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KEY MESSAGE: Underpinned natural variations and key genes associated with yield under different water regimes, and identified genomic signatures of genetic gain in the Indian wheat breeding program. A novel KASP marker for TKW under water stress was developed and validated. A comprehensive genome-wide association study was conducted on 300 spring wheat genotypes to elucidate the natural variations associated with grain yield and its eleven contributing traits under fully irrigated, restricted water, and simulated no water conditions. Utilizing the 35K Wheat Breeders' Array, we identified 1155 quantitative trait nucleotides (QTNs), with 207 QTNs exhibiting stability across diverse conditions. These QTNs were further delimited into 539 genomic regions using a genome-wide LD value of 3.0 Mbp, revealing pleiotropic control across traits and conditions. Sub-genome A was significantly associated with traits under irrigated conditions, while sub-genome B showed more QTNs under water stressed conditions. Favourable alleles with significantly associated QTNs were delineated, with a notable pyramiding effect for enhancing trait performance. Additionally, allele of only 921 QTNs significantly affected the population mean. Allele profiling highlighted C-306 as a most potential source of drought tolerance. Moreover, 762 genes overlapping significant QTNs were identified, narrowing down to 27 putative candidate genes overlapping 29 novel and functional SNPs expressing (≥ 0.5 tpm) relevance across various growth conditions. A new KASP assay was developed, targeting a gene TraesCS2A03G1123700 regulating thousand kernel weight under severe drought condition. Genomic selection models (GBLUP, BayesB, MxE, and R-Norm) demonstrated an average prediction accuracy of 0.06-0.58 across environments, indicating potential for trait selection. Retrospective analysis of the Indian wheat breeding program supported a genetic gain in GY at the rate of ca. 0.56% per breeding cycle, since 1960, supporting the identification of genomic signatures driving trait selection and genetic gain. These findings offer insight into improving the rate of genetic gain in wheat breeding programs globally.
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Grão Comestível , Genótipo , Fenótipo , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Triticum , Água , Triticum/genética , Triticum/crescimento & desenvolvimento , Grão Comestível/genética , Grão Comestível/crescimento & desenvolvimento , Estudos de Associação Genética , Secas , Mapeamento Cromossômico/métodos , Desequilíbrio de Ligação , Alelos , Estudo de Associação Genômica Ampla , ÍndiaRESUMO
Motion sickness also known as kinetosis is a condition in which there exists a disagreement between visually perceived movement and the vestibular system's sense of movement. Nausea, vomiting, dizziness, fatigue, and headache are the most common symptoms of motion sickness. This study mainly focuses on the taste masking of Promethazine Hydrochloride (PMZ) by inclusion complexation method, its formulation development in the chewing gum form by using directly compressible gum base HIG® and its quality and performance testing. Different molar ratios (1:1, 1:2, 1:3 and 1:4) of PMZ-cyclodextrin complexes were prepared by using ß-Cyclodextrin (ß-CD) as a taste masking agent. These complexes were evaluated for FTIR, DSC, % Entrapment Efficiency, % drug yield, and taste evaluation by E-Tongue. The optimized ratio was further evaluated by sophisticated analytical techniques such as Scanning Electron Microscopy (SEM) and X-Ray Diffraction (XRD). A central composite design (CCD) (3 ^2) was utilized to examine the effects of independent variables (amount of gum-X1 and amount of plasticizer-X2) on dependent variables (%CDRY1 and hardness Y2). The prepared gums were evaluated for drug content, organoleptic properties, in-vitro dissolution testing by fabricated disintegration apparatus, texture analysis, etc. The optimization statistics showed that on decreasing the amount of gum, in- vitro drug release increases and hardness decreases. The optimized batch MCG-2 of Promethazine MCG showed 92.34 ± 0.92% of drug release, whereas for marketed formulation (Phenergan®-25 mg) drug release value was 86.19 ± 1.88%. Results provided evidence that PMZ MCGs could be a better alternative to conventional tablet formulations with improved drug release, palatability and texture.
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Antieméticos , Goma de Mascar , Prometazina , Paladar , beta-Ciclodextrinas , Prometazina/química , Prometazina/administração & dosagem , beta-Ciclodextrinas/química , Paladar/efeitos dos fármacos , Antieméticos/administração & dosagem , Antieméticos/química , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Difração de Raios X/métodos , Solubilidade , Composição de Medicamentos/métodos , Humanos , Enjoo devido ao Movimento/prevenção & controleRESUMO
In the past, curcumin was the go-to medication for diabetes, but recent studies have shown that tetrahydrocurcumin is more effective. The problem is that it's not very soluble in water or very bioavailable. So, our research aims to increase the bioavailability and anti-diabetic efficacy of tetrahydrocurcumin in streptozotocin-induced diabetic rats by synthesizing tetrahydrocurcumin-loaded solid lipid nanoparticles. Box Behnken Design was employed for the optimization of tetrahydrocurcumin-loaded solid lipid nanoparticles (THC-SLNs). The optimal formulation was determined by doing an ANOVA to examine the relationship between the independent variables (drug-to-lipid ratio, surfactant concentration, and co-surfactant concentration) and the dependent variables (particle size, percent entrapment efficiency, and PDI). Particle size, PDI, and entrapment efficiency all showed statistical significance based on F-values and p-values. The optimized batch was prepared using a drug-to-lipid ratio (1:4.16), 1.21% concentration of surfactant, and 0.4775% co-surfactant (observed with a particle size of 147.1 nm, 83.58 ± 0.838 % entrapment efficiency, and 0.265 PDI, and the values were found very close with the predicted ones. As the THC peak vanishes from the DSC thermogram of the improved formulation, this indicates that the drug has been transformed from its crystalline form into its amorphous state. TEM analysis of optimized formulation demonstrated mono-dispersed particles with an average particle size of 145 nm which are closely related to zetasizer's results. In-vitro release study of optimized formulation demonstrated burst release followed by sustained release up to 71.04% throughout 24 hrs. Increased bioavailability of the adjusted THC-SLN was found in an in vivo pharmacokinetics research with 9.47 folds higher AUC(0-t) compared to plain THC-suspension. Additionally, pharmacodynamic experiments of optimized formulation demonstrated a marked decrease in blood glucose level to 63.7% and increased body weight from 195.8 ± 7.223 to 231.2 ± 7.653 on the 28th day of the study and showed a better anti-diabetic effect than plain drug suspension. Results of stability studies revealed that formulation can be stored for longer periods at room temperature. Tetrahydrocurcumin can be effectively administered by SLN for the treatment of diabetes.
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Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1ß1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1ß1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1ß1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1ß1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1ß1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1ß1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1ß1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1ß1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1ß1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.
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Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neuregulina-1/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Animais , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Mielite/imunologia , Mielite/metabolismo , Mielite/patologia , Medula Espinal/imunologiaRESUMO
Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70-80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, ß-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.
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Silimarina , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Flavonoides/metabolismo , Frutas , Silybum marianum/metabolismo , Silimarina/farmacologia , Silimarina/uso terapêuticoRESUMO
Metabolism, the umbrella term for complex biochemical pathways that sustain the basic functions of life, has garnered attention in recent years for its role in immune activation. Indeed, metabolic pathways and their intricate and complex connections with immune mechanisms constitute a new area of immunology termed 'immunometabolism'. One highlight is the existence of a switch in the key metabolic programs in immune cells, which executes their effector functions. 'Metabolic reprogramming' is observed in conditions of both peripheral diseases as well as in neurodegenerative conditions associated with inflammation such as multiple sclerosis. Moreover metabolic reprogramming occurs for almost every immune cell type. Whether metabolic changes are cause or effect of immune activation, however, remains to be fully understood. Being central to cellular activation, metabolism has become very topical in terms of exploring therapeutic targets. This review covers the major metabolic programs in immune cells, discuss metabolites as regulators of immune cell functions, and consider metabolic enzymes or pathways as therapeutic targets using examples from multiple sclerosis and its animal models.
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Leucócitos/imunologia , Leucócitos/metabolismo , Redes e Vias Metabólicas/imunologia , Microglia/imunologia , Microglia/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Animais , Humanos , InflamaçãoRESUMO
BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative condition of the central nervous system (CNS). It is associated with blood-brain barrier (BBB) breakdown and intravasation of leukocytes, particularly monocyte-derived macrophages, into the CNS. Pericytes are mural cells that are encased within the basement membrane of vasculature, and they contribute functionally to the neurovascular unit. These cells play an important role in maintaining BBB integrity and CNS homeostasis. However, the critical role of pericytes in mediating inflammation in MS or its models is unclear. Whether pericytes infiltrate into the CNS parenchyma in MS also needs clarification. METHODS: CNS samples from the experimental autoimmune encephalomyelitis (EAE) mouse model of MS were collected at different time points for immunohistochemical analysis of pericytes along the inflamed vasculature. These findings were validated using MS brain specimens, and further analysis of pericyte involvement in inflammation was carried out by culturing primary pericytes and macrophages. Multiplex ELISA, transmigration assay and real-time PCR were used to study the inflammatory potential of pericytes in cultures. RESULTS: We found that pericytes exhibit a heterogenous morphology, with notable elongation in the inflamed perivascular cuffs of EAE. This was manifested by a decrease in pericyte density but an increase in the coverage by pericytes along the vasculature. Chondroitin sulfate proteoglycans (CSPGs), a family of extracellular matrix proteins enriched within inflamed perivascular cuffs, elevated levels of pro-inflammatory chemokines/cytokines in pericytes in culture. Importantly, pericytes stimulated with CSPGs enhanced macrophage migration. We did not detect pericytes in the CNS parenchyma during EAE, and this was corroborated in MS brain samples. CONCLUSIONS: Our data suggest that pericytes seek to restore the BBB through increased coverage, but that their exposure to CSPGs prompt their facilitation of macrophages to enter the CNS to elevate neuroinflammation in EAE and MS.
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Encefalomielite Autoimune Experimental/patologia , Macrófagos/patologia , Esclerose Múltipla/patologia , Pericitos/patologia , Animais , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Encefalite/patologia , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Pericitos/ultraestrutura , Cultura Primária de CélulasRESUMO
BACKGROUND: The balance of tissue injury and repair ultimately determines outcomes of chronic neurological disorders, such as progressive multiple sclerosis (MS). However, the extent of pathology can be difficult to detect, particularly when it is insidious and/or offset by tissue regeneration. OBJECTIVES: The objective of this research is to evaluate whether tissue autofluorescence-typically a source of contamination-provides a surrogate marker of white matter injury. METHODS: Tissue autofluorescence in autopsied specimens both experimental and clinical was characterized by spectral confocal microscopy and correlated to severity and chronicity as determined by standard histopathology. RESULTS: Months after cuprizone (CPZ)-induced demyelination, despite robust remyelination, autofluorescent deposits progressively accumulated in regions of prior pathology. Autofluorescent deposits (likely reflecting myelin debris remnants) were conspicuously localized to white matter, proportional to lesion severity, and displayed differential fluorescence over time. Strikingly, similar features were apparent also in autopsied MS tissue. CONCLUSION: Autofluorescence spectroscopy illuminates prior and ongoing white matter injury. The accumulation of autofluorescence in proportion to the extent of progressive atrophy, despite robust remyelination in the CPZ brain, provides important proof-of-concept of a phenomenon (insidious ongoing damage masked by mechanisms of tissue repair) that we hypothesize is highly relevant to the progressive phase of MS.
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Doenças Desmielinizantes , Substância Branca , Animais , Cuprizona , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina , Análise Espectral , Substância Branca/diagnóstico por imagemRESUMO
Ageratum conyzoides L. (Family-Asteraceae) is an annual aromatic invasive herb, mainly distributed over the tropical and subtropical regions of the world. It owns a reputed history of indigenous remedial uses, including as a wound dressing, an antimicrobial, and mouthwash as well as in treatment of dysentery, diarrhea, skin diseases, etc. In this review, the core idea is to present the antifungal potential of the selected medicinal plant and its secondary metabolites against different fungal pathogens. Additionally, toxicological studies (safety profile) conducted on the amazing plant A. conyzoides L. are discussed for the possible clinical development of this medicinal herb. Articles available from 2000 to 2020 were reviewed in detail to exhibit recent appraisals of the antifungal properties of A. conyzoides. Efforts were aimed at delivering evidences for the medicinal application of A. conyzoides by using globally recognized scientific search engines and databases so that an efficient approach for filling the lacunae in the research and development of antifungal drugs can be adopted. After analyzing the literature, it can be reported that the selected medicinal plant effectively suppressed the growth of numerous fungal species, such as Aspergillus, Alternaria, Candida, Fusarium, Phytophthora, and Pythium, owing to the presence of various secondary metabolites, particularly chromenes, terpenoids, flavonoids and coumarins. The possible mechanism of action of different secondary metabolites of the plant against fungal pathogens is also discussed briefly. However, it was found that only a few studies have been performed to demonstrate the plant's dosage and safety profile in humans. Considered all together, A. conyzoides extract and its constituents may act as a promising biosource for the development of effective antifungal formulations for clinical use. However, in order to establish safety and efficacy, additional scientific research is required to explore chronic toxicological effects of ageratum, to determine the probability of interactions when used with different herbs, and to identify safe dosage. The particulars presented here not only bridge this gap but also furnish future research strategies for the investigators in microbiology, ethno-pharmacology, and drug discovery.
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Ageratum/química , Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Ageratum/classificação , Antifúngicos/efeitos adversos , Antifúngicos/química , Testes de Sensibilidade Microbiana , Metabolismo Secundário/efeitos dos fármacosRESUMO
Extensive experimental, clinical, and epidemiological evidence has explained and proven that products of natural origin are significantly important in preventing and/or ameliorating various disorders, including different types of cancer that researchers are extremely focused on. Among these studies on natural active substances, one can distinguish the emphasis on resveratrol and its properties, especially the potential anticancer role. Resveratrol is a natural product proven for its therapeutic activity, with remarkable anti-inflammatory properties. Various other benefits/actions have also been reported, such as cardioprotective, anti-ageing, antioxidant, etc. and its rapid digestion/absorption as well. This review aims to collect and present the latest published studies on resveratrol and its impact on cancer prevention, molecular signals (especially p53 protein participation), and its therapeutic prospects. The most recent information regarding the healing action of resveratrol is presented and concentrated to create an updated database focused on this topic presented above.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias/tratamento farmacológico , Resveratrol/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Pericytes are contractile cells that extend along the vasculature to mediate key homeostatic functions of endothelial barriers within the body. In the central nervous system (CNS), pericytes are important contributors to the structure and function of the neurovascular unit, which includes endothelial cells, astrocytes and neurons. The understanding of pericytes has been marred by an inability to accurately distinguish pericytes from other stromal cells with similar expression of identifying markers. Evidence is now growing in favor of pericytes being actively involved in both CNS homeostasis and pathology of neurological diseases, including multiple sclerosis, spinal cord injury, and Alzheimer's disease among others. In this review, we discuss the current understanding on the characterization of pericytes, their roles in maintaining the integrity of the blood-brain barrier, and their contributions to neuroinflammation and neurorepair. Owing to its plethora of surface receptors, pericytes respond to inflammatory mediators such as CCL2 (monocyte chemoattractant protein-1) and tumor necrosis factor-α, in turn secreting CCL2, nitric oxide, and several cytokines. Pericytes can therefore act as promoters of both the innate and adaptive arms of the immune system. Much like professional phagocytes, pericytes also have the ability to clear up cellular debris and macromolecular plaques. Moreover, pericytes promote the activities of CNS glia, including in maturation of oligodendrocyte lineage cells for myelination. Conversely, pericytes can impair regenerative processes by contributing to scar formation. A better characterization of CNS pericytes and their functions would bode well for therapeutics aimed at alleviating their undesirable properties and enhancing their benefits.
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Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Homeostase/fisiologia , Mediadores da Inflamação/metabolismo , Doenças do Sistema Nervoso/metabolismo , Pericitos/metabolismo , Animais , Barreira Hematoencefálica/imunologia , Encéfalo/imunologia , Endocitose/fisiologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Humanos , Mediadores da Inflamação/imunologia , Doenças do Sistema Nervoso/imunologia , Pericitos/imunologiaRESUMO
Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.
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Envelhecimento/fisiologia , Macrófagos/patologia , Microglia/metabolismo , Niacina/metabolismo , Rejuvenescimento/fisiologia , Remielinização/fisiologia , Animais , Axônios/patologia , Doenças Desmielinizantes/patologia , Humanos , Camundongos Transgênicos , Microglia/patologia , Esclerose Múltipla/patologia , Fagocitose/fisiologiaRESUMO
The article Niacinmediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet.
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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-ß, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.
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Antibacterianos/farmacologia , Basigina/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Minociclina/uso terapêutico , Esclerose Múltipla/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Basigina/genética , Sistema Nervoso Central/efeitos dos fármacos , Ensaios Clínicos Fase III como Assunto , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/prevenção & controle , Cloridrato de Fingolimode/farmacologia , Fumaratos/farmacologia , Humanos , Interferon beta/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Maleatos/farmacologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Minociclina/administração & dosagem , Minociclina/farmacologia , Monócitos , Esclerose Múltipla/genética , Esclerose Múltipla/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Inibidor Tecidual de Metaloproteinase-1/imunologiaRESUMO
UNLABELLED: MicroRNAs (miRNAs) are single-stranded small RNA molecules that regulate various cellular processes. miRNA 155 (miR-155) regulates various aspects of innate and adaptive immune responses and plays a key role in various viral infections and the resulting neuroinflammation. The present study evaluated the involvement of miR-155 in modulating Japanese encephalitis virus (JEV)-induced neuroinflammation. We observed that miR-155 expression was upregulated during JEV infection of mouse primary microglia, the BV-2 microglia cell line, and in both mouse and human brains. In vitro and in vivo knockdown of miR-155 minimized JEV-induced inflammatory responses. In the present study, we confirmed targeting of the Src homology 2-containing inositol phosphatase 1 (SHIP1) 3' untranslated region (UTR) by miR-155 in the context of JEV infection. Inhibition of SHIP1 by miR-155 resulted in higher beta interferon (IFN-ß) and proinflammatory cytokine production through activation of TANK-binding kinase 1 (TBK-1). Based on these observations, we conclude that miR-155 modulates the neuroinflammatory response during JEV infection via negative regulation of SHIP1 expression. Thus, modulation of miR-155 could be a novel strategy to regulate JEV-induced neuroinflammation. IMPORTANCE: Japanese encephalitis virus (JEV), a member of the family Flaviviridae that causes Japanese encephalitis (JE), is the most common mosquito-borne encephalitis virus in the Asia-Pacific region. The disease is feared, as currently there are no specific antiviral drugs available. JEV targets the central nervous system, leading to high mortality and neurological and psychiatric sequelae in some of those who survive. The level of inflammation correlates well with the clinical outcome in patients. Recently, microRNA (miRNA), a single-stranded noncoding RNA, has been implicated in various brain disorders. The present study investigates the role of miRNA in JEV-induced neuroinflammation. Our results show that miRNA 155 (miR-155) targets the Src homology 2-containing inositol phosphatase 1 (SHIP1) protein and promotes inflammation by regulating the NF-κB pathway, increasing the expression of various proinflammatory cytokines and the antiviral response. Thus, miR-155 is a potential therapeutic target to develop antivirals in JE and other brain disorders where inflammation plays a significant role in disease progression.
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Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/imunologia , Encefalite Japonesa/patologia , Interações Hospedeiro-Patógeno , MicroRNAs/metabolismo , Monoéster Fosfórico Hidrolases/biossíntese , Animais , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Inositol Polifosfato 5-Fosfatases , Camundongos , Camundongos Endogâmicos BALB C , Microglia/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-FosfatasesRESUMO
Japanese encephalitis virus (JEV), a single-stranded RNA (ssRNA) virus, is the leading cause of encephalitis in Asia. Microglial activation is one of the key events in JEV-induced neuroinflammation. Although the various microRNAs (miRNAs) has been shown to regulate microglia activation during pathological conditions including neuroviral infections, till date, the involvement of miRNAs in JEV infection has not been evaluated. Hence, we sought to evaluate the possible role of miRNAs in mediating JEV-induced microglia activation. Initial screening revealed significant up-regulation of miR-29b in JEV-infected mouse microglial cell line (BV-2) and primary microglial cells. Furthermore, using bioinformatics tools, we identified tumor necrosis factor alpha-induced protein 3, a negative regulator of nuclear factor-kappa B signaling as a potential target of miR-29b. Interestingly, in vitro knockdown of miR-29b resulted in significant over-expression of tumor necrosis factor alpha-induced protein 3, and subsequent decrease in nuclear translocation of pNF-κB. JEV infection in BV-2 cell line elevated inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokine expression levels, which diminished after miR-29b knockdown. Collectively, our study demonstrates involvement of miR-29b in regulating JEV- induced microglial activation.
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Cisteína Endopeptidases/biossíntese , Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , MicroRNAs/fisiologia , Microglia/metabolismo , Microglia/virologia , Animais , Animais Recém-Nascidos , Encefalite Japonesa/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
OBJECTIVE AND DESIGN: The present study was aimed to evaluate the anti-inflammatory potentials of Vespa tropica (VT) venom and its isolated peptides. Effects of whole venom and its two peptides (Vt1512 and Vt1386) on lipopolysaccharide (LPS) challenged BV-2 murine microglial cells was evaluated. MATERIALS: Mouse microglial cell line, BV-2 and crude venom extract as well as purified peptides from VT along with LPS from Salmonella enterica were used for the studies. TREATMENT: BV-2 cells were treated with 500 ng/ml of LPS and different doses of crude wasp venom as well as purified peptides. METHODS: We used immunoblotting, cytokine bead arrays and fluorescence activated cell sorter (FACS) to evaluate the levels of various proteins, cytokines and reactive oxygen species (ROS). RESULTS: Our studies suggest that treatment with whole venom significantly reduces oxidative stress and LPS-stimulated activation of microglia. Also, purified peptides from crude venom exhibited potential anti-inflammatory properties. Further, whole venom was found to be targeting Akt and p38 MAPK pathways, leading to suppressed NF-κB phosphorylation in LPS challenged BV-2 cells. CONCLUSIONS: VT venom possesses anti-inflammatory properties and can be further explored for their therapeutic potential in treating various inflammatory conditions of the central nervous system (CNS).
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Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Venenos de Vespas/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos , Camundongos , Microglia/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , VespasRESUMO
BACKGROUND: Fermented formulations are extensively used in Ayurveda due to several benefits like improved palatability, bioavailability, pharmacological potential, and shelf life. These formulations can also quench the heavy metals from the plant material and thus reduce the toxicity. Seeds of Silybum marianum (L.) Gaertn. are widely used for the management of many liver diseases. STUDY DESIGN AND METHODS: In the present study, we developed a novel fermented formulation of S. marianum seeds and evaluated parameters like safety (heavy metal analysis) and effectiveness (hepatoprotective). As the developed formulation's validation is crucial, the critical process variables (time, pH, and sugar concentration) are optimized for alcohol and silybin content using the Box-Behnken design (BBD). RESULTS: The response surface methodology coupled with BBD predicted the optimized conditions (fermentation time (28 days), pH 5.6, and sugar concentration (22.04%)) for the development of a fermented formulation of the selected herb. Moreover, the alcohol content (6.5 ± 0.9%) and silybin concentration (26.1 ± 2.1%) were confirmed in optimized formulation by GC-MS and HPTLC analysis. The optimized formulation was also analyzed for heavy metals (Pb, As, Hg, and Cd); their concentration is significantly less than the decoction of herbs. Further, the comparative evaluation of the developed formulation with the marketed formulation also confirmed that the fermented formulation's silybin concentration and percentage release were significantly enhanced. In addition, the developed fermented formulation's percentage recovery of HepG2 cell lines after treatment with CCl4 was significantly improved compared with the marketed formulation. CONCLUSION: It can be summarized that the developed fermented formulation improves safety and effectiveness compared to other market formulations. Finally, it can be concluded that the developed fermented formulation could be further explored as a better alternative for developing Silybum marianum preparation.
Assuntos
Metais Pesados , Silimarina , Silimarina/farmacologia , Silybum marianum , Silibina , Sementes/química , Metais Pesados/análise , Açúcares/análiseRESUMO
Lung cancer is the second deadliest disease in the world. A major portion of deaths related to cancer are due to lung cancer in both males and females. Interestingly, unbelievable advances have occurred in recent years through the use of nanotechnology and development in both the diagnosis and treatment of lung cancer. Due to their in vivo stability, the nanotechnology-based pharmacological system gained huge attractiveness, solubility, absorption from the intestine, pharmacological effectiveness, etc. of various anticancer agents. However, this field needs to be utilized more to get maximum results in the treatment of lung cancer, along with wider context medicines. In the present review, authors have tried to concentrate their attention on lung cancer`s difficulties along with the current pharmacological and diagnostic situation, and current advancements in approaches based on nanotechnology for the treatment and diagnosis of lung cancer. While nanotechnology offers these promising avenues for lung cancer diagnosis and treatment, it is important to acknowledge the need for careful evaluation of safety, efficacy, and regulatory approval. With continued research and development, nanotechnology holds tremendous potential to revolutionize the management of lung cancer and improve patient outcomes. The review also highlights the involvement of endocrine systems, especially estrogen in lung cancer proliferation. Some of the recent clinical trials and patents on nanoparticle-based formulations that have applications in the treatment and diagnosis of lung cancer are also discussed.
RESUMO
Background: Glioblastoma multiforme (GBM) is recognized as the most lethal and most highly invasive tumor. The high likelihood of treatment failure arises from the presence of the blood-brain barrier (BBB) and stem cells around GBM, which avert the entry of chemotherapeutic drugs into the tumor mass. Objective: Recently, several researchers have designed novel nanocarrier systems like liposomes, dendrimers, metallic nanoparticles, nanodiamonds, and nanorobot approaches, allowing drugs to infiltrate the BBB more efficiently, opening up innovative avenues to prevail over therapy problems and radiation therapy. Methods: Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases, for example, PubMed, Science Direct, Google Scholar, and others, using specific keyword combinations, including "glioblastoma," "brain tumor," "nanocarriers," and several others. Conclusion: This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management. Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.