RESUMO
Acute liver failure (ALF) is considered a fatal clinical disorder and novel therapeutic interventions are mandatory. Naringenin is a flavonoid with anti-inflammatory, antioxidant and antiapoptotic effects that have displayed beneficial effects in different animal models of ALF. The current study aimed at investigating the hepatoprotective effect and the possible underlying molecular mechanisms of naringenin in lipopolysaccharide (LPS)/D-galactosamine (D-Gal) mouse model of ALF. Interestingly, naringenin pretreatment substantially alleviated LPS/D-Gal-induced liver injury, enhanced survival, improved liver function and ameliorated histopathological liver changes. Importantly, naringenin potently activated autophagy as evidenced by the increased Beclin-1 expression and LC3 II/LC3 I ratio. Furthermore, results demonstrated that naringenin alleviated oxidative stress by inducing nuclear factor-erythroid 2-related factor 2 (Nrf2) and increasing hepatic SOD activity and GSH level as well as ameliorated endoplasmic reticulum (ER) stress. Likewise, naringenin mitigated LPS/D-Gal-triggered inflammation by suppressing NF-κB and NLRP3 pathways. Accordingly, apoptotic cell death provoked by LPS/D-Gal challenge was markedly attenuated as depicted by the decrease in caspase-3 and p53 in naringenin-treated mice. To investigate the contribution of autophagy to naringenin-conferred hepatoprotection, autophagy was inhibited using 3-methyladenine (3 MA). Strikingly, 3 MA co-treatment abolished the hepatoprotective effect of naringenin, a finding that strongly suggests that naringenin-afforded protection is, at least in part, attributed to autophagy. Taken together, the present study revealed that naringenin exerted a prominent hepatoprotective effect by promoting autophagy with consequent attenuation of inflammatory responses, oxidative stress, ER stress and apoptosis. Our results provide evidence that naringenin use holds a promise as a potential therapeutic agent for ALF management.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Flavanonas/farmacologia , Galactosamina/metabolismo , Lipopolissacarídeos/metabolismo , Falência Hepática Aguda/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Caspase 3/metabolismo , Modelos Animais de Doenças , Humanos , Fígado , Falência Hepática Aguda/prevenção & controle , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2 , NF-kappa B , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase-1/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Diabetes mellitus is a chronic disease affecting the globe and its incidence is increasing pandemically. The use of plant-derived natural products for diabetes management is of great interest. Polar fraction of Artemisia annua L. leaves has shown antidiabetic activity in vivo. In the present study, three major compounds were isolated from this polar fraction; namely, 3,5-dicaffeoylquinic acid (1); 4,5-dicaffeoylquinic acid (2), and 3,4- dicaffeoylquinic acid methyl ester (3), using VLC-RP-18 and HPLC techniques. The potential protective effects of these compounds against diabetes and its complications were investigated by employing various in vitro enzyme inhibition assays. Furthermore, their antioxidant and wound healing effectiveness were evaluated. Results declared that these dicaffeoylquinic acids greatly inhibited DPPIV enzyme while moderately inhibited α-glucosidase enzyme, where compounds 1 and 3 displayed the most prominent effects. In addition, compound 3 showed pronounced inhibition of α-amylase enzyme. Moreover, these compounds markedly inhibited aldose reductase enzyme and exerted powerful antioxidant effects, among which compound 3 exhibited the highest activity implying a notable potentiality in impeding diabetes complications. Interestingly, compounds 2 and 3 moderately accelerated scratch wound healing. Our findings suggest that these dicaffeoylquinic acids can be promising therapeutic agents for managing diabetes and its complications.
Assuntos
Artemisia annua/química , Complicações do Diabetes/prevenção & controle , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Folhas de Planta/química , Ácido Quínico/análogos & derivados , Linhagem Celular , Complicações do Diabetes/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Ácido Quínico/química , Ácido Quínico/isolamento & purificação , Ácido Quínico/farmacologiaRESUMO
Diabetes is a major health problem that is associated with high risk of various complications. Medicinal plants hold great promise against diabetes. The traditional use of Cleome droserifolia as an antidiabetic agent was correlated to its flavonol glycosides content. In the current study, five major flavonol glycosides appeared on the RP-HPLC chromatogram of the aqueous extract namely; quercetin-3-O-ß-d-glucosyl-7-O-α-rhamnoside (1), isorhamnetin-7-O-ß-neohesperidoside (2), isorhamnetin-3-O-ß-d-glucoside (3) kaempferol-4'-methoxy-3,7-O-α-dirhamnoside (4), and isorhamnetin-3-O-α-(4â³-acetylrhamnoside)-7-O-α-rhamnoside (5). The inhibitory activities of these compounds were tested in vitro against several enzymes involved in diabetes management. Only the relatively less polar methoxylated flavonol glycosides (4, 5) showed mild to moderate α-amylase and α-glucosidase inhibitory activities. Compounds 1-4 displayed remarkable inhibition of dipeptidyl peptidase IV (DPPIV) enzyme (IC50 0.194 ± 0.06, 0.573 ± 0.03, 0.345 ± 0.02 and 0.281 ± 0.05 µg/mL, respectively) comparable to vildagliptin (IC50 0.154 ± 0.02 µg/mL). Moreover, these compounds showed high potential in preventing diabetes complications through inhibiting aldose reductase enzyme and combating oxidative stress. Both isorhamnetin glycoside derivatives (2, 3) exhibited the highest activities in aldose reductase inhibition and compound 2 (IC50 5.45 ± 0.26 µg/mL) was even more potent than standard quercetin (IC50 7.77 ± 0.43 µg/mL). Additionally, these flavonols exerted excellent antioxidant capacities through 2, 2-diphenyl-1-picrylhydrazil (DPPH) and ferric reducing antioxidant (FRAP) assays.
Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Glicosídeos/farmacologia , Aldeído Redutase/química , Aldeído Redutase/metabolismo , Antioxidantes/química , Compostos de Bifenilo/química , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Cleome , Desenho de Fármacos , Sequestradores de Radicais Livres , Humanos , Hipoglicemiantes , Técnicas In Vitro , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estresse Oxidativo , Picratos/química , Vildagliptina/farmacologia , alfa-Amilases/química , alfa-Glucosidases/metabolismoRESUMO
A novel series of thiazole-based heterocycles was synthesized using 1,3-dipolar cycloaddition reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. The molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis. Various in vitro biological assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of the newly synthesized compounds. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compounds displayed antitumor activities with the chlorine-containing derivatives, 11c and 6g, being the most potent. The majority of the tested thiazole derivatives exhibited satisfactory antibacterial activity towards the used gram positive and gram-negative bacterial species. Moreover, many derivatives showed weak hepatoprotective activity against CCl4-induced hepatotoxicity.
Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Tetracloreto de Carbono/antagonistas & inibidores , Química Verde , Compostos Heterocíclicos/síntese química , Tiazóis/síntese química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Tetracloreto de Carbono/toxicidade , Catálise , Quitosana/química , Reação de Cicloadição , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Células HCT116 , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Células MCF-7 , Testes de Sensibilidade Microbiana , Polivinil/química , Cultura Primária de Células , Piridinas/química , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
RATIONALE, AIMS AND OBJECTIVES: Diabetes mellitus is a global serious health problem that has a clear negative impact on economy. The high prevalence of diabetes worldwide urges for prevention and educational programs. Engagement of community pharmacists in offering various diabetes care services enables delivery of quality of care for patients and could play key role in diabetes management. The current study was designed to assess the knowledge towards diabetes among community pharmacists and to investigate their role in diabetes management through identifying different diabetes care services they provide in Asir region, Saudi Arabia. In addition, possible barriers for providing these services were evaluated. METHOD: A cross-sectional study was performed using an online self-administered anonymous survey that consisted of 4 domains: demographics, knowledge, practice and barriers related to diabetes management. RESULTS: A total of 258 pharmacists completed the survey, and one-third of respondents (34.5%) demonstrated good knowledge while 42.2% showed moderate knowledge towards diabetes. Respondents of the age group (30-39) years, males, those with bachelor's degree and those with 5 years or less of experience had higher mean knowledge. Nearly half of the participants had positive practice. The most prominent (75%) services offered by the community pharmacists were counselling on the appropriate administration, handling and storage of insulin and the appropriate time to administer oral antidiabetic drugs. Pharmacists who received training had higher mean practice scores. Lack of time, lack of diabetic patients visiting the pharmacy and low patient expectations regarding pharmacists' role in diabetes care were identified as the most important barriers they encountered. CONCLUSION: Community pharmacists of Asir region exhibited moderate knowledge and practices regarding diabetes management. Our results support the need for national advanced diabetes training programs targeting community pharmacists for providing quality of care services for diabetic patients Moreover, strategies to overcome the reported barriers are indispensable.
RESUMO
Cassia occidentalis L., from Fabaceae family phytochemical screening, revealed several biologically active principles mainly flavonoids and anthraquinones. GLC analysis of the lipoidal matter afforded 12 hydrocarbons: 9-dodecyl-tetradecahydro-anthracene (48.97 %), 9-dodecyl-tetradecahydro-phenanthrene (14.43 %), and 6 sterols/triterpenes: isojaspisterol (11.99%) and fatty acids were palmitic acid (50 %), and Linoleic acid (16.06%). Column chromatography led to the isolation of fifteen compounds (1-15), elucidated using spectroscopic evidence. First report of undecanoic acid (4) from the family Fabaceae, while p-dimethyl amino-benzaldehyde (15) was first time isolated from a natural origin. Eight compounds isolated for the first time from C. occidentalis L.; ß-amyrin (1), ß-sitosterol (2), stigmasterol (3), camphor (5), lupeol (6), chrysin (7), pectolinargenin (8), and 1, 2, 5-trihydroxy anthraquinone (14) besides five known compounds previously isolated; apigenin (9), kaempferol (10), chrysophanol (11), physcion (12), and aloe-emodin (13). In-vivo evaluation of anti-inflammatory and analgesic effects of C. occidentalis L. extracts where the n-butanol and total extracts showed the highest activities. The percentage of the inhibitory effect of the n-butanol extract was 29.7 at a dose of 400 mg/Kg. Furthermore, identified phytoconstituents were docked into the active sites of enzymes nAChRs, COX-1, and COX-2 to evaluate binding affinity. Phyto-compounds Physcion, aloe-emodin, and chrysophanol were found to have a good affinity for targeted receptors compared to co-crystalized inhibitors, validating the analgesic and anti-inflammatory effects of the phytochemicals.
Assuntos
Emodina , Senna , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Senna/química , 1-Butanol , Egito , Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Analgésicos/farmacologia , Compostos Fitoquímicos/farmacologiaRESUMO
Type 1 diabetes (T1D) is a multi-factorial, organ-specific autoimmune disease in genetically susceptible individuals, which is characterized by a selective and progressive loss of insulin-producing ß-cells. Cells mediating innate as well as adaptive immunity infiltrate pancreatic islets, thereby generating an aberrant inflammatory process called insulitis that can be mirrored by a pathologic autoantibody production and autoreactive T-cells. In tight cooperation with infiltrating innate immune cells, which secrete high levels of pro-inflammatory cytokines like IL-1ß, TNFα, and INFγ effector T-cells trigger the fatal destruction process of ß-cells. There is ongoing discussion on the contribution of inflammation in T1D pathogenesis, ranging from a bystander reaction of autoimmunity to a dysregulation of immune responses that initiate inflammatory processes and thereby actively promoting ß-cell death. Here, we review recent advances in anti-inflammatory interventions in T1D animal models and preclinical studies and discuss their mode of action as well as their capacity to interfere with T1D development.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Autoimunidade/efeitos dos fármacos , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Modelos Biológicos , NF-kappa B/metabolismoRESUMO
Ulcerative colitis (UC) is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum. Currently available medications carry multiple detrimental adverse effects, which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives. Melittin is the main constituent of bee venom and exhibits potent anti-inflammatory properties. The antiulcerogenic effect of oral melittin (40 µg/kg) was explored in the current study using the acetic acid-induced colitis model. Increase in body weight and decrease in colon mass index were observed in the melittin group. Microscopically, melittin ameliorated acetic acid-induced histological damage. Melittin administration has efficiently amended the elevated levels of the cytokines, tumor necrosis factor (TNF-α) and interleukin 6 (IL-6) seen in the colitis group. This was accompanied by inhibition of the upstream signaling molecules, Toll-like receptor 4 (TLR4), tumor necrosis factor receptor (TNF-R)-associated factor (TRAF6), mitogen-activated protein kinase 38 (p38 MAPK), and nuclear factor kappaB (NF-κB) in the melittin group. Moreover, treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 (PGE2) together with the enzymes involved in its synthesis, secretory phospholipase A2 (sPLA2) and cyclooxygenase 2 (COX-2). Additionally, melittin has attenuated acetic acid-induced oxidative stress as manifested by the significant diminishment in malondialdehyde (MDA) as well as the increase in superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Therefore, melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment.
Assuntos
Antiulcerosos/farmacologia , Meliteno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Ácido Acético/toxicidade , Administração Oral , Animais , Antiulcerosos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Meliteno/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating ß-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting ß-cell stress and ultimately leading to cell death, we asked whether additional ß-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge ß-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/- mice were found glucose intolerant without progressing to diabetes, additional challenge of ß-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of ß-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling ß-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and ß-cell mass. Our findings implicate that the avoidance of additional ß-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when ß-cell stress is normalized.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animais , Glicemia/metabolismo , Morte Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Fisiológico , Transativadores/genética , Transativadores/metabolismoRESUMO
Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic ß-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. Inhibitor of κB kinase (IKK)/nuclear factor-κB (NF-κB) signaling is a master regulator of inflammation; however, its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-κB in ß-cells, we generated a gain-of-function model allowing conditional IKK2/NF-κB activation in ß-cells. A transgenic mouse model that expresses a constitutively active mutant of human IKK2 dependent on Pdx-1 promoter activity (IKK2-CA(Pdx-1)) spontaneously develops full-blown immune-mediated diabetes with insulitis, hyperglycemia, and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased major histocompatibility complex class I/II expression by ß-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data give the first direct evidence that ß-cell-specific IKK2/NF-κB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CA(Pdx-1) mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing ß-cell degeneration/regeneration.