RESUMEN
Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.
Asunto(s)
Adipogénesis , Flavonoides , Lipasa , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Animales , Adipogénesis/efectos de los fármacos , Flavonoides/farmacología , Ratones , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Masculino , Células 3T3-L1 , Dieta Alta en Grasa/efectos adversos , Páncreas/efectos de los fármacos , Páncreas/patología , Fármacos Antiobesidad/farmacología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Humanos , Orlistat/farmacología , FlavonasRESUMEN
Extracellular vesicles are membrane-bound cargos that vary in size and are stably transported through various bodily fluids. Extracellular vesicles communicate information between the cells and organs. Extracellular vesicles from the diseased cells alter cellular responses of the recipient cells contributing to disease progression. In obesity, adipocytes become hypertrophic and the extracellular vesicles from these dysfunctional adipocytes showed altered cargo contents instigating pathophysiological response leading to chronic liver diseases. In this review, the role of adipocyte-derived extracellular vesicles on the progression of liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are extensively discussed. Newer approaches are crucial to take advantage of extracellular vesicles and their content as biomarkers to diagnose initial liver inflammation before reaching to an irreversible liver failure stage.
Asunto(s)
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Adipocitos , Vesículas Extracelulares/patología , Inflamación/patologíaRESUMEN
Liver fibrosis is a major health concern occurring worldwide. It arises due to prolonged wound healing response of various insults like viral, autoimmune, cholestatic, drug-induced, and metabolic diseases. Currently, there is no clinically approved drug for liver fibrosis treatment. Hepatic stellate cells are the principal liver cells that are activated during liver fibrosis, and targeting these activated cells is an ideal therapeutic strategy. Numerous phytochemicals have been demonstrated in vitro and in vivo treating experimental liver fibrosis; however, none of them have been clinically approved for therapeutic use. This review mainly focuses on such hepatoprotective phytochemicals reported inhibiting major signaling pathways that are dysregulated in activated hepatic stellate cells. PRACTICAL APPLICATIONS: Liver fibrosis is a global health concern and there is no FDA approved drug to treat liver fibrosis. Although notable pharmacological agents like pentoxifylline, gliotoxin, imatinibmesylate, Gleevec, and so on are reported to exhibit anti-fibrotic effect, the major concern is their side effect. Hence, phytochemicals are promising candidates that could be employed against liver fibrosis. In this review, the anti-fibrotic potential of phytochemicals targeting activated HSCs are summarized. Understanding these phytochemicals will further help in the development of agents that are more effective against liver fibrosis.
Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Humanos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/tratamiento farmacológico , Fibrosis , Transducción de Señal , Fitoquímicos/farmacología , Fitoquímicos/metabolismoRESUMEN
This study aimed to evaluate the role of spices/spice active principles on physical, biochemical, and molecular targets of bioaccessibility/bioavailability. Carotenoids-rich micellar fraction obtained through simulated digestion of green leafy vegetables (GLV) with individual or two/three combinations were correlated to their influence on bioaccessibility, cellular uptake, and basolateral secretion of carotenoids in Caco-2 cells. Results suggest that carotenoids' bioaccessibility depends on micelles physicochemical properties, which is affected due to the presence of co-treated dietary spices and their composition. Increased bioaccessibility of ß-carotene (BC) and lutein (LUT) is found in GLV (spinach) digested with turmeric (TM) than red pepper (RP) and black pepper (BP). In contrast, enhanced cellular uptake and secretion of BC and LUT-rich triglyceride-rich lipoprotein is observed in the presence of RP and BP compared to the control group. In contrast, TM inhibited absorption, while retinol levels significantly reduced in the presence of TM and RP than BP. Control cells have indicated higher cleavage of ß-carotene to retinol than the spice-treated group. Besides, spice active principles modulate facilitated transport of carotenoids by scavenger receptor class B type 1 (SR-B1) protein. The effect of spices on carotenoids' bioavailability is validated with active spice principles. Overall, carotenoids' bioavailability (cellular uptake and basolateral secretion) was found in the following order of treatments; piperine > capsaicin > piperine + capsaicin > curcumin + capsaicin + piperine > control > turmeric. These findings suggested that the interaction of specific dietary factors, including spice ingredients at the enterocyte level, could provide greater insight into carotenoid absorption. PRACTICAL APPLICATION: Spices/spice active principles play a role in the digestion process by stimulating digestive enzymes and bile acids secretion. Since carotenoids are lipid soluble and have low bioavailability, spice ingredients' influence on intestinal absorption of carotenoids is considered crucial. Hence, understanding the interaction of co-consumed spices on the absorption process of carotenoids may help to develop functional foods/formulation of nutraceuticals to improve their health benefits.
Asunto(s)
Capsicum , Curcumina , Piper nigrum , Alcaloides , Benzodioxoles , Disponibilidad Biológica , Células CACO-2 , Capsaicina/farmacología , Carotenoides , Curcuma , Curcumina/farmacología , Humanos , Micelas , Piperidinas , Alcamidas PoliinsaturadasRESUMEN
Coronavirus Disease-2019 (COVID-19), a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a global pandemic by WHO in 2020. In this scenario, SARS-CoV-2 main protease (COVID-19 Mpro), an enzyme mainly involved in viral replication and transcription is identified as a crucial target for drug discovery. Traditionally used medicinal plants contain a large amount of bioactives and pave a new path to develop drugs and medications for COVID-19. The present study was aimed to examine the potential of Emblica officinalis (amla), Phyllanthus niruri Linn. (bhumi amla) and Tinospora cordifolia (giloy) bioactive compounds to inhibit the enzymatic activity of COVID-19 Mpro. In total, 96 bioactive compounds were selected and docked with COVID-19 Mpro and further validated by molecular dynamics study. From the docking and molecular dynamics study, it was revealed that the bioactives namely amritoside, apigenin-6-C-glucosyl7-O-glucoside, pectolinarin and astragalin showed better binding affinities with COVID-19 Mpro. Drug-likeness, ADEMT and bioactivity score prediction of best drug candidates were evaluated by DruLiTo, pkCSM and Molinspiration servers, respectively. Overall, the in silico results confirmed that the validated bioactives could be exploited as promising COVID-19 Mpro inhibitors.
Asunto(s)
Phyllanthus emblica , Phyllanthus , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Tinospora , COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Humanos , Medicina Ayurvédica , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Péptido Hidrolasas , Phyllanthus/química , Phyllanthus emblica/química , Fitoquímicos/farmacología , Plantas Medicinales/química , Tinospora/químicaRESUMEN
Breakdown of outer blood-retina barrier (BRB) has been associated with the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) might play a detrimental role in the pathogenesis of DME, a major clinical manifestation of DR. In the present study, we investigated the inhibitory mechanism of astaxanthin on VEGF and its upstream signaling pathways under in vitro and in vivo conditions. Astaxanthin has been observed to downregulate VEGF expression under hyperglycemic (HG) and CoCl2 induced hypoxic conditions in ARPE-19 cells. There were compelling pieces of evidence for the involvement of transcription factors like HIF1α and XBP1 in the upregulation of VEGF under HG and hypoxic conditions. Thus, we investigated the role of astaxanthin in the expression and nuclear translocation of HIF1α and XBP1. The activation and translocation of HIF1α and XBP1 induced by HG or CoCl2 conditions were hindered by astaxanthin. Additionally, treatment with HIF1α siRNA and IRE1 inhibitor STF-083010 also inhibited the expression of VEGF induced by HG and CoCl2 conditions. These results indicated that the anti-VEGF property of astaxanthin might be associated with the downregulation of HIF1α and XBP1. Furthermore, astaxanthin mitigated the enhanced migration of retinal pigment epithelial (RPE) cells under DR conditions. As well, astaxanthin protected disorganization of zona occludin-1 (ZO-1) tight junction protein in RPE and reduced HG or hypoxic induced permeability of RPE cells. In streptozotocin-induced diabetic rat model, astaxanthin reduced the expression of HIF1α, XBP1, and VEGF as well as protected the abnormalities in the retinal layers induced by diabetes condition. Thus, astaxanthin may be used as a potential nutraceutical to prevent or treat retinal dysfunction in diabetic patients.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Factor A de Crecimiento Endotelial Vascular/genética , Proteína 1 de Unión a la X-Box/genética , Animales , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Fibrinolíticos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Masculino , ARN/genética , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Proteína 1 de Unión a la X-Box/biosíntesis , Xantófilas/farmacologíaRESUMEN
Angiogenesis, a process involved in neovascularization, has been found to be associated with several metabolic diseases like cancer, retinopathy etc. Thus, currently, the focus on anti-angiogenic therapy for treatment and prevention of diseases has gained significant attention. Currently available Food and Drug Administration (FDA) approved drugs are targeting either vascular endothelial growth factor or it's receptor, but in the long term, these approaches were shown to cause several side effects and the chances of developing resistance to these drugs is also high. Therefore, identification of safe and cost-effective anti-angiogenic molecules is highly imperative. Over the past decades, dietary based natural compounds have been studied for their anti-angiogenic potential which provided avenues in improving the angiogenesis based therapy. In this review, major emphasis is given to the molecular mechanism behind anti-angiogenic effect of natural compounds from dietary sources.