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expression of phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurin Aß content were assessed. In isolated mitochondria, the Ca2+ response, Ca2+ retention capacity, and membrane potential were measured. ETZ decreased infarct size by 60%, improved postischemic recovery of myocardial contractile and diastolic relaxation increased P-p38MAPK, P-PKCε, P-HSP27, and P-Drp1 expression, decreased calcineurin content, and normalized calcium and membrane potential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SB or Chel. These data show that ETZ protects the myocardium and mitochondria against ischemia-reperfusion injury through p38MAPK- and PKCε-dependent pathways and reinforces the role of CA as a possible target in the management of acute cardiac ischemic diseases.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Etoxzolamida/farmacologia , Coração/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Benzofenantridinas/farmacologia , Cálcio/metabolismo , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Preparação de Coração Isolado , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica , Proteína Quinase C/antagonistas & inibidores , Piridinas/farmacologia , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. Many malignant tumor cells always display glutamine addiction. The "kidney-type" glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. Interestingly, GLS1 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, GLS1 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that its inhibitors could provide a benefit strategy for cancer therapy. Herein, we summarize the prognostic value of GLS1 in multiple cancer type and its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for GLS1 inhibitors. On the basis of case studies, our perspectives for targeting GLS1 and development of GLS1 antagonist are discussed in the final part.
Assuntos
Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Glutamina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Apoptose/fisiologia , Benzofenantridinas/farmacologia , Proliferação de Células/fisiologia , Diazo-Oxo-Norleucina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Genes myc/fisiologia , Humanos , MicroRNAs/fisiologia , NF-kappa B/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Oxirredução , Fosfatos/metabolismo , Prognóstico , Proteína do Retinoblastoma/metabolismo , Sulfetos/farmacologia , Tiadiazóis/farmacologiaRESUMO
Commonly called the Mexican prickly poppy, Argemone mexicana is a stress-resistant member of the Papaveraceae family of plants that has been used in traditional medicine for centuries by indigenous communities in Mexico and Western parts of the United States. This plant has been exploited to treat a wide variety of ailments, with reported antimicrobial and antioxidant properties, as well as cytotoxic effects against some human cancer cell lines. Due to its various therapeutic uses and its abundance of secondary metabolites, A. mexicana has great potential as a drug discovery candidate. Herein, the germination conditions of A. mexicana are described and the cytotoxic activities of different parts (seeds, leaves, inner vs. outer roots) of the plant from methanol or hexane extracts are preliminarily characterized against cells of seven unique organisms. When comparing 1 mg of each sample normalized to background solvent alone, A. mexicana methanol outer root and leaf extracts possessed the strongest antimicrobial activity, with greatest effects against the Gram-positive bacteria tested, and less activity against the Gram-negative bacteria and fungi tested. Additionally, using the MTT colorimetric assay, the outer root methanol and seed hexane extracts displayed pronounced inhibitory effects against human colon cancer cells. Quantification of c-MYC (oncogene) and APC (tumor suppressor) mRNA levels help elucidate how the A. mexicana root methanol extract may be affecting colon cancer cells. After ultra-performance liquid chromatography coupled with mass spectrometry and subsequent nuclear magnetic resonance analysis of the root and leaf methanol fractions, two main antibacterial compounds, chelerythrine and berberine, have been identified. The roots were found to possess both phytocompounds, while the leaf lacked chelerythrine. These data highlight the importance of plants as an invaluable pharmaceutical resource at a time when antimicrobial and anticancer drug discovery has plateaued.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Argemone/química , Citotoxinas/farmacologia , Benzofenantridinas/farmacologia , Berberina/farmacologia , Linhagem Celular Tumoral , Humanos , México , Extratos Vegetais/farmacologia , Folhas de Planta/química , Raízes de Plantas/química , Solventes/químicaRESUMO
The prophylactic administration of ceftiofur to newly hatched chicks is a common practice in some hatcheries worldwide to mitigate early gastrointestinal infections caused by Enterobacteriaceae. In spite of the crucial role of the gut microbiome for the broiler's health, there is still limited information on how the microbial composition is affected by such procedure. We investigated the effects of posthatch prophylactic application of ceftiofur on the cecal microbiota of 14-day-old broilers fed regular or sanguinarine-supplemented diets. DNA samples were extracted from cecal contents, amplified for the V3-V4 regions of the microbial 16S rRNA gene, and sequenced in a high-throughput sequencing platform (Illumina MiSeq). After downstream bioinformatics and statistical analyses, our results demonstrated that both ceftiofur and sanguinarine treatments similarly increased the proportions of the phylum Bacteroidetes and the genera Bacteroides and Megamonas, whereas reduced the relative abundances of Firmicutes and Lachnospiraceae in the ceca of the birds. Such changes are probably associated with increased carbohydrate fermentation processes favoring the production of short-chain fatty acids. This was also corroborated by the functional prediction findings, which suggest an increase in some metabolic pathways associated with digestibility in broilers receiving ceftiofur. Considering that antimicrobial stewardship in animal production systems is strongly needed to mitigate the threat of antimicrobial resistance, our findings show that supplementation with a phytogenic feed additive can lead to a similar microbial composition in the ceca of commercial broiler chickens, suggesting that the use of alternative products could lead to functional modifications without increasing pressure for antimicrobial resistance.
Assuntos
Benzofenantridinas , Cefalosporinas , Galinhas , Suplementos Nutricionais , Microbioma Gastrointestinal , Isoquinolinas , Ração Animal/análise , Animais , Animais Recém-Nascidos , Antibacterianos/farmacologia , Benzofenantridinas/farmacologia , Biodiversidade , Ceco/microbiologia , Cefalosporinas/farmacologia , Dieta/veterinária , Suplementos Nutricionais/análise , Microbioma Gastrointestinal/efeitos dos fármacos , Isoquinolinas/farmacologia , RNA Ribossômico 16S/genéticaRESUMO
COVID-19 has become disastrous for world and spread all over. Researchers all around the globe are working to discover a drug to cure from COVID-19. RNA dependent RNA polymerase plays a key role in SARS-CoV-2 replication and thus it could be a potential target for SARS-CoV-2. This study revealed that Protopine, Allocryptopine and (±) 6- Acetonyldihydrochelerythrine could be potential RdRp inhibitors of SARS-CoV-2.
Assuntos
Argemone/química , Benzofenantridinas/farmacologia , Alcaloides de Berberina/farmacologia , Tratamento Farmacológico da COVID-19 , Extratos Vegetais/uso terapêutico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/farmacologia , Simulação por Computador , Reposicionamento de Medicamentos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Fenantrenos/farmacologia , Compostos Fitoquímicos/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
17ß-Estradiol (E2) has been shown to modulate the renin-angiotensin system in hydromineral and blood pressure homeostasis mainly by attenuating angiotensin II (ANGII) actions. However, the cellular mechanisms of the interaction between E2 and angiotensin II (ANGII) and its physiological role are largely unknown. The present experiments were performed to better understand the interaction between ANGII and E2 in body fluid control in female ovariectomized (OVX) rats. The present results are the first to demonstrate that PKC/p38 MAPK signaling is involved in ANGII-induced water and sodium intake and oxytocin (OT) secretion in OVX rats. In addition, previous data from our group revealed that the ANGII-induced vasopressin (AVP) secretion requires ERK1/2 signaling. Therefore, taken together, the present observations support a novel concept that distinct intracellular ANGII signaling gives rise to distinct neurohypophyseal hormone release. Furthermore, the results show that E2 attenuates p38 MAPK phosphorylation in response to ANGII but not PKC activity in the hypothalamus and the lamina terminalis, suggesting that E2 modulates ANGII effects through the attenuation of the MAPK pathway. In conclusion, this work contributes to the further understanding of the interaction between E2 and ANGII signaling in hydromineral homeostasis, as well as it contributes to further elucidate the physiological relevance of PKC/p38 MAPK signaling on the fluid intake and neurohypophyseal release induced by ANGII.
Assuntos
Angiotensina II/farmacologia , Encéfalo/efeitos dos fármacos , Estradiol/farmacologia , Proteína Quinase C-alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Benzofenantridinas/farmacologia , Encéfalo/enzimologia , Ingestão de Líquidos/efeitos dos fármacos , Interações Medicamentosas , Feminino , Homeostase/efeitos dos fármacos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ovariectomia , Ocitocina/metabolismo , Proteína Quinase C-alfa/antagonistas & inibidores , Piridinas/farmacologia , Ratos Wistar , Vasopressinas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
BACKGROUND: A glioblastoma is a primary CNS tumor that is more aggressive and lethal than other brain tumors. Its location, rapid proliferation, invasive growth, angiogenesis and immunosuppression are the main factors that limit its treatment, making it a major challenge to neuro-oncology. OBJECTIVE: This study investigated the in vitro effects of the alkaloid dihydrochelerythrine (DHC), which is extracted from Zanthoxylum stelligerum, on the viability, proliferation, cell death and ß-catenin, NFκB, STAT3/pSTAT3 and interleukins roles. METHOD: In vitro experimental models of human (U251 and GL-15) and murine (C6) glioblastoma cells were cultured in the presence of DHC at increasing concentrations for MTT assay and exclusion trypan blue dye to determine EC50. Afterward, C6 and U251 cells were treated with 100 µM DHC or DMSO 0.1% for cell cycle, annexin and expression of ß-catenin/NFκB/STAT3/pSTAT3 by flow cytometry or immunofluorescence. Interleukin quantification was made by Cytometric Bead Array. RESULTS: A significant decrease was observed in C6 and U251 cell viability in a time and dose-dependent manner. GL-15 cell viability decreased only when treated with 200 µM DHC. This maximum concentration affected neither astrocytes nor microglia viability. A cytostatic effect of DHC was observed in C6 and U251 cells after 48 h of 100 µM DHC treatment. After 72 h of DHC treatment, C6 presented 80% of annexin-V+ cells compared to 10% of annexin-V+ U251 cells. C6 cells demonstrated significant high levels of NFκ B and ß-catenin cytoplasmic fraction. Additionally, DHC treatment resulted in higher significant levels of IL-6 than did other interleukins and STAT3 up-regulation in U251 cells. CONCLUSION: These results demonstrate that DHC acts as a chemosensitizing agent selective for glioma cells not affecting non-tumor cells. Considering tumor heterogeneity, DHC demonstrated an anti-cancer potential to activate different cell death pathways. DHC demonstrated could be used for chemotherapy and immunotherapy applications in glioblastomas in the future.
Assuntos
Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofenantridinas/síntese química , Benzofenantridinas/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Interleucina-6/metabolismo , Camundongos , Conformação Molecular , NF-kappa B/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , beta Catenina/metabolismoRESUMO
Angiotensin II-preconditioning (APC) has been shown to reproduce the cardioprotective effects of ischaemic preconditioning (IPC), however, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC or both (IPC/APC) followed by ischaemia-reperfusion (IR), to determine translocation of PKCε, PKCδ, Akt, Erk1/2, JNK, p38 MAPK and GSK-3ß to mitochondria as an indicator of activation of the protein kinases. In agreement with previous observations, IPC, APC and IPC/APC increased the recovery of left ventricular developed pressure (LVDP), reduced infarct size (IS) and lactate dehydrogenase (LDH) release, compared to controls. These effects were associated with increased mitochondrial PKCε/PKCδ ratio, Akt, Erk1/2, JNK, and inhibition of permeability transition pore (mPTP) opening. Chelerythrine, a pan-PKC inhibitor, abolished the enhancements of PKCε but increased PKCδ expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug had no effect on the APC- and IPC/APC-induced cardioprotection as previously reported, but enhanced the post-ischaemic LVDP in controls. Losartan, an angiotensin II type 1 receptor (AT1-R) blocker, abolished the APC-stimulated increase of LVDP and reduced PKCε, Akt, Erk1/2, JNK, and p38. Both drugs reduced ischaemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC/APC. These results suggest that the cardioprotection induced by APC and IPC/APC involves an AT1-R-dependent translocation of PKCε and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine-treated hearts, however, alternate mechanisms appear to maintain cardiac function.