Topical menthol, a pharmacological cold mimic, induces cold sensitivity, adaptive thermogenesis and brown adipose tissue activation in mice.

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.

Production and characterization of anti-hypertensive and anti-diabetic peptides from fermented sheep milk with anti-inflammatory activity: in vitro and molecular docking studies.

BACKGROUND: The present study aimed to evaluate the anti-hypertensive and anti-diabetic activities from biologically active peptides produced by fermented sheep milk with Lacticaseibacillus paracasei M11 (MG027695), as well as to purify and characterize the angiotensin-converting enzyme (ACE) inhibitory and anti-diabetic peptides produced from fermented sheep milk. RESULTS: After 48 h of fermentation at 37 °C, sheep milk demonstrated significant changes in anti-diabetic effects and ACE-I effects, with inhibition percentages observed for ACE inhibition (76.32%), α-amylase (70.13%), α-glucosidase (70.11%) and lipase inhibition (68.22%). The highest level of peptides (9.77 mg mL-1) was produced by optimizing the growth conditions, which included an inoculation rate of 2.5% and a 48 h of incubation period. The comparison of molecular weight distributions among protein fractions was conducted through sodium dodecyl-sulfate polyacrylamide gel electrophoresis analysis, whereas spots were separated using 2D gel electrophoresis according to both the molecular weight and pH. Peptide characterization with ultra-filtration membranes at 3 and 10 kDa allowed the study to assess molecular weight-based separation. Nitric oxide generated by lipopolysaccharide and the secretion of pro-inflammatory cytokines in RAW 264.7 immune cells were both inhibited by sheep milk fermented with M11. Fourier-transform infrared spectroscopy was employed to assess changes in functional groups after fermentation, providing insights into the structural changes occurring during fermentation. CONCLUSION: The present study demonstrates that fermentation with L. paracasei (M11) led to significant changes in fermented sheep milk, enhancing its bioactive properties, notably in terms of ACE inhibition and anti-diabetic activities, and the generation of peptides with bioactive properties has potential health benefits. © 2024 Society of Chemical Industry.

Immunomodulatory action of synbiotic comprising of newly isolated lactic acid producing bacterial strains against allergic asthma in mice.

Given the reported role of gut-microbiota in asthma pathogenesis, the present work was carried to evaluate immunomodulatory action of newly isolated lactic acid producing bacterial strains Bifidobacterium breve Bif11 and Lactiplantibacillus plantarum LAB31 against asthma using ovalbumin (OVA) based mouse model. Our results show that both strains modulate Th2 immune response potentially through production of short chain fatty acids (SCFAs), resulting in suppression of OVA-induced airway inflammation. Furthermore, synbiotic comprising of both strains and prebiotic, Isomaltooligosaccharide exhibited superior potential in amelioration of OVA-induced airway inflammation through improved modulation of Th2 immune response. Further, synbiotic protects against OVA-induced mucus hyper-production and airway-hyperresponsiveness. Such protection was associated with normalization of gut microbiome and enhanced production of SCFAs in cecum which correlates closely with population of T-regulatory cells in spleen. Overall, our novel synbiotic possesses the ability to fine-tune the immune response for providing protection against allergic asthma.

Molecular binding mechanism and novel antidiabetic and anti-hypertensive bioactive peptides from fermented camel milk with anti-inflammatory activity in raw macrophages cell lines.

The investigation was to determine the effect of camel milk fermented with Limosilactobacillus fermentum KGL4 (MTCC 25515) on ACE-inhibiting, anti-inflammatory, and diabetes-preventing properties and also to release the novel peptides with antidiabetic and anti-hypertensive attributes with molecular interaction studies. Growth conditions were optimised on the basis of total peptide production by inoculating the culture in camel milk at different rates (1.5, 2.0, and 2.5%) along with different incubation periods (12, 24, 36, and 48 h). However, after 48 h of fermentation with a 2.5% rate of inoculum, the highest proteolytic activity was obtained. Reverse phase high-pressure liquid chromatography (RP-HPLC) was used to calculate the % Rpa from permeates of 3 kDa and 10 kDa fractions. Molecular weight distributions of fermented and unfermented camel milk protein fractions were compared using SDS-PAGE. Spots obtained from 2D gel electrophoresis were separated on the basis of pH and molecular weight. Spots obtained from 2D gel were digested with trypsin, and the digested samples were subjected to RP-LC/MS for the generation of peptide sequences. The inhibition of tumour necrosis factor alpha, interleukin-6, and interleukin-1 during fermentation was studied using RAW 264.7 macrophages. In the study, fermented camel milk with KGL4 (CMKGL4) inhibited LPS-induced nitric oxide (NO) production and pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1ß) by the murine macrophages. The results showed that the peptide structures (YLEELHRLNK and YLQELYPHSSLKVRPILK) exhibited considerable binding affinity against hPAM and hMGA during molecular interaction studies.

Superior Photophysical and Photosensitizing Properties of Nanoaggregates of Weakly Emissive Dyes for Use in Bioimaging and Photodynamic Therapy.

The development of luminescent dyes based on 1,1,4,4-tetracyanobuta-1,3-dienes (TCBDs) is an active research area, and a quantum yield (ΦF) of 7.8% has been achieved so far in cyclohexane by appending a fluorophore. Our novel method radically refines weakly emissive 2,3-disubstituted TCBD (phenyl-TCBD 1) (ΦF = 2.3% in CH3CN) into a water-soluble, biocompatible nanoformulation as highly emissive aggregates 1NPs ⊂ PF-127 with ΦF = 7.9% in H2O and without fluorophore conjugation. Characterization of 1NPs ⊂ PF-127 was carried out using various spectroscopic techniques, and its predominant size was found to be 80-100 nm according to transmission electron microscopy and dynamic light scattering techniques. Spectroscopic studies including Fourier transform infrared spectroscopy revealed that aggregated phenyl-TCBD particles were encapsulated in a nonluminescent triblock copolymer (PF-127)-based nanomicelles with the TCBD entrapment efficiency of 77%. With increasing water fraction, the phenyl-TCBD nanoaggregates exhibited a 3-fold higher quantum yield, a greater lifetime, and a red shift (155 nm). This remarkable enhancement in red emissivity enabled them to be used as a bioprobe for bioimaging applications and in photodynamic therapy to selectively target cancer cell lines with singlet oxygen generation capability (ΦΔ = 0.25). According to the MTT assay, compared to the native molecular form (1229 nM), the aggregated 1NPs ⊂ PF-127 (13.51 nM) exhibited dose-dependent cell death when exposed to light with 91-fold increased activity. The histoarchitectures of various vital organs (liver, kidneys, heart, lungs, and spleen) were intact when tested for in vivo biocompatibility. This study has significant implications for developing nonplanar push-pull chromophore-based dyes as biosensors and with potential applications beyond bioimaging.

Short-term trivalent arsenic and hexavalent chromium exposures induce gut dysbiosis and transcriptional alteration in adipose tissue of mice.

BACKGROUND: Inorganic arsenic [As(III)] and hexavalent chromium [Cr(VI)] can potentially affect metabolic functions. These heavy metal(s)/metalloids can also affect the gut microbial architecture which affects metabolic health. Here, we assessed the effects of short-term exposure of As(III) and Cr(VI) on key transcription factors in adipose tissues and on selected gut microbial abundances to understand the possible modulatory role of these toxicants on host metabolic health. METHODS AND RESULTS: qRT-PCR based relative bacterial abundance studies in cecal samples, gene expression analysis for gut wall integrity in ileum and colon and adipogenesis, lipolysis, and thermogenic genes in gonadal white and brown adipose tissue (gWAT and BAT), along with tissue oxidative stress parameters have been performed. As(III) and Cr(VI) exposure reduced beneficial Lactobacilli, Bifidobacteria, Akkermansia, Lachenospiraceae, Fecalibacterium, Eubacterium, and clostridium coccoid group while increasing lipopolysaccharides producing Enterobacteriaceae abundances. It also impaired structural features and expression of key tight junction and mucin production genes in ileum and colon (Cld-2, Cld-4, ZO-1, ZO-2, MUC-2 and - 4). In gWAT it inhibited adipogenesis (PPARγ, FASN, SREBP1a), lipolysis (HSL, ACOX-1), and thermogenesis (UCP-1, PGC1a, PRDM-16, PPARa) related genes expression, whereas in BAT, it enhanced adipogenesis and reduced thermogenesis. These exposures also reduces the endogenous antioxidants levels in these tissues and promote pro-inflammatory cytokines genes expression (TLRs, IL-6, MCP-1). The combinatorial exposure appears to have more deleterious effects. CONCLUSION: These effects of As(III) and Cr(VI) may not directly be linked to their known toxicological effects, instead, more intriguing crosstalk with gut microbial ecosystem hold the key.

Health risk assessment of arsenic, lead and cadmium from milk consumption in Punjab, India.

Milk is an integral part of the human diet and its contamination with heavy metals may alter the health of its consumers. The study was conducted to assess the health risk associated with the heavy metals in milk samples collected from urban and rural households of Ludhiana and Bathinda districts of Punjab, India. One hundred and fifty milk samples were analyzed for heavy metals i.e. arsenic, cadmium, lead and mercury using Inductively Coupled Plasma Mass Spectrometry ICP-MS. The health risks, such as non-carcinogenic and carcinogenic risks from heavy metals in milk samples, were calculated for selected males and females of adults, children and elderly subjects. The results indicated that the arsenic, cadmium and lead content in milk samples were within permissible limit whereas mercury was not detected in any sample. The mean values showed that the selected urban and rural population of both districts was safe from non-carcinogenic risk associated with heavy metal content of milk. However, urban (50% males and 86% females) and rural (25% males) children of Bathinda district were at risk of cancer from arsenic and cadmium present in milk samples, respectively. It was also observed that the selected population of both districts were safe from carcinogenic risk due to the combined effects of heavy metals. It was concluded that even with a small amount of heavy metal in milk samples, the rural adults, rural male children and urban female children of Bathinda district had carcinogenic risk due to milk consumption. Hence, regular monitoring and testing of milk samples must be done as a public health measure to prevent heavy metal contamination in milk to safeguard the health of consumers.

Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice.

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.

Neuroprotective Effect of 2-Aminoethoxydiphenyl Borate (2-APB) in Amyloid ß-Induced Memory Dysfunction: A Mechanistic Study.

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.

Whole genome re-sequencing of indian wheat genotypes for identification of genomic variants for grain iron and zinc content.

BACKGROUND: Whole-genome sequencing information which is of abundant significance for genetic evolution, and breeding of crops. Wheat (Triticum spp) is most widely grown and consumed crops globally. Micronutrients are very essential for healthy development of human being and their sufficient consumption in diet is essential for various metabolic functions. Biofortification of wheat grains with iron (Fe) and zinc (Zn) has proved the most reliable and effective way to combat micronutrient associated deficiency. Genetic variability for grain micronutrient could provide insight to dissect the traits. METHODS AND RESULTS: In the current study, 1300 wheat lines were screened for grain Fe and Zn content, out of which only five important Indian wheat genotypes were selected on the basis of Fe and Zn contents. These lines were multiplied during at the National Agri-Food Biotechnology Institute (NABI) and re-sequenced to identify genomic variants in candidate genes for Fe and Zn between the genotypes. Whole genome sequencing generated Ì´ 12 Gb clean data. Comparative genome analysis identified 254 genomic variants in the candidate genes associated with deleterious effect on protein function. CONCLUSIONS: The present study demonstrated the fundamental in understanding the genomic variations for Fe and Zn enrichment to generate healthier wheat grains.

Occupational lead exposure is an independent modulator of hypertension and poor pulmonary function: A cross-sectional comparative study in lead-acid battery recycling workers.

Blood lead level (BLL) is the primary biomarker for lead-exposure monitoring in occupationally exposed workers. We evaluated occupational lead-exposure (OE) impact on cardiopulmonary functions in lead-acid battery recycling unit workers. Seventy-six OE cases and 30 control subjects were enrolled for questionnaire-based socio-demographic, dietary, tobacco usage, and medical history data. Anthropometric measurements, systolic and diastolic blood pressure (SBP and DBP), and pulmonary function tests were performed. Venous blood was collected for BLL, hematological analysis, and biochemical analysis. OE caused a significant increase in BLL, SBP, DBP, and small airways obstruction in lung function tests. It also impaired platelet indices, affected renal and liver biochemical measurements, and promoted oxidative stress and DNA damage. Multilinear regression analysis suggested that BLL affected SBP (ß = 0.314, p = .034) and increased small airways obstruction (FEV1/FVC, ß = -0.37, p = .05; FEV25-75%, ß = -0.351, p = .016). Higher BLL appears to be an independent modulator of hypertension and poor pulmonary function upon occupational lead exposure in lead-acid battery recyclers.

Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice.

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.

Significance of whey protein hydrolysate on anti-oxidative, ACE-inhibitory and anti-inflammatory activities and release of peptides with biofunctionality: an in vitro and in silico approach.

The study aimed to investigate potent antioxidant activities (ABTS assay, Hydroxyl free radical scavenging assay, and Superoxide free radical assay), ACE inhibitory activity, and anti-inflammatory activity in the WPC (whey protein concentrate) hydrolysate using Alcalase. The hydrolysis conditions (addition rate and incubation times) for peptide synthesis were also optimized using proteolytic activity. The generation of proinflammatory cytokines by lipopolysaccharide-treated murine macrophages was reduced when the protein hydrolysate concentration was low. In comparison to unhydrolyzed WPC, SDS-PAGE examination revealed no protein bands in WPC hydrolysates. Two-Dimensional (2D) gel electrophoresis did not show any protein spots. Using the 'In-solution trypsin digestion' approach, the trypsin digested protein samples were put into RPLC/MS for amino acid sequencing. Peptides were also identified using RPLC/MS on fractions of 3 and 10 kDa permeates and retentates. The MASCOT database was used to look up the raw masses of LC/MS. By comparing hydrolyzed whey protein to the BLASTp (NCBI), PIR, BIOPEP, and AHTPDB databases, novel antioxidative and ACE inhibitory peptides were reported. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-021-05282-3.

Dual Blood-Brain Barrier-Glioma Targeting Peptide-Poly(levodopamine) Hybrid Nanoplatforms as Potential Near Infrared Phototheranostic Agents in Glioblastoma.

Combined chemo-phototherapy for boosting the efficacy of individual modalities by synergism for antiglioma treatments is in its embryonic stage and far away from effective clinical translation. Herein, moving a step closer, we recommend a facile stratagem to fabricate smart biocompatible and biodegradable multifunctional nanoplatforms comprising inherently fluorescent poly(levodopamine) nanoparticles (FLs) co-loaded with doxorubicin (DOX) and indocyanine green (ICG). The designed near-infrared (NIR) phototheranostic agents upon NIR laser irradiation helped precipitate combined chemo-phototherapy [both photothermal therapy (PTT) and photodynamic therapy (PDT)] and optical imaging under one roof. Excellent glioma-targeting ability was allocated to the nanoplatforms by conjugating them with a novel chimeric therapeutic peptide with glioma homing and antiglioma dual functionality. Further, DOX/ICG/peptide co-loaded nanoplatforms (FLDIPs) exhibited triggered drug release in response to multiple stimuli. Studies performed in 2D C6 glioma cells and 3D spheroids exhibited superior combined chemo-PDT/PTT effects (∼94% killing in cells and ∼87% in spheroids) of the designed FL based nanoplatforms compared to individual therapeutic components. Herein, the FL based multifunctional nanoplatforms with active targeting ability and stimuli responsive drug release behavior will further help in nullifying chemotherapy based adverse effects and mitigate chemo-resistance by adopting a combinatorial approach.

Designing, fabrication and evaluation of a rapid, point-of-care and noninvasive system for the detection of lead (Pb2+).

Non-invasive collection of biological sample such as sweat, urine, saliva, hairs and, stool and onsite detection of anlaytes in those samples is an interesting and viable approach for rapid screening of various toxicants in body. Environmental exposure/presence of lead (82Pb) and its rapid detection provide one such opportunity. A chemical spot based colorimetric method and a transdermal patch device based on this spot test, is developed for rapid and qualitative assessment of inorganic lead (Pb2+) in non-coloured biological or environmental liquid samples. The transdermal patch system contains two important parts, a chemical spot prepared on a thin glass sheet and, an absorbent paper (11 µm pore size). A one step colour development reaction is able to identify the presence or absence of Pb2+. In-vitro evaluation for sensitivity and cut-off value determination, within run and between run precision testing, specificity testing were done. In-vivo evaluation of the developed patch system was performed in occupationally lead-exposed subjects and in control volunteers. In-vivo field testing results were further validated with gold standard test for lead detection. Blood lead levels and patch lead levels were found to be positively correlated (r = 0.57, P < 0.0001). In addition, the sensitivity and specificity of device in identification of Pb2+ was found to be 75.93% (95% CI = 62.36%-86.51%) and 95.24% (95% CI = 76.18%-99.88%). The developed system appears as a reliable, non-invasive rapid test with minimum step involve for identification of Pb2+ in a given system.

Naringenin Ameliorates Chronic Sleep Deprivation-Induced Pain via Sirtuin1 Inhibition.

Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreased levels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia.

Neurobehavioral alterations in a mouse model of chronic partial sleep deprivation.

The night shift paradigm induces a state of chronic partial sleep deprivation (CPSD) and enhances the vulnerability to neuronal dysfunction. However, the specific neuronal impact of CPSD has not been thoroughly explored to date. In the current study, the night shift condition was mimicked in female Swiss albino mice. The classical sleep deprivation model, i.e., Modified Multiple Platform (MMP) method, was used for 8 h/day from Monday to Friday with Saturday and Sunday as a weekend off for nine weeks. Following nine weeks of night shift schedule, their neurobehavioral profile and physiological parameters were assessed along with the activity of the mitochondrial complexes, oxidative stress, serotonin levels, and inflammatory markers in the brain. Mice showed an overall hyperactive behavioral profile including hyperlocomotion, aggression, and stereotyped behavior accompanied by decreased activity of mitochondrial enzymes and serotonin levels, increased oxidative stress and inflammatory markers in whole brain homogenates. Collectively, the study points towards the occurrence of a hyperactive behavioral profile akin to mania and psychosis as a potential consequence of CPSD.

Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington's disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway.

Huntington's disease (HD) is a progressive neurodegenerative and hyperkinetic movement disorder. Decreased activity of cAMP-responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in HD. The present study has been designed to explore the possible role of roflumilast against qunilonic acid (QA) induced neurotoxicity in rats intending to investigate whether it inhibits the neuroinflammatory response through activation of the cAMP/CREB/BDNF signaling pathway. QA was microinjected (200 nmol/2 µl, bilaterally) through the intrastriatal route in the stereotaxic apparatus. Roflumilast (0.5, 1, and 2 mg/kg, orally) once-daily treatment for 21 days significantly improved locomotor activity in actophotometer, motor coordination in rotarod, and impaired gait performance in narrow beam walk test. Moreover, roflumilast treatment significantly attenuated oxidative and nitrosative stress (p < 0.05) through attenuating lipid peroxidation nitrite concentration and enhancing reduced glutathione, superoxide dismutase, and catalase levels. Furthermore, roflumilast also significantly decreased elevated pro-inflammatory cytokines like TNF-α (p < 0.01), IL-6 (p < 0.01), IFN-γ (p < 0.05), NF-κB (p < 0.05) and significantly increased BDNF(p < 0.05) in the striatum and cortex of rat brain. The results further demonstrated that roflumilast effectively increased the gene expression of cAMP(p < 0.05), CREB(p < 0.05) and decreased the gene expression of PDE4 (p < 0.05) in qRT-PCR. These results conclusively depicted that roflumilast could be a potential candidate as an effective therapeutic agent in the management of HD through the cAMP/CREB/BDNF signaling pathway.

Role of TRPV1/TRPV3 channels in olanzapine-induced metabolic alteration: Possible involvement in hypothalamic energy-sensing, appetite regulation, inflammation and mesolimbic pathway.

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.

Prevalence and associated factors of overweight/obesity among school going children in Chandigarh, India.

BACKGROUND: An increasing prevalence of childhood obesity is reported worldwide. Few data are available regarding childhood obesity in North India. The present study aimed to study the prevalence of overweight/obesity among adolescents aged 10-14, in schools of Chandigarh, and to examine associated factors. METHODS: Nine co-educational schools were chosen to include both government and private schools in Chandigarh. We randomly sampled students from different subsections/batches of classes fifth to ninth (aged 10-14), and those present on the day were measured and completed questionnaires. Obesity was classified according to the methods recommended by the Indian Association of Pediatrics (IAP) growth charts committee. RESULTS: A total of 1,030 participants were included, 502 students from government and 528 students from private schools. The overall prevalence of overweight and obesity evaluated by using age-specific body mass index (BMI) cut-offs was found to be 9.9% and 14.0%, respectively. The prevalence of overweight (adult equivalent of 23) was 10.3% in boys and 9.4% in girls and that of obesity (adult equivalent of 27) was found to be 13.3% and 14.7%, respectively, in boys and girls. In univariate analyses, statistically significant associations were found between the risk of obesity and gender, socio-economic status (SES) and reported physical activity. CONCLUSION: We found significant levels of overweight and obesity among children aged 10-14 and found associations with SES, gender and reported physical activity as has been previously reported elsewhere.