RESUMEN
Ulcerative colitis (UC) is a chronic inflammation-related disease that severely affects the colon and rectum regions. A variety of therapy regimens are used for the treatment of UC. Clinically, therapeutic enema is the choice of therapy for UC patients. Irrespective of on-site administration, the major limitation of therapeutic enemas is the dispossession of the medicine followed by low drug availability for the therapeutic action. In our present work, we have developed an enzyme-responsive injectable hydrogel (ER-hydrogel) to overcome the limitations of therapeutic enema. The hydrogels possess two major advantages, which are being exploited for therapeutic drug delivery in UC: prolonged retention and enzyme responsiveness. The former is one of the prominent advantages of hydrogel compared to free drug enema and the latter controls the release of the drug or provides drug release on-demand. The ER-hydrogel was formulated by the heat-cool method and for therapeutic purposes, a corticosteroid drug, budesonide (Bud), was encapsulated into the ER-hydrogel and evaluated for its various physicochemical and therapeutic potentials in dextran sodium sulfate (DSS)-induced UC. In vitro and ex vivo adhesion studies confirm the retention or mucoadhesive nature of the ER-hydrogel, and the upsurge in Bud release from the Bud-loaded ER-hydrogel upon the addition of esterase enzyme confirms the enzyme-mediated drug release from the ER-hydrogel. Moreover, Bud-loaded ER-hydrogel exhibited promising results in alleviating the disease activity index of UC, and restored the length of the colon, which is the main hallmark of UC. In terms of the health of the colon tissue, the Bud-loaded ER-hydrogel restored the colonic tissue damage, as seen in the H&E-stained, AB-NR-stained, and HID-AB-stained colon sections. Finally, the Bud-loaded ER-hydrogel also markedly subsided the IL-1ß, TNF-α, MPO, and nitrite levels in serum and colon tissues. Thus, the fabricated Bud-loaded ER-hydrogel possesses appreciable translational potential due to its ability to significantly ameliorate inflammatory changes compared to naive or water-based therapeutic enema in acute experimental colitis in mice.
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Colitis Ulcerosa , Colitis , Animales , Ratones , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Hidrogeles/uso terapéuticoRESUMEN
The present study sought to understand the effects of a combination of altered colonic mucosal health (intrarectal capsazepine administration) and high-fat diet (HFD) administration in mice. Furthermore, we also studied whether this combination prevents protective actions of dietary prebiotic, isomaltooligosaccharides. We studied the alterations in intestinal permeability, histological and transcriptional changes, short-chain fatty acid (SCFA) concentrations, and gut microbial abundance. Capsazepine (CPZ) was administered rectally twice a day along with HFD feeding. Following confirmation of CPZ action (loss of TRPA1 and TRPV1-associated nocifensive behavior), the intrarectal dose of CPZ was reduced to once in 2 days up to 8 weeks. Simultaneous intrarectal administration of CPZ exacerbated the HFD (8 weeks feeding)-induced damage to mucosal lining, intestinal permeability, tight junction protein expression, SCFA levels, and gut bacterial abundances. This higher degree of mucosal damage and pathological alteration in colonic mucosa prevented the previously reported protective actions of isomaltooligosaccharides as a prebiotic in HFD-fed mice. Overall, we present evidence that colonic precondition (gut permeability and mucosal lining) is an important factor in determination of HFD-induced changes in the colon, and success of diet-associated interventions (dietary fibers, pre/probiotics, etc.) is dependent on it.
RESUMEN
Cereal bran consumption improves gastrointestinal and metabolic health. Unprocessed cereal brans have a limited shelf-life and contain anti-nutrient phytochemicals. In the present study, lipids and antinutrients (flavonoids, tannin, and polyphenol) were removed from finger millet, kodo millet and rice bran using chemo-enzymatic processing. The thus-obtained modified cereal brans (MCBs) were evaluated for their potential in preventing high fat diet (HFD)-induced obesity. C57BL/6 mice were fed a HFD or a HFD supplemented with 10% w/w modified finger millet bran (mFMB), modified kodo millet bran (mKMB), modified rice bran (mRB), or a combination of the modified brans (1 : 1 : 1) for twelve weeks. The MCBs reduced HFD-induced body weight gain, improved glucose homeostasis, decreased the Firmicutes/Bacteroidetes ratio, and increased the short chain fatty acid (SCFA) levels in the cecum. Liver dyslipidemia, oxidative stress, inflammation, visceral white adipose tissue (vWAT) hypertrophy, and lipolysis were also prevented by the MCBs. Among the individual MCBs, mRB showed a greater effect in preventing HFD-induced increase in the inflammatory cytokines (IL-6, TNF-α, and LPS) than mFMB and mKMB. mFMB and mKMB supplementation more significantly restored the relative abundance of Akkermansia muciniphila and butyrate-producing genera such as Lachnospiraceae, Eubacterium, and Ruminococcus than mRB. Ex vivo gut permeability assay, immunohistochemistry of tight junction proteins, and gene expression analysis in the colon revealed that the combination of three brans was better in preventing HFD-induced leaky gut in comparison to the individual brans. Hierarchical clustering analysis showed that the combination group was clustered closest to the NPD group, suggesting an additive effect. Our study implies that a combination of mFMB, mKMB, and mRB could be used as a nutraceutical or functional food ingredient for preventing HFD-induced gut derangements and associated metabolic complications.
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Eleusine , Oryza , Paspalum , Animales , Ratones , Grano Comestible , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BLRESUMEN
Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and luminal microbial community. The present study focuses on the effects' intra rectal administration of capsazepine (modulator of TRPA1/TRPV1 expressing peptidergic sensory neurons) on colonic mucus production and gut health. We performed histological analysis, gut permeability alteration, gene expression changes, metabolite profiling, and gut microbial abundance in the ileum, colon, and cecum content of these animals. Intra rectal administration of capsazepine modulates TRPA1/TRPV1-positive nociceptors (behavioral pain assays) and resulted in damaged mucosal lining, increased gut permeability, and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. These results suggest that caution must be exercised before employing TRPA1/TRPV1 modulation as a therapeutic option to alleviate pain caused due to IBD.
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Enfermedades Inflamatorias del Intestino , Canales de Potencial de Receptor Transitorio , Animales , Capsaicina/análogos & derivados , Colon/metabolismo , Ratones , Dolor , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/genética , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
The gut barrier - including tight junction proteins (TJPs) and mucus layers, is the first line of defense against physical, chemical or pathogenic incursions. This barrier is compromised in various health disorders. Capsaicin, a dietary agonist of Transient receptor potential vanilloid 1 (TRPV1) channel, is reported to alleviate the complications of obesity. While it is well known to improve energy expenditure and metabolism, and prevent dysbiosis, the more local effects on the host gut - particularly the gut barrier and mucus system remain elusive. To investigate the effect of capsaicin on the gut barrier and mucus production and to understand the involvement of mucus, bacteria, and TRPV1 in these phenomena, we employed a diet-induced obesity model in C57BL/6 mice, and capsaicin (2 mg/kg/day p.o.) or mucin (1 g/kg/day p.o.) as interventions, for 12 weeks. Parameters like weight gain, glucose homeostasis, TJPs expression, mucus staining, intestinal permeability etc were studied. 16 S rDNA sequencing and in vitro Ca2+ measurement experiments were performed to explore the role of microbiota in the beneficial effects. Mucin feeding reflected several anti-obesity effects produced by capsaicin, suggesting that mucus modulation might play a crucial role in capsaicin-induced anti-obesity effects. 16 S rDNA sequencing and in vitro Ca2+ measurement experiments pointed to TRPV1 modulation by bacteria besides capsaicin. Capsaicin, bacteria and the host mucus system seem to act in a cyclic cascade involving TRPV1, which can be activated by capsaicin and various bacteria. These findings provide new insight into the role of TRPV1 in maintaining a healthy gut environment.
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Capsaicina , Microbiota , Mucinas , Obesidad , Canales Catiónicos TRPV/agonistas , Animales , Capsaicina/metabolismo , Capsaicina/farmacología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Microbiota/efectos de los fármacos , Microbiota/fisiología , Mucinas/metabolismo , Mucinas/farmacología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
BACKGROUND: Bioactive dietary constituents activating Transient receptor potential (TRP) channels have emerged as promising candidates for the prevention of metabolic disorders. OBJECTIVE: The present study is an attempt to evaluate anti-obesity potential of a dietary TRP-based tri-agonist, combination of sub-effective doses of capsaicin (TRPV1 agonist), menthol (TRPM8 agonist), and cinnamaldehyde (TRPA1 agonist) in high-fat diet (HFD)-fed mice. DESIGN: Male C57BL/6 J mice divided into three groups (n = 8), were fed on normal pellet diet (NPD), or high-fat diet (HFD) (60% energy by fat) and HFD + CB (combination of capsaicin 0.4 mg/Kg, menthol 20 mg/Kg, and cinnamaldehyde 2 mg/Kg; p.o) for 12 weeks. Effects on HFD-induced weight gain, biochemical, histological and genomic changes in the WAT, BAT, liver and hypothalamus tissues were studied. RESULTS: Administration of tri-agonist prevented HFD-induced increase in weight gain, improved altered morphometric parameters, glucose homeostasis, and adipose tissue hypertrophy. Tri-agonist supplementation was found to induce browning of white adipose tissue and promote brown adipose tissue activation. Enhanced glucose utilization and prevention of lipid accumulation and insulin resistance in the liver was observed in mice supplemented with a tri-agonist. CONCLUSION: The present work provides evidence that the new approach based on combination of sub-effective doses of TRP channel agonists (TRI-AGONIST) can be employed to develop concept-based functional food for therapeutic and preventive strategies against HFD-associated pathological complications.
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Metabolismo Energético/efectos de los fármacos , Canales de Potencial de Receptor Transitorio/agonistas , Acroleína/administración & dosificación , Acroleína/análogos & derivados , Acroleína/uso terapéutico , Animales , Capsaicina/administración & dosificación , Capsaicina/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Dieta Alta en Grasa/métodos , Modelos Animales de Enfermedad , Mentol/administración & dosificación , Mentol/uso terapéutico , Ratones , Ratones Endogámicos C57BL/crecimiento & desarrollo , Ratones Endogámicos C57BL/metabolismo , Fenotipo , Canales de Potencial de Receptor Transitorio/farmacologíaRESUMEN
Peaches are good source of nutrients and known for their taste and aroma. The highly perishable nature of the peaches tends to decay rapidly during transportation and storage is a serious constraint for efficient transportation and storage. Therefore, the effect of arabinoxylan (AX) and ß-D-glucan stearic acid ester (SABG) composite coating material was examined for the postharvest storage quality of peach under storage at 22 ± 2 °C with 85% relative humidity (RH). Both, AX-SABG and shellac (1-2%) coatings significantly reduced the change in the quality attributes like weight loss (1.2-1.4 fold), respiration rate (1.1-1.2 fold), ripening index (1.3-1.5 fold) and firmness (1.3-1.5 fold) during 6 days storage as compared to the uncoated peaches. In addition, AX-SABG (1-2%) coating was more effective in retaining aroma volatiles and reducing disease incidence compared to shellac. Further, acute and chronic toxicological studies have shown no tissue related toxicity and mortality in mice. Our results suggest that AX-SABG as an edible coating has the potential to preserve the fruit quality during 6 days storage at 22 ± 2 °C and extend the postharvest shelf life of peach during storage.
RESUMEN
Scope. Given the global epidemic of diabesity (co-existence of both diabetes and obesity), novel approaches that target gut hormone secretion and their modulation may offer the dual benefits of increased efficacy and limited side effects. In the present study, we tested the hypothesis that agonism of Transient Receptor Potential Ankyrin 1 (TRPA1), using a dietary activator, has a modulatory role in high fat diet (HFD)-induced dysregulation of post-prandial gut hormone responses and prevention of metabolic alterations. Methods and results. The effect of HFD on TRPA1 expression in different parts of the gut using immunohistochemistry, western blotting and RT-PCR was studied. Dietary TRPA1 agonist, Allicin Rich Garlic Juice (ARGJ), was co-administered along with HFD in mice for three months and various metabolic health parameters, relative gut hormone levels and inflammation were observed. The HFD caused substantial reduction in gut TRPA1 expression along with dysregulation in post-prandial normalization of gut hormone levels, particularly GLP-1, precipitating hunger phenotype, altered glucose homeostasis, hepatic inflammation and fat accumulation. TRPA1 agonism through ARGJ co-supplementation prevented HFD-induced dysregulation in post-prandial normalization of gut hormone levels and averted metabolic and inflammatory complications in peripheral tissues. Conclusion. Our findings provide evidence that ARGJ (diet-based TRPA1 agonism) can be employed as a feasible strategy, as nutraceuticals or food, to prevent HFD-induced metabolic complications.
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Dieta Alta en Grasa/efectos adversos , Disulfuros/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación , Ácidos Sulfínicos/farmacología , Canal Catiónico TRPA1/agonistas , Animales , Inflamación/metabolismo , Inflamación/fisiopatología , Masculino , RatonesRESUMEN
Short-chain fatty acids (SCFAs), metabolites of colonic bacterial fermentation of complex carbohydrates, are closely related to the release of gut hormones. In this study, we examined the involvement of transient receptor potential ankyrin 1 (TRPA1) in SCFA-induced increase in intracellular calcium ([Ca2+ ]i ) and its impact on gut hormone secretion using naturally TRPA1 expressing intestinal secretin tumour cell-1 (STC-1) cell line. Individual SCFAs and their physiological mix enhanced calcium influx in TRPA1-dependent manner. SCFA mix also significantly increased membrane expression of TRPA1. Gene expression studies revealed that SCFA mix elevated the expression of genes involved in calcium-activated calcineurin pathway in TRPA1-dependent manner and cAMP-regulated transcriptional co-activators (CRTC) pathway independent to TRPA1. Genes representing synaptic vesicular exocytosis and gut hormone precursors were significantly elevated with SCFA mix treatment. Treatment with TRPA1 antagonist HC-030031 markedly reduced these effects. The release of gut hormones was elevated with 10 mm SCFA mix in TRPA1 dependent manner. Our in vivo prebiotic study results suggested presence of an environment conducive to increase in gut hormone secretion. Overall, our findings provide an evidence for the possible role of TRPA1 in SCFA-induced increase in gut hormone secretion, hence another mechanism of action for prebiotics.
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Calcio , Neoplasias , Ácidos Grasos Volátiles , Humanos , Secretina , Transducción de SeñalRESUMEN
Recent evidence supports the role of menthol, a TRPM8 agonist, in enhanced energy expenditure, thermogenesis and BAT-like activity in classical WAT depots in a TRPM8 dependent and independent manner. The present study was designed to analyse whether oral and topical administration of menthol is bioavailable at subcutaneous adipose tissue and is sufficient to directlyinduce desired energy expenditure effects. GC-FID was performed to study menthol bioavailability in serum and subcutaneous white adipose tissue following oral and topical administration. Further, 3T3L1 adipocytes were treated with bioavailable menthol doses and different parameters (lipid accumulation, "browning/brite" and energy expenditure gene expression, metal analysis, mitochondrial complex's gene expression) were studied. No difference was observed in serum levels but significant difference was seen in the menthol concentration on subcutaneous adipose tissues after oral and topical application. Menthol administration at bioavailable doses significantly increased "browning/brite" and energy expenditure phenotype, enhanced mitochondrial activity related gene expression, increased metal concentration during adipogenesis but did not alter the lipid accumulation as well as acute experiments were performed with lower dose of menthol on mature adipocytes In conclusion, the present study provides evidence that bioavailable menthol after single oral and topical administration is sufficient to induce "brite" phenotype in subcutaneous adipose tissue However, critical dose characterization for its clinical utility is required.