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AIM: Coronary artery disease (CAD) is the leading cause of mortality. Though percutaneous transluminal angioplasty followed by stenting is still the default treatment of choice for revascularization of obstructive CAD, the high rate of restenosis compromises the outcomes of endovascular procedures. To overcome restenosis, drug-eluting stents (DES) and drug-coated balloons (DCB) are designed that release antiproliferative drugs like sirolimus, paclitaxel, everolimus, etc., over time to inhibit cell growth and proliferation. Our review aims to summarize the challenges and progress of DES/DCBs in clinical settings. MATERIAL AND METHODS: The comprehensive review, search and selection encompasses in relevant articles through Google Scholar, Springer online, Cochrane library and PubMed that includes research articles, reviews, letters and communications, various viewpoints, meta-analyses, randomized trials and quasi-randomized trials. Several preclinical and clinical data have been included from National Institutes of Health and clinicaltrials.gov websites. KEY FINDINGS: Challenges like delayed endothelialization, stent thrombosis (ST), and inflammation was prominent in first-generation DES. Second-generation DES with improved designs and drug coatings enhanced biocompatibility with fewer complications. Gradual absorption of bioresorbable DES over time mitigated long-term issues associated with permanent implants. Polymer-free DES addressed the inflammation concerns but still, they leave behind metallic stents in the vasculature. As an alternative therapeutic strategy, DCB were developed to minimize inflammation in the vessel. Although both DES and DCBs have shown considerable progress, challenges persist. SIGNIFICANCE: This review illustrates the advancements in the designs, preparation technologies, biodegradable materials, and drugs used as well as challenges associated with DES and DCBs in clinical settings.
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Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Humanos , Enfermedad de la Arteria Coronaria/terapia , Materiales Biocompatibles Revestidos , Animales , Reestenosis Coronaria/prevención & control , Angioplastia Coronaria con Balón/métodos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéuticoRESUMEN
Parkinson's disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.
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Snow mountain garlic (SMG) is a trans-Himalayan medicinal plant used in the traditional medicine system for several ailments, including inflammatory arthritis. Research studies are insufficient to validate its folk medicinal applications. In the present study, the comparative abundance of its key bioactive phytocompounds, viz., S-allyl-L-cysteine (SAC), alliin, and S-methyl-L-cysteine (SMC) against normal garlic were assessed using the LC-MS/MS-MRM method. In addition, the study also explored the antioxidant and anti-inflammatory potency of crude extract of SMG and purified signature phytocompounds (i.e., SMC, SAC, and alliin) in comparison with normal garlic and dexamethasone in LPS-stimulated RAW264.7 macrophage cells. The LC-MS/MS-MRM study revealed significant differences among SMG and normal garlic, viz., alliin 22.8-fold higher in SMG, and SMC could be detected only in SMG. In the bioassays, SMG extract and purified signature phytocompounds significantly downregulated oxidative damage in activated macrophages, boosting endogenous antioxidants' activity. SMG extract-treated macrophages significantly suppressed NF-κB expression and related inflammatory indicators such as cytokines, COX-2, iNOS, and NO. Notably, the observed anti-inflammatory and antioxidant bioactivities of SMG extract were comparable to signature phytocompounds and dexamethasone. In addition, SAC being uniformly found in SMG and normal garlic, its comparative pharmacokinetics was studied to validate the pharmacodynamic superiority of SMG over normal garlic. Significantly higher plasma concentrations (Cmax), half-life (t1/2), and area under curve (AUC) of SAC following SMG extract administration than normal garlic validated the proposed hypothesis. Thus, the abundance of bioactive phytocompounds and their better pharmacokinetics in SMG extract might be underlying its medicinal merits over normal garlic.
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Antiinflamatorios , Antioxidantes , Ajo , Macrófagos , Extractos Vegetales , Ajo/química , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Ratones , Antioxidantes/farmacología , Antioxidantes/farmacocinética , Células RAW 264.7 , Extractos Vegetales/farmacología , Extractos Vegetales/farmacocinética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectrometría de Masas en Tándem/métodos , Cisteína/farmacología , Cromatografía Liquida/métodos , Fitoquímicos/farmacología , Fitoquímicos/farmacocinética , Estrés Oxidativo/efectos de los fármacos , MasculinoRESUMEN
Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD. VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20 mg/kg) and Donepezil (10 mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1ß, and NF-kß), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats. Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus. These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.
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Demencia Vascular , Ratas , Animales , Demencia Vascular/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor Neurotrófico Derivado del Encéfalo , Aprendizaje por Laberinto , Estrés Oxidativo , Apoptosis , Inflamación/tratamiento farmacológico , Hipocampo/metabolismo , Colinérgicos/farmacologíaRESUMEN
This study was conducted to investigate the γ-aminobutyric acid (GABA) production ability of 20 Lactobacillus and 25 Bifidobacterium strains which were previously isolated in our laboratory. Effect of initial pH, incubation time, monosodium glutamate (MSG), and pyridoxal-5'-phosphate (PLP) concentration for highest GABA production by two potent bacterial strains, Levilactobacillus brevis LAB6 and Limosilactobacillus fermentum LAB19 were optimized in the MRS media. A threefold increase in GABA production at an initial pH 4.0, incubation time of 120 h in medium supplemented with 3% MSG and 400 µM of PLP for LAB6 and 300 µM for LAB19 lead to the production of 19.67 ± 0.28 and 20.77 ± 0.14 g/L of GABA, respectively. Coculturing both strains under optimized conditions led to a GABA yield of 20.02 ± 0.17 g/L. Owing to potent anti-inflammatory activity in-vitro, as reported previously, and highest GABA production ability of LAB6 (MTCC 25662), its whole-genome sequencing and bioinformatics analysis was carried out for mining genes related to GABA metabolism. LAB6 harbored a complete glutamate decarboxylase (GAD) gene system comprising gadA, gadB, and gadC as well as genes responsible for the beneficial probiotic traits, such as for acid and bile tolerance and host adhesion. Comparative genomic analysis of LAB6 with 28 completely sequenced Levilactobacillus brevis strains revealed the presence of 95 strain-specific genes-families that was significantly higher than most other L. brevis strains. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03918-7.
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Vascular smooth muscle cells (VSMCs) are the predominant cell type in the media of the blood vessels and are responsible for maintaining vascular tone. Emerging evidence confirms that VSMCs possess high plasticity. During vascular injury, VSMCs switch from a "contractile" phenotype to an extremely proliferative "synthetic" phenotype. The balance between both strongly affects the progression of vascular remodeling in many cardiovascular pathologies such as restenosis, atherosclerosis and aortic aneurism. Proliferating cells demand high energy requirements and to meet this necessity, alteration in cellular bioenergetics seems to be essential. Glycolysis, fatty acid metabolism, and amino acid metabolism act as a fuel for VSMC proliferation. Metabolic reprogramming of VSMCs is dynamically variable that involves multiple mechanisms and encompasses the coordination of various signaling molecules, proteins, and enzymes. Here, we systemically reviewed the metabolic changes together with the possible treatments that are still under investigation underlying VSMC plasticity which provides a promising direction for the treatment of diseases associated with VSMC proliferation. A better understanding of the interaction between metabolism with associated signaling may uncover additional targets for better therapeutic strategies in vascular disorders.
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Proliferación Celular , Glucólisis , Músculo Liso Vascular , Miocitos del Músculo Liso , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Humanos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Animales , Transducción de Señal , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patologíaRESUMEN
Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI.
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Deterioro Cognitivo Relacionado con la Quimioterapia , Factor 2 Relacionado con NF-E2 , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedades Neuroinflamatorias , Calidad de Vida , Estrés Oxidativo , Transducción de SeñalRESUMEN
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.
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Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague-Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV-visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway.
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Disfunción Cognitiva , Ácido Tióctico , Animales , Ratas , Acetilcolinesterasa/metabolismo , Antioxidantes , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Doxorrubicina/toxicidad , Hipocampo/metabolismo , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Estrés Oxidativo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Probiotics are known to stimulate, modulate, and regulate host immune response by regulating specific sets of genes and improve glucose homeostasis through regulating dipeptidyl peptidase (DPP-IV) activity, but the mechanism behind their protective role is not clearly understood. Therefore, the present study was designed to isolate indigenous lactic acid bacterial (LAB) strains from different fermented food samples, vegetables, and human infant feces exhibiting anti-inflammatory, antioxidant, and DPP-IV inhibitory activity. A total of thirty-six Gram-positive, catalase-negative, and rod-shaped bacteria were isolated and screened for their anti-inflammatory activity using lipopolysaccharide (LPS)-induced inflammation on the murine (RAW264.7) macrophages. Among all, sixteen strains exhibited more than 90% reduction in nitric oxide (NO) production by the LPS-treated RAW264.7 cells. Prioritized strains were characterized for their probiotic attributes as per the DBT-ICMR guidelines and showed desirable probiotic attributes in a species and strain-dependent manner. Accordingly, Lacticaseibacillus rhamnosus LAB3, Levilactobacillus brevis LAB20, Lactiplantibacillus plantarum LAB31, Pediococcus acidilactici LAB8, and Lactiplantibacillus plantarum LAB39 were prioritized. Furthermore, these strains when co-supplemented with LPS and treated on RAW264.7 cells inhibited the mitogen-activated protein kinases (MAPKs), i.e., p38 MAPK, ERK1/2, and SAPK/JNK, cyclooxygenase-2 (COX-2), relative to the LPS-alone-treated macrophages. LAB31 and LAB39 also showed 64 and 95% of DPP-IV inhibitory activity relative to the Lacticaseibacillus rhamnosus GG ATCC 53103, which was used as a reference strain in all the studies. Five prioritized strains ameliorated the LPS-induced inflammation by downregulating the JNK/MAPK pathway and could be employed as an alternative bio-therapeutic strategy in mitigating gut-associated inflammatory conditions. The potential mechanism of action of prioritized LAB strains in preventing the LPS-induced inflammation in RAW 264.7 macrophage cells.
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Lactobacillales , Humanos , Animales , Ratones , Lactobacillales/metabolismo , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/uso terapéutico , Ácido Láctico , Óxido NítricoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Snow Mountain Garlic (SMG) (Allium ampeloprasum L.) is a wild trans-Himalayan member of the genus Allium, valued for its anti-inflammatory and anti-arthritic properties in the mountain folk medicinal system (Sowa-Rigpa). Despite its age-old medicinal usage by traditional therapists and the native population for various ailments including rheumatism, there is no scientific validation of its phyto-pharmaceutical merits. AIM OF THE STUDY: The present pre-clinical study compared the in-vivo anti-arthritic effects of SMG with reported efficacy doses of normal garlic (Allium sativum L.) extract and dexamethasone in a complete Freund's adjuvant (CFA)-induced arthritis rat model. MATERIALS AND METHODS: The female Wistar rats were immunized by the subplannter injection of CFA into the right hind footpad. Aqueous extracts of SMG and normal garlic were administered orally at a dose of 250 mg/kg and 500 mg/kg for 28 days. Dexamethasone was used as positive control drug. Behavioral parameters including paw markers, arthritis index, joint stiffness, body weight change, etc. were measured. Also, the changes in histopathological indices, hematological profile, inflammatory mediators, and serum cytokines level was determined. RESULTS: Treatment of rats with SMG extracts significantly (p < 0.001) prevented the reduction in body weight and hematological changes as well as ameliorated clinical symptoms such as arthritic index, joint stiffness, arthritis score, edema, hyperalgesia, and histopathological indices. This was associated with a significant reduction in the serum levels of RF, CRP, anti-CCP, and proinflammatory cytokines exhibiting strong anti-arthritic potential. SMG extracts could also significantly down regulate the NF-κB, COX-2, and iNOS expression in the ankle joint tissues. CONCLUSIONS: The present study is the first attempt to validate the phyto-pharmaceutical efficacy of this folk garlic variety from the trans-Himalayan region. Overall, SMG extract showed remarkable preventive anti-inflammatory and anti-arthritic activities which were closely comparable to therapeutic effects of dexamethasone and at par or even better than normal garlic w.r.t. several study parameters.
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Artritis Experimental , Productos Biológicos , Ajo , Animales , Femenino , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Peso Corporal , Citocinas/metabolismo , Dexametasona/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas WistarRESUMEN
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
Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague-Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1ß, and NF-kß) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits.
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Disfunción Cognitiva , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Acetilcolinesterasa , Animales , Apoptosis , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Aprendizaje por Laberinto , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas , Ratas , Ratas Sprague-DawleyRESUMEN
Central insulin resistance is considered as one of the pathological hallmarks of Alzheimer's disease (AD), similar to formation of amyloid plaques and neurofibrillary tangles (NFT). Activation of α7nAChR by GTS-21 has been indicated to reverse peripheral insulin resistance and exert neuroprotection. Therefore, the aim of the present study was to determine the effect of α7nAChR agonist (GTS-21) on intracerebroventricular administration of streptozotocin (ICV-STZ)-induced oxidative stress, neuroinflammation, cholinergic dysfunction, central insulin resistance and cognitive deficits. GTS-21 (1, 4 and 8 mg/kg; i.p.) was administered for 21 days following bilateral ICV-STZ administration (3 mg/kg) in C57BL/6 mice. Neurobehavioral assessments were performed using Morris water maze (MWM) and novel object recognition (NOR). Inflammatory markers (TNF-α, IL-6 and IL-1ß) were determined using ELISA. Oxido-nitrosative stress (GSH, MDA and nitrite) and cholinergic activity (acetylcholine esterase and choline acetyltransferase) were estimated in the cortex and hippocampus through biochemical methods. Gene expression of insulin receptor (IR), IRS1, IRS2, BACE1, APP, PI3-K, AKT and GSK3ß were determined by q-RT-PCR. ICV-STZ administration induced memory impairment, increased oxidative stress and neuroinflammation, and caused cholinergic dysfunction. Our results demonstrated that activation of α7nAChR by GTS-21 treatment improved memory in MWM and NOR test. Moreover, GTS-21 treatment significantly decreased oxido-nitrosative stress, inflammatory markers and cholinergic dysfunction in cortex and hippocampus. Finally, GTS-21 treatment restored ICV-STZ induced downregulation of IR, IRS1, IRS2, PI3-k, Akt and attenuated GSK3ß, APP and BACE-1 indicating improved insulin signalling. Therefore, activation of α7nAChR through GTS-21 might be the potential target for the amelioration of central insulin resistance induced AD.
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Enfermedad de Alzheimer , Resistencia a la Insulina , Receptor Nicotínico de Acetilcolina alfa 7 , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas , Compuestos de Bencilideno/farmacología , Colinérgicos/farmacología , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
AIM: The study aimed to profile the volatile phytocomposition of snow mountain garlic (SMG) compared to normal garlic and investigate the anti-Candida efficacy against clinically relevant multi-drug resistant isolates of Candida species. METHODS AND RESULTS: Herein, SMG has shown significantly superior fungicidal power at 2x-MIC dose against C. albicans and C. glabrata in killing kinetic evaluation unlike the fungistatic effect of normal garlic. GC-MS headspace-based profiling of SMG showed 5 unique volatile compounds and a 5-fold higher content of saponins than normal garlic. In an in-silico analysis, cholesta-4,6-dien-3-ol,(3-beta) was uniquely identified in SMG as a potential inhibitor with high binding affinity to the active site of exo-1,3-betaglucan synthase, an established anti-candida drug target crucial for the biofilm matrix formation, thus suggesting a plausible anti-Candida mechanism. CONCLUSION: The in-vitro and in-silico studies have demonstrated the Candida-cidal and anti-biofilm activities of SMG, distinguishing it from the Candida-static efficacy of normal garlic. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report that identifies several phytochemical signatures of SMG along with a potential anti-Candida compound, that is cholesta-4,6-dien-3-ol,(3-beta)-, which appears worthy of detailed studies in the future to explore the utility of SMG as a fungal phytotherapy agent, especially against drug-resistant Candida sp.
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Ajo , Antifúngicos/metabolismo , Candida , Candida albicans , Candida glabrata , Ajo/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: There have been reports of patients suffering from typhoid fever, particularly those involving infants and immunocompromised patients, which at times present with Salmonella induced brain infection. Although rare, it has frequently been associated with adverse neurological complications and increased mortality. In this context, the gut-brain axis, involving two-way communication between the gut and the brain, holds immense significance as various gut ailments have been associated with psychiatric complications. In turn, several neurodegenerative diseases have been associated with an altered gut microbiota profile. Given the paucity of effective antimicrobials and increasing incidence of multi-drug resistance in pathogens, alternate treatment therapies such as probiotics have gained significant attention in the recent past. RESULTS: In the current study, prophylactic effect of Lactiplantibacillus plantarum (RTA 8) in preventing neurological complications occurring due to Salmonella brain infection was evaluated in a murine model. Along with a significant reduction in bacterial burden and improved histoarchitecture, L. plantarum (RTA 8) administration resulted in amelioration in the level of neurotransmitters such as serotonin, norepinephrine and dopamine in the gut as well as in the brain tissue. Simultaneously, increased gene expression of physiologically essential molecules such as mucin (MUC1 and MUC3) and brain-derived neurotrophic factor (BDNF) was also observed in this group. CONCLUSION: Present study highlights the potential benefits of a probiotic supplemented diet in improving various aspects of host health due to their multi-targeted approach, thereby resulting in multi-faceted gains.
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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
Excessive generation of oxygen free radicals plays a pivotal role in destruction of biological molecules like DNA, proteins, lipids, carbohydrates and results in various pathologies including neuronal disorders. Antioxidant molecules from natural products are reported to have ability to mitigate their production or at least halt their progression and metastasis in the system. Different studies have been performed to spot antioxidants from natural sources and attempts have been made to integrate them in conventional therapy. In our present study, food grade Phycocyanin, a nutraceutical isolated from Spirulina platensis, has been evaluated for its in vitro and in vivo antioxidant potential using a battery of antioxidant assays viz. DPPH, TAC, FRAP, hydroxyl radical, hydrogen peroxide scavenging, SOD, GSH, and LPO assays. Reducing properties of Phycocyanin were also assessed by FRAC assay. For in vivo evaluation of antioxidant profile, animal model of intracerebroventricular administration of streptozotocin was employed. Levels of oxidative stress biomarkers were measured in cortex and hippocampal parts of brain. Results obtained depicted that Phycocyanin demonstrated a dose-dependent pattern in its efficacy, which indicates the presence of free radical scavenger moieties and possible role as a neuroprotective agent.
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BACKGROUND: Studies have shown that there is a critical time period to start hormone therapy after the loss of ovarian function during menopause. The length of estrogen deprivation may evolve different pathophysiological manifestations. OBJECTIVE: The aim of the present study was to investigate behavioral, biochemical, and molecular alterations at different time points after surgical menopause with an aim and identify various pathophysiological targets to exploit "window of opportunity" and to design newer therapeutic modalities for menopause-associated neurobehavioral and vascular deficits. MATERIALS AND METHODS: Bilateral ovariectomy was performed to induce surgical menopause and estrogen deficiency state. Menopause-associated neuronal and vascular dysfunctions were noted after 1, 2, and 3 months of the study. RESULTS: Neuronal and vascular endothelial dysfunction post ovariectomy revealed that behavioral, biochemical, molecular, and vascular endothelial dysfunction appeared after 1 month of ovariectomy except hyperglycemia, which occurs after 3 months. CONCLUSIONS: Time-response studies measuring behavioral, biochemical, and molecular markers at various time points after ovariectomy reveal that there is a fast onset of neuronal and vascular complications, but the duration of insulin resistance is a relatively late phenomenon.
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Endotelio Vascular/fisiopatología , Menopausia , Neuronas/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Ovariectomía , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Protein tyrosine phosphatase 1B (PTP1B) inhibitors are potential candidates for the treatment of peripheral insulin resistance and diabetes mellitus. Similar to peripheral action within the brain also, PTP1B activation impairs insulin signaling pathways. Activation of PTP1B in brain also accentuates neuroinflammation, oxidative stress and decreases neurotrophic factors in various brain dysfunctions including cognitive decline. OBJECTIVES: The main objective of our study was to elucidate the role of alendronate, a potent PTP1B inhibitor (blood brain barrier crossing bisphosphonate) in central insulin resistance and associated memory deficits. METHODOLOGY: To induce central insulin resistance, streptozotocin (3 mg/kg) intracerebroventricular (ICV) was administered in two alternate days (1st and 3rd). After 21 days, memory was assessed via using the passive avoidance and Morris water maze paradigm. At the end of behavioral studies, animals were sacrificed to assess a variety of biochemical and molecular parameters in the hippocampus and cerebral cortex region of the brain. Treatment drug alendronate (3 mg/kg/day, p.o) and standard drug donepezil (3 mg/kg/i.p.) were administered from the 3rd day of STZ administration till the end of the study. Inhibition of PTP1B activates phosphoinsotide-3 kinase (PI3 K) (down-stream regulator of insulin signaling pathway).Thus, to illuminate the mechanism of action of alendronate, PI3 K inhibitor, wortmannin was administered in presence of alendronate in one group. RESULTS: Administration of alendronate to ICV streprozotocin treated rats resulted in modulation of the insulin signaling pathway and associated behavioral, biochemical and molecular changes in central insulin resistance. However, the protective effect of alendronate was entirely vanished when it was administered in the presence of wortmannin. CONCLUSION: Alendronate can be an important treatment strategy in central insulin signaling pathway dysfunction and associated cognitive deficits. Protective effect of alendronate is via modulation of PI3-K/Akt signaling pathway.