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AIM: Brown adipose tissue (BAT) thermogenesis has profound energy-expanding potential, which makes it an attractive target tissue to combat ever-increasing obesity and its other associated metabolic complications. Although it is fairly accepted that cold is a potent inducer of BAT activation and function, there are limited studies on the mechanisms of pharmacological cold-mimicking agents, such as the TRPM8 agonist, menthol, on BAT thermogenesis and activation. METHODS: Herein, we sought to determine the effect of topical application of menthol (10% w/v [4 g/kg] cream formulation/day for 15 days) on temperature sensitivity behaviour (thermal gradient assay, nesting behaviour), adaptive thermogenesis (infrared thermography, core body temperature), BAT sympathetic innervation (tyrosine hydroxylase immunohistochemistry) and activation (18F-FDG PET-CT analysis, Uncoupling Protein 1 immunohistochemistry and BAT gene expression), whole-body energy expenditure (indirect calorimetry) and other metabolic variables in male C57BL/6N mice. RESULTS: We show that male C57BL/6N mice: (a) develop a warm-seeking and cold-avoiding thermal preference phenotype; (b) display increased locomotor activity and adaptive thermogenesis; (c) show augmented sympathetic innervation in BAT and its activation; (d) exhibit enhanced gluconeogenic capacity (increased glucose excursion in response to pyruvate) and insulin sensitivity; and (e) show enhanced whole-body energy expenditure and induced lipid-utilizing phenotype after topical menthol application. CONCLUSIONS: Taken together, our findings highlight that pharmacological cold mimicking using topical menthol application presents a potential therapeutic strategy to counter weight gain and related complications.
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As a high-metabolic-rate organ, the kidney exhibits metabolic reprogramming (MR) in various disease states. Given the >800 million cases of kidney disease worldwide in 2022, understanding the specific bioenergetic pathways involved and developing targeted interventions are vital needs. The reprogramming of metabolic pathways (glucose metabolism, amino acid metabolism, etc.) has been observed in kidney disease. Therapies targeting these specific pathways have proven to be an efficient approach for retarding kidney disease progression. In this review, we focus on potential pharmacological interventions targeting MR that have advanced through Phase III/IV clinical trials for the management of kidney disease and promising preclinical studies laying the groundwork for future clinical investigations.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Neoplasias Renales/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Redes y Vías Metabólicas , Riñón/metabolismo , Metabolismo EnergéticoRESUMEN
Kynurenine pathway, a neuroimmunological pathway plays a substantial role in depression. Consistently, increased levels of neurotoxic metabolite of kynurenine pathway; quinolinic acid (QA) found in the suicidal patients and remitted major depressive patients. QA, an endogenous modulator of N-methyl-d-aspartate receptor is produced by microglial cells, may serve as a potential candidate for a link between antioxidant defence system and immune changes in depression. Further, nuclear factor (erythroid-derived 2) like 2 (Nrf2), an endogenous antioxidant transcription factor plays a significant role in maintaining antioxidant homeostasis during basal and stress conditions. The present study was designed to explore the effects of KMO-inhibition (Kynurenine monooxygenase) and association of reduced QA on Keap1/Nrf2/ARE pathway activity in olfactory bulbectomized mice (OBX-mice). KMO catalysis the neurotoxic branch of kynurenine pathway directing the synthesis of QA. KMO inhibitionshowed significant reversal of depressive-like behaviour, restored Keap-1 and Nrf2 mRNA expression, and associated antioxidant levels in cortex and hippocampus of OBX-mice. KMO inhibition also increased PI3K/AKT mRNA expression in OBX-mice. KMO inhibition and associated reduced QA significantly decreased inflammatory markers, kynurenine and increased the 5-HT, 5-HIAA and tryptophan levels in OBX-mice. Furthermore, molecular docking studies has shown good binding affinity of QA towards ubiquitin proteasome complex and PI3K protein involved in Keap-1 dependent and independent proteasome degradation of Nrf2 respectively supporting our in-vivo findings. Hence, QA might act as pro-oxidant through downregulating Nrf2/ARE pathway along with modulating other pathways and KMO inhibition could be a potential therapeutic target for depression treatment.
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Trastorno Depresivo Mayor , Ácido Quinolínico , Animales , Antioxidantes , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ácido Quinolínico/metabolismo , ARN MensajeroRESUMEN
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
ß-Amyloid (Aß) peptide is a characteristic feature of Alzheimer's disease (AD) and accumulation of Aß is associated with loss of synaptic plasticity and neuronal cell death. Aggregation of Aß initiates numerous molecular signalling pathways leading to oxidative stress, mitochondrial dysfunction as well as an imbalance of calcium ion influx homeostasis. Recently, it has been shown that transient receptor potential melastatin 2 (TRPM2), a non-selective calcium-permeable cation channel has been postulated to play a vital role in the neuronal death, indicating the potential of TRPM2 inhibition in CNS disease. In this study, neuroprotective potential of 2-aminoethoxydiphenyl borate (2-APB), a broad-spectrum calcium channels blocker was investigated in Aß-induced memory deficits in rats. In addition, effect of 2-APB on TRPM2 channels gene and protein expressions and also on calcium and memory related proteins was investigated in the hippocampus. Intracerebroventricular (I.C.V.) administration of Aß (Aß25-35, 10 µg) markedly induced cognitive impairment and upregulation of mRNA and protein expression of TRPM2 in the hippocampus. In addition, AChE activity was also increased in the cortex of the Aß administered animals. Three-week treatment with 2-APB led to the down-regulation of TRPM2 mRNA and protein expression in the hippocampus and also improved the cognitive functions which was evident from the behavioral parameters. Moreover, 2-APB treatment also increased the calcium and memory associated proteins namely p-CaMKII, p-GSK-3ß, p-CREB and PSD-95 in the hippocampus and reduced the mRNA level of calcium buffering proteins and calcineurin A (PPP3CA) in the hippocampus. Furthermore, 2-APB treatment significantly reduced the AChE activity in the cortex. Thus, our findings suggest the neuroprotective effect of 2-APB in Aß-induced cognitive impairment.
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Péptidos beta-Amiloides , Fármacos Neuroprotectores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Animales , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , RatasRESUMEN
BACKGROUND: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson's disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. OBJECTIVE: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. METHODS: PD was induced using a bilateral intranigral administration of MPTP in Sprague Dawley rats, and different parameters were evaluated. RESULTS: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. CONCLUSION: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.
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PPAR gamma , Enfermedad de Parkinson , Animales , Cognición , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , PPAR gamma/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Roedores/metabolismoRESUMEN
Transient receptor potential ankyrin 1 (TRPA1) channel is a calcium permeable, non-selective cation channel, expressed in the sensory neurons and non-neuronal cells of different tissues. Initially studied for its role in pain and inflammation, TRPA1 has now functionally involved in multiple other physiological functions. TRPA1 channel has been extensively studied for modulation by pungent compounds present in the spices and herbs. In the last decade, the role of TRPA1 agonism in body weight reduction, secretion of hunger and satiety hormones, insulin secretion and thermogenesis, has unveiled the potential of the TRPA1 channel to be used as a preventive target to tackle obesity and associated comorbidities including insulin resistance in type 2 diabetes. In this review, we summarized the recent findings of TRPA1 based dietary/non-dietary modulation for its role in obesity prevention and therapeutics.
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Productos Biológicos/farmacología , Moduladores del Transporte de Membrana/farmacología , Obesidad/prevención & control , Canal Catiónico TRPA1/agonistas , Canal Catiónico TRPA1/fisiología , Animales , Humanos , Canal Catiónico TRPA1/químicaRESUMEN
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
Finger millet (FM) and kodo millet (KM) are known for their multiple health benefits. Several studies have indicated the antioxidant and hypoglycemic potential of polyphenol rich extracts (PREs) from them. However, the protective roles of PREs from these millets in overcoming high-fat diet (HFD)-induced obesity have not yet been investigated. This study aimed to identify the polyphenols in FM-PREs and KM-PREs using HPLC-DAD/ESI-MS, and to evaluate the role of PREs in mitigating lipopolysaccharide induced inflammation in murine macrophage cells and in the reduction of HFD-induced metabolic complications using male Swiss albino mice. The results suggested that KM-PRE had higher polyphenol content than FM-PRE, of which taxifolin (98%) and catechin (86.6%) were the major fractions respectively. FM-PRE and KM-PRE prevented obesity, however, KM-PRE was more profound in preventing weight gain, adipose tissue hypertrophy, hepatic steatosis, and systemic inflammation than FM-PRE. This study suggests that FM-PRE and KM-PRE could be exploited for developing functional foods or nutraceuticals against obesity and comorbidities.
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Tejido Adiposo/efectos de los fármacos , Mijos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Animales , Dieta Alta en Grasa , Dislipidemias/prevención & control , Alimentos Funcionales , Masculino , RatonesRESUMEN
Crohn's and ulcerative colitis are common inflammatory conditions associated with Inflammatory bowel disease. Owing to the importance of diet based approaches for the prevention of inflammatory gut conditions, the present study was aimed to screen the human isolates of Bifidobacterium strains based on their ability to reduce LPS-induced inflammation in murine macrophage (RAW 264.7) cells and to evaluate prioritized strains for their preventive efficacy against ulcerative colitis in mice. Twelve out of 25 isolated strains reduced the production of LPS-induced nitric oxide and inflammatory cytokines. Furthermore, three strains, B. longum Bif10, B. breve Bif11, and B. longum Bif16 conferred protection against dextran sodium sulfate induced colitis in mice. The three strains prevented shortening of colon, spleen weight, percentage body weight change and disease activity index relative to colitis mice. Lower levels of Lipocalin-2, TNF-α, IL-1ß and IL-6 and improved SCFA levels were observed in Bifidobacterium supplemented mice relative to DSS counterparts. Bacterial composition of B. longum Bif10 and B. breve Bif11 fed mice was partly similar to the normal mice, while DSS and B. longum Bif16 supplemented mice showed deleterious alterations. At the genus level, Bifidobacterium supplementation inhibited the abundances of pathobionts such as Haemophilus, Klebsiella and Lachnospira there by conferring protection.
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Antiinflamatorios/metabolismo , Bifidobacterium/fisiología , Colitis Ulcerosa/microbiología , Colitis/microbiología , Disbiosis/microbiología , Microbioma Gastrointestinal/fisiología , Animales , Línea Celular , Colitis/inducido químicamente , Colitis/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Colon/microbiología , Citocinas/metabolismo , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Disbiosis/inducido químicamente , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/microbiología , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/microbiología , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7 , Bazo/metabolismo , Bazo/microbiologíaRESUMEN
This study focuses on exploring the role of sensory cation channel Transient Receptor Potential channel subfamily Vanilloid 1 (TRPV1) in gut health, specifically mucus production and microflora profile in gut. We employed resiniferatoxin (ultrapotent TRPV1 agonist) induced chemo-denervation model in rats and studied the effects of TRPV1 ablation on colonic mucus secretion patterns. Histological and transcriptional analysis showed substantial decrease in mucus production as well as in expression of genes involved in goblet cell differentiation, mucin production and glycosylation. 16S metagenome analysis revealed changes in abundance of various gut bacteria, including decrease in beneficial bacteria like Lactobacillus spp and Clostridia spp. Also, TRPV1 ablation significantly decreased the levels of short chain fatty acids, i.e. acetate and butyrate. The present study provides first evidence that systemic TRPV1 ablation leads to impairment in mucus production and causes dysbiosis in gut. Further, it suggests to address mucin production and gut microbiota related adverse effects during the development of TRPV1 antagonism/ablation-based therapeutic and preventive strategies.
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Colon/metabolismo , Microbioma Gastrointestinal/fisiología , Mucinas/antagonistas & inhibidores , Mucinas/biosíntesis , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/deficiencia , Técnicas de Ablación/métodos , Animales , Disbiosis/genética , Disbiosis/metabolismo , Masculino , Ratas , Ratas Wistar , Canales Catiónicos TRPV/genéticaRESUMEN
Atypical antipsychotics (AAPs) have the tendency of inducing severe metabolic alterations like obesity, diabetes mellitus, insulin resistance, dyslipidemia and cardiovascular complications. These alterations have been attributed to altered hypothalamic appetite regulation, energy sensing, insulin/leptin signaling, inflammatory reactions and active reward anticipation. Line of evidence suggests that transient receptor potential vanilloid type 1 and 3 (TRPV1 and TRPV3) channels are emerging targets in treatment of obesity, diabetes mellitus and could modulate feed intake. The present study was aimed to investigate the putative role TRPV1/TRPV3 in olanzapine-induced metabolic alterations in mice. Female BALB/c mice were treated with olanzapine for six weeks to induce metabolic alterations. Non-selective TRPV1/TRPV3 antagonist (ruthenium red) and selective TRPV1 (capsazepine) and TRPV3 antagonists (2,2-diphenyltetrahydrofuran or DPTHF) were used to investigate the involvement of TRPV1/TRPV3 in chronic olanzapine-induced metabolic alterations. These metabolic alterations were differentially reversed by ruthenium red and capsazepine, while DPTHF didn't show any significant effect. Olanzapine treatment also altered the mRNA expression of hypothalamic appetite-regulating and nutrient-sensing factors, inflammatory genes and TRPV1/TRPV3, which were reversed with ruthenium red and capsazepine treatment. Furthermore, olanzapine treatment also increased expression of TRPV1/TRPV3 in nucleus accumbens (NAc), TRPV3 expression in ventral tegmental area (VTA), which were reversed by the respective antagonists. However, DPTHF treatment showed reduced feed intake in olanzapine treated mice, which might be due to TRPV3 specific antagonism and reduced hedonic feed intake. In conclusion, our results suggested the putative role TRPV1 in hypothalamic dysregulations and TRPV3 in the mesolimbic pathway; both regulate feeding in olanzapine treated mice.
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Regulación del Apetito/efectos de los fármacos , Inflamación/metabolismo , Olanzapina/farmacología , Canales Catiónicos TRPV/metabolismo , Animales , Capsaicina/administración & dosificación , Capsaicina/análogos & derivados , Capsaicina/farmacología , Colorantes/administración & dosificación , Colorantes/farmacología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Femenino , Furanos/administración & dosificación , Furanos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Hipotálamo/efectos de los fármacos , Inflamación/genética , Metformina/administración & dosificación , Metformina/farmacología , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Rojo de Rutenio/administración & dosificación , Rojo de Rutenio/farmacología , Fármacos del Sistema Sensorial/administración & dosificación , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/genéticaRESUMEN
SCOPE: Effective health-promoting results of either anthocyanins or whole wheat against chronic diseases are well reported. The current study is designed to understand the effect and underlying mechanism of anthocyanins-biofortified whole wheat on high-fat diet (HF)-induced obesity and its comorbidities. METHOD AND RESULTS: Mice are fed a HFD supplemented with isoenergetic white, purple, or black whole wheat for 12 weeks and analyzed by physiological, biochemical, and nutrigenomics studies (qRT-PCR and RNA-Seq analysis). Black wheat significantly reduces body weight gain and fat pad. Both black and purple wheats reduce total cholesterol, triglyceride, and free fatty acid levels in serum, with the restoration of blood glucose and insulin resistance. Black wheat significantly elevates the expression of enzymes related to fatty acid balancing, ß-oxidation, and oxidative stress that supported the biochemical and physiological positive outcomes. Moreover, the transcriptome analysis of adipose and liver tissue reveals activation of multiple pathways and genes related to fatty acid-ß oxidation (crat, acca2, lonp2 etc.), antioxidative enzymes (gpx1, sod1, nxnl1 etc.), along with balancing of fatty acid metabolism specifically in black wheat supplemented mice. CONCLUSION: Taken together, the results suggest that the incorporation of colored wheat (especially black wheat) in the diet can prevent obesity and related metabolic complications.
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Antocianinas/farmacología , Dieta Alta en Grasa/efectos adversos , Triticum/química , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Color , Metabolismo Energético/efectos de los fármacos , Alimentos Fortificados , Regulación de la Expresión Génica/efectos de los fármacos , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Nutrigenómica/métodos , Obesidad/dietoterapia , Obesidad/etiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
Encapsulation techniques and materials, explored for addressing compromised probiotic gut survival, report significant production losses resulting in <10% entrapment. Presently, we report three-time enhanced entrapment (30 ± 1.2%) of Lactobacillus acidophilus (LAB) in calcium-alginate beads, by modifying process parameters and employing polyethylene glycol (PEG). Water-loving, viscolysing and osmotic-building effects of PEG create numerous, fine voids in the alginate gel allowing efficient diffusion of crosslinking calcium ions, resulting in less leaky beads. Eudragit S100 overcoat improved LAB survival by 690 times in simulated GIT stresses.In DMH-DSS induced colitis and precancerous lesions in rats, while free LAB failed to show any protection, pharmabiotic beads significantly (p < .05) reduced lipid peroxidation, increased antioxidant levels; decreased serum inflammatory burden; downregulated COX-2, iNOS, and c-Myc expression; elevated levels of the selected gut bacteria and SCFAs especially butyrate, all of which add up to antioxidant, anti-inflammatory, balanced gut biota, and ultimately anticancer effects.
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Colitis/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Lactobacillus acidophilus , Probióticos/farmacología , Tecnología Farmacéutica/métodos , Alginatos/química , Animales , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Polietilenglicoles/química , Ácidos Polimetacrílicos/química , Ratas , Ratas WistarRESUMEN
Diabetic neuropathy is a peripheral nervous system disorder affecting both somatic and autonomic components of nervous system. A growing body of evidence have depicted that high glucose levels can induce activation of the Wnt/ß-catenin pathway, however there are no studies targeting this pathway in DN. The intent of the present study was to investigate the effects of isoquercitrin (ISQ), a Wnt/ß-catenin signaling pathway inhibitor, in diabetic neuropathy. Streptozotocin (50 mg/kg, i.p.) was used to induce diabetes in rats. 6-week diabetic rats were treated intrathecally with ISQ at 10 and 30 µM doses for 3 days. Furthermore, to confirm the results of the intrathecal study, a 2-week intraperitoneal treatment of ISQ was given to diabetic rats. After 6 weeks, diabetic rats developed neuropathy which was evident from reduced thermal and mechanical hyperalgesia thresholds and significant deterioration in motor nerve conduction velocity (MNCV), nerve blood flow (NBF). Sciatic nerves of diabetic neuropathy rats showed increased expression of Wnt pathway proteins namely ß-catenin, c-myc and MMP2. Treatment with ISQ, both intrathecally (10 and 30 µM) and intraperitoneally (10 mg/kg), significantly ameliorated the alterations in behavioral pain thresholds and improved functional parameters in diabetic rats. Moreover, ISQ also downregulated the expression of Wnt/ß-catenin pathway proteins significantly in diabetic rats as compared to vehicle-treated diabetic rats. Results of the present study suggest the neuroprotective potential of ISQ in the treatment of DN via inhibition of Wnt/ß-catenin signaling pathway.
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Antioxidantes/farmacología , Neuropatías Diabéticas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Quercetina/análogos & derivados , Vía de Señalización Wnt/efectos de los fármacos , Animales , Cateninas/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Masculino , Quercetina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Mentol/farmacología , Grasa Subcutánea/efectos de los fármacos , Canales Catiónicos TRPM/agonistas , Células 3T3-L1 , Adipogénesis/genética , Administración Oral , Administración Tópica , Animales , Disponibilidad Biológica , Metabolismo Energético/genética , Expresión Génica/efectos de los fármacos , Masculino , Mentol/administración & dosificación , Mentol/farmacocinética , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Termogénesis/efectos de los fármacosRESUMEN
Glucagon mediated mechanisms have been shown to play clinically significant role in energy expenditure. The present study was designed to understand whether pharmacological mimicking of cold using menthol (TRPM8 modulator) can induce glucagon-mediated energy expenditure to prevent weight gain and related complications. Acute oral and topical administration of TRPM8 agonists (menthol and icilin) increased serum glucagon concentration which was prevented by pre-treatment with AMTB, a TRPM8 blocker. Chronic administration of menthol (50 and 100 mg/kg/day for 12 weeks) to HFD fed animals prevented weight gain, insulin resistance, adipose tissue hypertrophy and triacylglycerol deposition in liver. These effects were not restricted to oral administration, but also observed upon the topical application of menthol (10% w/v). The metabolic alterations caused by menthol in liver and adipose tissue mirrored the known effects of glucagon, such as increased glycogenolysis and gluconeogenesis in the liver, and enhanced thermogenic activity of white and brown adipose tissue. Correlation analysis suggests a strong correlation between glucagon dependent changes and energy expenditure markers. Interestingly, in-vitro treatment of the serum of menthol treated mice increased energy expenditure markers in mature 3T3L1 adipocytes, which was prevented in the presence of non-competitive glucagon receptor antagonist, L-168,049, indicating that menthol-induced increase in serum glucagon is responsible for increase in energy expenditure phenotype. In conclusion, the present work provides evidence that glucagon plays an important role in the preventive effect of menthol against HFD-induced weight gain and related complications.
RESUMEN
Aim of the study was to evaluate a combination of ginger extract (GE; antioxidant, anti-inflammatory) and Lactobacillus acidophilus (LAB; probiotic), in DMH-DSS-induced inflammation-driven colon cancer, in Wistar rats. Effect of varying GE concentration on growth of LAB was assessed in vitro. Colonic histology and permeability, oxidative stress, serum proinflammatory cytokines, expression of selected genes, gut bacteria, and SCFA determination of gut content was monitored after treatment with agents alone or in combination, postdisease induction. Significant increase in LAB CFU was observed following 48 and 96 hr of incubation with GE; 0.4% w/v GE showed the best results and was used in the cobiotic. Cobiotic administration significantly reversed the DMH-DSS-induced colonic histological alterations. Significant (p < .05) reduction in lipid peroxidation and increase in antioxidant levels (catalase and SOD) was observed in cobiotic group, whereas individual agents did not show any effect. Restoration of colonic permeability, decrease in serum inflammatory burden, and downregulation of COX-2, iNOS, and c-Myc expression on treatment with cobiotic was significantly (p < .05) better than individual agents. Neither LAB nor cobiotic administration produced any change in gut bacteria nor SCFA levels, probably due to loss of LAB viability under adverse gut conditions. Study concludes that presented cobiotic has a promising therapeutic potential, which can be improved by a smartly designed formulation.
Asunto(s)
Inflamación/tratamiento farmacológico , Lactobacillus acidophilus , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Probióticos , Zingiber officinale/química , Animales , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Carcinógenos , Neoplasias del Colon/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo , Interleucina-6/sangre , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Despite the lipolytic and thermogenic properties of capsaicin, its putative use as a weight-lowering dietary supplement has been limited because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes. A potential alternative to capsaicin are the capsinoids, nonpungent capsaicin analogs that exhibit effects similar to capsaicin. Whereas the antiobesity properties of capsinoids have been reported, the effectiveness of FDA-approved synthetic dihydrocapsiate has not yet been investigated. In the present study, we hypothesized that dihydrocapsiate might ameliorate high-fat diet (HFD)-induced metabolic disorders in a manner similar to capsaicin and therefore can be its nonpungent alternative. To test this hypothesis, HFD-fed mice were orally administered dihydrocapsiate (2 and 10mg/kg body weight) for 12weeks. Dihydrocapsiate modestly reduced the HFD-induced weight gain and significantly prevented the associated hyperglyceridemia and hyperinsulinemia while improving glucose tolerance. Histological and gene expression analysis showed that dihydrocapsiate significantly prevented the lipid accumulation in white adipose tissue and brown adipose tissue via targeting genes involved in energy expenditure and mitochondrial biogenesis, respectively. Dihydrocapsiate corrected hepatic triglyceride concentrations and normalized expression of genes regulating hepatic lipid and glucose metabolism. Moreover, dihydrocapsiate administration significantly improved gut morphology and altered gut microbial composition, resulting in reduced host energy availability. Collectively, these results indicate that dihydrocapsiate administration improved glucose tolerance, prevented adiposity and hepatic steatosis, as well as improved HFD-induced gut alterations, positing dihydrocapsiate as a potential food ingredient for the dietary management of HFD-induced metabolic alterations.