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In the mammalian heart, fetal cardiomyocytes proliferate prior to birth; however, they exit the cell cycle shortly after birth. Recent studies show that adult cardiomyocytes re-enters the cell cycle postinjury to promote cardiac regeneration. The endoplasmic reticulum (ER) orchestrates the production and assembly of different types of proteins, and a disruption in this machinery leads to the generation of ER stress, which activates the unfolded protein response. There is a very fine balance between ER stress-mediated protective and proapoptotic responses. T-box transcription factor 20 (Tbx20) promotes embryonic and adult cardiomyocyte proliferation postinjury to restore cardiac homeostasis. However, the function and regulatory interactions of Tbx20 in ER stress-induced cardiomyopathy have not yet been reported. We show here that ER stress upregulates Tbx20, which activates downstream bone morphogenetic protein 2 (Bmp2)-pSmad1/5/8 signaling to induce cardiomyocyte proliferation and limit apoptosis. However, augmenting ER stress reverses this protective response. We also show that increased expression of tbx20 during ER stress is mediated by the activating transcription factor 6 arm of the unfolded protein response. Cardiomyocyte-specific loss of Tbx20 results in decreased cardiomyocyte proliferation and increased apoptosis. Administration of recombinant Bmp2 protein during ER stress upregulates Tbx20 leading to augmented proliferation, indicating a feed-forward loop mechanism. In in vivo ER stress, as well as in diabetic cardiomyopathy, the activity of Tbx20 is increased with concomitant increased cardiomyocyte proliferation and decreased apoptosis. These data support a critical role of Tbx20-Bmp2 signaling in promoting cardiomyocyte survival during ER stress-induced cardiomyopathies.
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Proteína Morfogenética Ósea 2 , Estrés del Retículo Endoplásmico , Miocitos Cardíacos , Proteínas de Dominio T Box , Animales , Apoptosis , Proteína Morfogenética Ósea 2/metabolismo , Regulación de la Expresión Génica , Mamíferos/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Proteínas de Dominio T Box/metabolismoRESUMEN
Antimicrobial resistance is a prevalent problem witnessed globally and creating an alarming situation for the treatment of infections caused by resistant pathogens. Available armaments such as antibiotics often fail to exhibit the intended action against resistant pathogens, leading to failure in the treatments that are causing mortality. New antibiotics or a new treatment approach is necessary to combat this situation. P. aeruginosa is an opportunistic drug resistant pathogen and is the sixth most common cause of nosocomial infections. P. aeruginosa due to its genome organization and other factors are exhibiting resistance against drugs. Bacterial biofilm formation, low permeability of outer membrane, the production of the beta-lactamase, and the production of several efflux systems limits the antibacterial potential of several classes of antibiotics. Combination of phytoconstituents with antibiotics is a promising strategy to combat multidrug resistant P. aeruginosa. Phytoconstituents such as flavonoids, terpenoids, alkaloids, polypeptides, phenolics, and essential oils are well known antibacterial agents. In this review, the activity of combination of the phytoconstituents and antibiotics, and their corresponding mechanism of action was discussed elaborately. The combination of antibiotics and plant-derived compounds exhibited better efficacy compared to antibiotics alone against the antibiotic resistance P. aeruginosa infections.
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Antibacterianos , Biopelículas , Fitoquímicos , Pseudomonas aeruginosa , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Antibacterianos/farmacología , Fitoquímicos/farmacología , Fitoquímicos/química , Biopelículas/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Urticaria is a clinical condition characterized by the appearance of wheals (hives), angioedema, or both. Over the last several decades, a better understanding of the mechanisms at play in the immunopathogenesis of urticaria has underscored the existence of numerous urticaria subtypes. Separating the different kinds of urticaria explicitly helps find the best detection method for the management of this skin disorder. Subtypes of urticaria also include both spontaneous and physical types. The conventional ones include spontaneous urticaria, constituting both acute and chronic urticaria. Therefore, a broad and effective therapy is essential for the diagnosis and treatment of urticaria. METHODS: To understand the immunopathogenesis of urticaria, various databases, including PubMed, Scopus, and Web of Science, were used to retrieve original articles and reviews related to urticaria. While information on several clinical trials were obtained from clinicaltrials.gov database. RESULTS: This article highlights the immunopathogenesis involved in the intricate interaction between cellular infiltration, immune reactions, coagulation cascades, and autoantibodies that underlie urticaria's pathophysiology. CONCLUSION: The recent progress in understanding urticaria can help to understand the intricate characteristics in the immunopathogenesis of urticaria and could play a beneficial role in the management of urticaria.
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Citocinas , Histamina , Urticaria , Humanos , Urticaria/inmunología , Histamina/inmunología , Citocinas/inmunología , AnimalesRESUMEN
Non-alcoholic fatty liver disease (NAFLD), with a global prevalence of 25%, continues to escalate, creating noteworthy concerns towards the global health burden. NAFLD causes triglycerides and free fatty acids to build up in the liver. The excessive fat build-up causes inflammation and damages the healthy hepatocytes, leading to non-alcoholic steatohepatitis (NASH). Dietary habits, obesity, insulin resistance, type 2 diabetes, and dyslipidemia influence NAFLD progression. The disease burden is complicated due to the paucity of therapeutic interventions. Obeticholic acid is the only approved therapeutic agent for NAFLD. With more scientific enterprise being directed towards the understanding of the underlying mechanisms of NAFLD, novel targets like lipid synthase, farnesoid X receptor signalling, peroxisome proliferator-activated receptors associated with inflammatory signalling, and hepatocellular injury have played a crucial role in the progression of NAFLD to NASH. Phytocompounds have shown promising results in modulating hepatic lipid metabolism and de novo lipogenesis, suggesting their possible role in managing NAFLD. This review discusses the ameliorative role of different classes of phytochemicals with molecular mechanisms in different cell lines and established animal models. These compounds may lead to the development of novel therapeutic strategies for NAFLD progression to NASH. This review also deliberates on phytomolecules undergoing clinical trials for effective management of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Fitoquímicos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Humanos , Animales , Fitoquímicos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Sustancias Protectoras/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismoRESUMEN
OBJECTIVE: Regardless of having desired therapeutic properties many of the recently approved drugs are removed from the developmental pipeline for their clinical use due to low solubility and permeability. Conventional dosage forms are found relatively unsuitable for achieving desired pharmacokinetic and pharmacodynamics profiles. Cilnidipine is 1,4 dihydropyridine derivative calcium channel blocker used for the treatment of hypertension. METHOD: The aim and objective of this study was to develop a precise and significant method in LC-MS/MS for quantification of pharmacokinetic parameters of a cilnidipine-loaded self-micro-emulsifying drug delivery system in rat plasma and simultaneously assessed pharmacodynamic characters in comparison with the marketed cilnidipine tablet. Another potential aim of this study is to reduce the dose of the drug in order to counter the dose-dependent toxicities related to chronic use. In the present study, the parent and product ion of cilnidipine was m/z 491.3\237.1. RESULT: The plasma was extracted by protein precipitation technique. The calibration standard concentrations were 1.875, 3.75, 7.50, 15.00, 30.00, 60.00ng/mL and LLOQ, low-quality control, middle-quality control and high-quality control were 1.87, 5.62, 22.50, 45.00ng/mL, respectively. The mobile phase composition was 0.1% formic acid in Milli Q water with 10mM Ammonium acetate as an aqueous solvent and 0.1% formic acid in methanol as an organic solvent. Following oral administration of optimized formulation Cmax (peak plasma concentration) was achieved 21.02±3.17ng/mL at 0.866±0.11h (Tmax), whereas in the case of marketed tablet Cmax (peak plasma concentration) was achieved 10.16±0.89ng/mL at 0.93±0.11h (Tmax). DISCUSSION: The in-vivo characterizations of the optimized SMEDDS showed significantly better pharmacokinetic parameters in Wistar rats and showed almost 2.4 times enhanced relative bioavailability as compared to the marketed tablet of cilnidipine which was observed to be correlating to our findings with noninvasive blood pressure parameter of Wistar rats.
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A South African traditional formulation, PHELA®, is consumed by the traditional people for severe chest problems with coughing, diarrhea, oral ulcers etc. The present study focused on establishing the anti-infective properties of a safe and standardized poly-herbal formulation through a series of criteria and specifications.
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Antiinfecciosos/química , Antiinfecciosos/farmacología , Biopelículas/efectos de los fármacos , Medicinas Tradicionales Africanas , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antiinfecciosos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/aislamiento & purificaciónRESUMEN
The discovery of new antimicrobials is the prime target in the fight against antimicrobial resistance. The continuous search for new lead compounds from bacteria of untapped and extreme ecosystems such as mangroves is currently being undertaken. This study describes the metabolite profiling of the Streptomyces euryhalinus culture extract. Previously, Streptomyces euryhalinus was isolated from the mangrove forest of Indian Sundarbans as a novel microorganism. The antimicrobial mechanism of action of Streptomyces euryhalinus culture extract against bacteria and fungi has been analyzed in this study. The gas chromatography-mass spectrometry profile of the ethyl acetate extract bacterial culture displayed the presence of several bioactive compounds with antibacterial, antifungal and antioxidant properties. The bacterial extract showed significant antimicrobial activity in terms of zone of inhibition, minimum inhibitory concentration, minimum bactericidal concentration, and minimum fungicidal concentration. Moreover, substantial capacity to alter or damage the inner membrane as well as the outer membrane of the gram-positive and gram-negative bacteria was exhibited by the bacterial extract. This membrane alteration or damaging potential of the extract is the mechanism of action. Biofilm formation inhibition property of the extract also signified its antimicrobial action, and possible use against resistant bacteria. The extract has shown notable activity against the virulence factors like prevention of hemolysis in bacteria and inhibition of secreted aspartyl proteinase in fungi. These functions of the bacterial extract have revealed the extent of its action in the prevention of infection by terminating the secretory virulence factors and by damaging the tissue.
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Antibacterianos , Ecosistema , Antibacterianos/farmacología , Bacterias Gramnegativas , Bacterias Grampositivas , StreptomycesRESUMEN
Management of infectious wounds, particularly chronic wounds and burn injuries, is a matter of global concern. Worldwide estimates reveal that, billions of dollars are being spent annually for the management of such chronic ailments. Evidently, bacterial biofilms pose a greater problem in the effective management of infection in chronic wounds, since most of the currently available antibiotics are unable to act on the microorganisms residing inside the protected environment of the biofilms. Accordingly, in the present study, we have attempted to evaluate the anti-biofilm properties of human placental extract (PLX) and also other virulence factors that are mediated via the quorum sensing (QS) signalling system. PLX is well known for its anti inflammatory action and it has been shown earlier some anti microbial and enzymatic activity also. PLX was found to produce significant inhibition of biofilm formation and also decreased the levels of pyoverdin and pyocyanin. The microscopic analysis (both light microscopy and atomic force microscopy) of biofilms was also used for substantiating the findings from spectrophotometric (crystal violet estimation) and fluorescence analysis (resazurin uptake). PLX pre-treatment decreased the hydrophobicity of gram-positive and gram negative cells, indicating the effect of placental extract on adherence property of planktonic cell, serving as an indicator for its antibiofilm effect on microorganisms. The reduced extracellular DNA (eDNA) content in biofilm matrix following treatment with PLX also indicates the effectiveness of placenta extract on bacterial adherence, which in turn serves as evidence substantiating the antibiofilm effects of the PLX. Furthermore, PLX was also found to be significantly effective in the in vitro wound biofilm model. Thus the present study, the first of its kind with PLX, establishes the therapeutic benefit of the same particularly in infected wounds, opening up newer avenue for further exploration.
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Biopelículas/efectos de los fármacos , Extractos Placentarios/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Infección de Heridas/microbiología , Humanos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/fisiología , Percepción de Quorum/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/fisiologíaRESUMEN
Oral paclitaxel (PTXL) formulations freed from cremophor® EL (CrEL) is always in utmost demand by the cancerous patients due to toxicities associated with the currently marketed formulation. In our previous investigation [Int. J. Pharm. 2014; 460:131], we have developed an oral oil based nanocarrier for the lipophilic drug, PTXL to target bioavailability issue and patient compliance. Here, we report in vivo antitumor activity and 28-day sub-chronic toxicity of the developed PTXL nanoemulsion. It was observed that the apoptotic potential of oral PTXL nanoemulsion significantly inhibited the growth of solid tumor (59.2 ± 7.17%; p < 0.001) without causing any explicit toxicity. The 6.5 mg/kg and 3 mg/kg oral PTXL nanoemulsion dose did not cause any notable alteration in haematological, biochemical/structural characteristics during 28-day sub-chronic toxicity studies in the experimental mice. Whereas, the toxicity of 12.8 mg/kg body weight dose showed decrease in RBC, haemoglobin and neutrophil counts. In contrast, marketed PTXL (Taxol®) was found to be comparatively more toxic to the experimental animals. Taxol® treatment resulted glomerulonephritis in histopathological examination, which could be correlated with increased level of creatinine and associated nephrotoxicity. This investigations conclude that the developed oral nanoemulsion presents a viable therapeutics bio-system to step towards clinical application as well as substitute CrEL based PTXL formulations.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos Fitogénicos/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Administración Oral , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Química Farmacéutica/métodos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Emulsiones/efectos adversos , Emulsiones/química , Emulsiones/farmacología , Eritrocitos/efectos de los fármacos , Femenino , Hemoglobinas/metabolismo , Masculino , Ratones , Neoplasias/metabolismo , Neutrófilos/efectos de los fármacos , Paclitaxel/efectos adversos , Paclitaxel/química , Polietilenglicoles/químicaRESUMEN
Gymnema sylvestre is traditionally used for diabetes mellitus. A literature survey revealed very few reports, particularly on rat liver microsomal stability, caco-2 permeability and efflux concerns and its correlation with the bioavailability of gymnemagenin, an important component of G. sylvestre. Therefore, the objective of our study was to investigate the in vitro rat liver microsomal stability and caco-2 permeability along with the efflux of gymnemagenin and establish a probable correlation of these in vitro findings with pharmacokinetic parameters after oral and intravenous administration in rats.Rat liver microsomal stability studies to estimate the in vitro intrinsic half-life, clearance, and Caco-2 permeability after 21 days of culture to determine the apparent permeability from apical to basal and from basal to apical, and efflux ratio of gymnemagenin were performed using liquid chromatography-tandem mass spectrometry. A sensitive, robust bioanalytical method was validated and successfully applied to determine the plasma exposure of gymnemagenin. In vitro rat liver microsomal stability demonstrated that gymnemagenin metabolizes rapidly with a short apparent and intrinsic half-life (~ 7 min) and high intrinsic clearance, i.e., 190.08 µL/min/mg of microsomes. The results of the Caco-2 study indicated a poor permeability (1.31 × 10(- 6 )cm/sec) with a very high efflux ratio. The pharmacokinetic study revealed poor oral bioavailability (~ 14 %) of gymnemagenin and it was found to have a short half-life and a high clearance in rats. Our in vitro findings indicated low metabolic stability and poor Caco-2 permeability with high efflux, which might have a role in the observed poor oral bioavailability in rats.
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Alcaloides/farmacocinética , Administración Oral , Alcaloides/administración & dosificación , Animales , Disponibilidad Biológica , Células CACO-2/efectos de los fármacos , Cromatografía Liquida/métodos , Estabilidad de Medicamentos , Semivida , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Permeabilidad , Proyectos Piloto , Ratas Wistar , Espectrometría de Masas en Tándem/métodosRESUMEN
A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method.
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Benzofuranos/química , Receptores Histamínicos H1/metabolismo , Tephrosia/química , Antialérgicos/síntesis química , Antialérgicos/química , Antialérgicos/farmacología , Benzofuranos/aislamiento & purificación , Benzofuranos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Isomerismo , Componentes Aéreos de las Plantas/química , Componentes Aéreos de las Plantas/metabolismo , Receptores Histamínicos H1/genética , Tephrosia/metabolismoRESUMEN
CONTEXT: Andrographis paniculata (Burm.f.) Nees (Acanthaceae) is widely used in tribal medicine in India and some other countries for multiple clinical applications. It contains andrographolide (AG) (diterpenoid lactone), a major phytomarker which probably accounts for its medicinal properties. OBJECTIVE: This study investigates the site-specific distribution of AG in different tissues of rats and its pharmacokinetic parameter evaluation by using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: A simple and sensitive LC-MS/MS method has been developed and validated to quantify the presence of AG in plasma and various tissues of rat following oral administration of A. paniculata extract and AG in a dose of 133.33 and 100 mg/kg/day, respectively, for four weeks. RESULTS: The present study showed that the highest concentration of AG was in kidney (156.12 ng/g) followed by liver, spleen and brain while almost same concentration was found in heart and lung. The apparent C(max), T(max), elimination half-life and total exposure (AUC(0-α)) were 115.81 ng/ml, 0.75, 2.45 and 278.44 ngh/ml, respectively. CONCLUSION: This was an attempt to determine the presence of AG (a known biomarker) in tissues such as kidney, heart, lungs, brain and plasma of rats using a validated LC-MS/MS method. Furthermore, the observed reduced concentration in plasma and various tissues from 1 to 8 h might be attributed to relatively rapid elimination or distribution of AG from the central compartment.
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Andrographis/química , Cromatografía Liquida/métodos , Diterpenos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Área Bajo la Curva , Diterpenos/administración & dosificación , Diterpenos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Semivida , India , Masculino , Medicina Tradicional , Ratas , Ratas Wistar , Factores de Tiempo , Distribución TisularRESUMEN
Free fatty acid receptor 1 (FFAR1 or GPR40) is a potential target for treating type 2 diabetes mellitus (T2DM) and related disorders that have been extensively researched for many years. GPR40/FFAR1 is a promising anti-diabetic target because it can activate insulin, promoting glucose metabolism. It controls T2DM by regulating glucose levels in the body through two separate mechanisms: glucose-stimulated insulin secretion and incretin production. In the last few years, various synthetic GPR40/FFAR1 agonists have been discovered that fall under several chemical classes, viz. phenylpropionic acid, phenoxyacetic acid, and dihydrobenzofuran acetic acid. However, only a few synthetic agonists have entered clinical trials due to various shortcomings like poor efficacy, low lipophilicity and toxicity issues. As a result, pharmaceutical firms and research institutions are interested in developing synthetic GPR40/FFAR1 agonists with superior effectiveness, lipophilicity, and safety profiles. This review encompasses the most recent research on synthetic GPR40/FFAR1 agonists, including their chemical classes, design strategies and structure-activity relationships. Additionally, we have emphasised the structural characteristics of the most potent GPR40/FFAR1 agonists from each chemical class of synthetic derivatives and analysed their chemico-biological interactions. This work will hopefully pave the way for developing more potent and selective synthetic GPR40/FFAR1 agonists for treating T2DM and related disorders.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Glucosa , Relación Estructura-ActividadRESUMEN
The human immune defensesystem routinely expresses the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is the most prevalent element for antitumor immunity. TRAIL associates with its death receptors (DRs), DR4 (TRAIL-R1), and DR5 (TRAIL-R2), in cancer cells to initiate the intracellular apoptosis cascade. Accordingly, numerous academic institutions and pharmaceutical companies havetried to exploreTRAIL's capacity to kill tumourcells by producing recombinant versions of it (rhTRAIL) or TRAIL receptor agonists (TRAs) [monoclonal antibody (mAb), synthetic and natural compounds, etc.] and molecules that sensitize TRAIL signalling pathway for therapeutic applications. Recently, several microRNAs (miRs) have been found to activate or inhibit death receptor signalling. Therefore, pharmacological regulation of these miRs may activate or resensitize the TRAIL DRs signal, and this is a novel approach for developing anticancer therapeutics. In this article, we will discuss TRAIL and its receptors and molecular pathways by which it induces various cell death events. We will unravel potential innovative applications of TRAIL-based therapeutics, and other investigated therapeutics targeting TRAIL-DRs and summarize the current preclinical pharmacological studies and clinical trials. Moreover, we will also emphasizea few situations where future efforts may be addressed to modulate the TRAIL signalling pathway.
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Neoplasias , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Necroptosis , Neoplasias/patología , Apoptosis , Proteínas Reguladoras de la ApoptosisRESUMEN
The pathophysiology of chronic wounds related to diabetes mellitus is a result of a series of complications induced by hyperglycemia. The symptoms include impaired growth factor production, decreased keratinocyte proliferation and migration, reduced angiogenesis and cytokine synthesis, lowered matrix metalloproteinase (MMP) production, neuropathy, reduced nitric oxide synthase production, decreased fibroblast synthesis and migration, and impaired inflammatory cell functions. This multifaceted mechanism of diabetic wounds needs a suitable novel topical formulation that can deliver the active constituent by a controlled means, target the various stages of wound healing, absorb the wound exudates, and prevent secondary infections. To meet the above requirements, the Clerodendrum glandulosum (CG) extract reduced silver nanoparticle (AgNP) impregnated chitosan-polyethylene glycol (PEG) hydrogel was synthesized. The findings of the physicochemical characterization studies suggested that the hydrogel exhibited excellent formulation characteristics and showed controlled release for seven days, making it suitable for chronic wound healing studies. In subsequent studies, these formulations showed good antioxidant and antimicrobial properties, and hemocompatibility, with the least cytotoxic properties. The results of the diabetic wound healing studies showed a faster wound closure rate and improved extracellular matrix formation. These antioxidant, antimicrobial, anti-inflammatory and wound-healing properties suggest that the CG-AgNP loaded chitosan-PEG hydrogel is a promising material for novel topical formulation of diabetic wounds.
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Quitosano , Clerodendrum , Hidrogeles , Nanopartículas del Metal , Extractos Vegetales , Polietilenglicoles , Plata , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Quitosano/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Nanopartículas del Metal/química , Nanopartículas del Metal/administración & dosificación , Animales , Hidrogeles/química , Hidrogeles/administración & dosificación , Hidrogeles/farmacología , Plata/química , Plata/farmacología , Plata/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Clerodendrum/química , Aprendizaje Automático , Ratas , Diabetes Mellitus Experimental/tratamiento farmacológico , Humanos , Masculino , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/administración & dosificación , RatonesRESUMEN
This study aims to pharmacologically validate Haridra Khanda (HK) and Manjishthadi Kwatham (brihat) (MMK) in allergy management using invivo and invitro studies to rationalize the prescription of these two ayurvedic polyherbal drug formulations, which are currently used in Indian government hospitals. Experimental animals received HK and MMK orally from day 0 to day 14 and histamine (1 mg/kg b.w/i.v) and 1 % evans blue (EB) (0.1 mL) via tail vein on day 14. The compound 48/80 (intracutaneous) challenged mice model followed the same technique. The former mimicked acute anaphylaxis and the latter mast cell degranulation. For both models, EB dye leakage was quantified spectrophotometrically to determine vascular permeability. Plasma histamine was measured in Compound 48/80-induced animals using LC-ESI-MS/MS. The guineapig received HK and MMK p.o. and 0.6 % histamine sprayed in a histamine chamber to simulate allergic rhinitis. Blood eosinophil count and sneeze rate were measured in histamine-challenged guineapigs. Goat R.B.C. membrane stability assay (mammalian cell membrane toxicity) and intracellular histamine-induced cytosolic Ca2+ release assay in Chinese hamster ovary (CHO) cells were performed in vitro. For both histamine and Compound 48/80 challenged animals, HK (22.81 % and 14.58 %) and MMK (19.71 % and 22.40 %) significantly reduced EB dye leakage (p < 0.05). Both formulations, HK and MMK considerably (p < 0.05) decreased plasma histamine (29.62 % and 25.37 % respectively) in mice and eosinophilic count (11.56 % and 9.94 % respectively) and sneeze rate (42.58 % and 29.03 % respectively) in guinea pigs. In membrane stability experiment, HK and MMK reduced RBC lysis. Both HK and MMK raw/dialysate blocked CHO cell cytosolic Ca2+ release. HK and MMK activities mimic mast cell stabilization with possible H1 receptor inactivation seen by decreased Ca2+ efflux and thus indicate potential for allergic rhinitis management. The combination of activities is usually related with curative and prophylactic therapy and might lead future clinical trials and therapies.
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Metoprolol succinate (MET), a cardioselective ß blocker and telmisartan (TEL), an angiotensin receptor blocker were administered orally, both individually and in combination to Wistar albino rats for evaluation of their pharmacokinetics, pharmacodynamics and repeated dose oral toxicity (28 days). Pharmacokinetic study was performed by analyzing drug concentration in plasma by a developed and validated LC-MS/MS method following oral administration of MET and TEL at 2.5 mg/kg and 2.0 mg/kg dose, respectively, both individually and in combination. Antihypertensive activity of MET and TEL in above dose and manner was evaluated on artificially induced hypertension on laboratory animals. In repeated dose oral toxicity study, MET (60, 120 and 240 mg/kg/day) and/or TEL (12, 24 and 48 mg/kg/day) were administered to animals for 28 days followed by a recovery period of 14 days. Pharmacokinetic data revealed the probable absence of any pharmacokinetic interaction when co-administered. Improved blood pressure lowering effect was observed by combination therapy. Moreover, toxic effects obtained at high dose level of each treatment groups were transient and reversible and no evidence of additive toxic effects were observed due to concomitant administration. So, this combination can primarily be stated as safe which will be confirmed after clinical interaction studies in humans.
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Antagonistas Adrenérgicos beta/toxicidad , Bloqueadores del Receptor Tipo 1 de Angiotensina II/toxicidad , Bencimidazoles/toxicidad , Benzoatos/toxicidad , Metoprolol/análogos & derivados , Administración Oral , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Masculino , Metoprolol/administración & dosificación , Metoprolol/farmacocinética , Metoprolol/toxicidad , Ratas , Ratas Wistar , Espectrometría de Masas en Tándem , TelmisartánRESUMEN
It has been demonstrated that noncoding RNAs have significant physiological and pathological roles. Modulation of noncoding RNAs may offer therapeutic approaches as per recent findings. Small RNAs, mostly long noncoding RNAs, siRNA, and microRNAs make up noncoding RNAs. Inhibiting or promoting protein breakdown by binding to 3' untranslated regions of target mRNA, microRNAs post-transcriptionally control the pattern of gene expression. Contrarily, long non-coding RNAs perform a wider range of tasks, including serving as molecular scaffolding, decoys, and epigenetic regulators. This article provides instances of long noncoding RNAs and microRNAs that may be a biomarker of CVD (cardiovascular disease). In this paper we highlight various RNA-based vaccine formulation strategies designed to target these biomarkers-that are either currently in the research pipeline or are in the global pharmaceutical market-along with the physiological hurdles that need to be overcome.
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Background: Systemic arterial hypertension, which is associated with an increased risk of cardiovascular disease(CVD), is the most significant modifiable risk factor for mortality and morbidity worldwide. WHO has recognized Unanipathy as an alternate system of medicine. The aim of the present study is to investigate the anti-hypertensive activity of some selected unani formulations using L-NAME model. Method: Group I or hypertensive control group: L-NAME administered for 7 days and left for the next 7 days; Group II or KASgroup: L-NAME administered (i.p) for 7 days and L-NAME + KAS (1000 mg/kg b.w) for the next 7 days; Group III or DMM group: L-NAME administered (i.p) for 7 days and L-NAME + DMM (2000 mg/kg b.w) for the next 7 days; Group IV or MSR group: L-NAME administered (i.p) for 7 days and L-NAME + MSR (300 mg/kg b.w) for the next 7 days; Group V or HJ group: L-NAME administered (i.p) for 7 days and L-NAME + HJ (113 mg/kg b.w) for the next 7 days; Group VI or KGS group: L-NAME administered (i.p) for 7 days and L-NAME +KGS (2000 mg/kg b.w) for the next 7 days. Non-invasive systolic blood pressure and RR-interval (ECG) was measured. Plasma was investigated forsodium, potassium, nitrite, ANP, adrenaline, noradrenaline and aldosterone on day 0, 7 and 14 using LC-MS/MS. Result: Treatment showed a non-significant lowreduction in SBP (systolic blood pressure) of KAS, MSR and HJ while that of DMM was quite significant (p < 0.05), but in the case of KGS, SBP increased. DMM on day 14 significantly (p < 0.05) reduced plasma nitrite while no significant plasma Na+ was noted. In the case of both DMM and KGS, potassium increased significantly (p < 0.05) on day 14. No significant changes in plasma ANP and aldosterone was observed against DMM and KGS while blood levels of adrenaline and noradrenaline significantly (p < 0.05) changed. No significant change in body weight was found. Conclusions: L-NAME KAS, MSR and HJ showed no change in SBP while DMM showed a significant reduction in SBP with decreased plasma nitrite. Probably, DMM may have anti-hypertensive activity mediated through NO inhibition while KGS may involve central sympathomimetic action.
RESUMEN
Many of the recently approved drug molecules that are therapeutically successful are found to be incompatible for the development of a novel delivery system and to take part in various health care management. Regardless of having better therapeutic properties, these molecules are barred from their effective clinical uses. The main reason attributed to it is poor solubility and/or poor permeability of drugs which finally emerges the drug to be low bioavailable. Nanoemulsions are one of the most acceptable nanolipoidal drug delivery system and appears to be a hope for the delivery of many of the Biopharmaceutical Classification System (BCS) class II and IV drugs. A nanoemulsion is a thermodynamically unstable isotropic mixture of oil, surfactant, and co-surfactants and is biphasic in nature. It can be either water in oil or oil in water and droplets are found in the range of 5 to 500 nm. The manufacturing and fabrication of nanoemulsions involve various natural, synthetic and semi synthetic materials using either low or high-energy methods. Application of nanoemulsions as a novel drug delivery system through several routes, especially oral, transdermal, ophthalmic, and intranasal, have been increased for various pharmacological aspects such as cardiovascular, anticancer, antimicrobial, and ophthalmic due to their stability, high solubilization capacity, and ease of preparation. The objective of this review is to focus on the aspects of manufacturing, fabrication, application, and some toxicological concerns related to nanoemulsions.