Immunopathogenesis of urticaria: a clinical perspective on histamine and cytokine involvement.

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.

Bioprotective Role of Phytocompounds Against the Pathogenesis of Non-alcoholic Fatty Liver Disease to Non-alcoholic Steatohepatitis: Unravelling Underlying Molecular Mechanisms.

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.

Evaluation of cilnidipine-loaded self-micro-emulsifying drug delivery system (SMEDDS) by quantification of comparative pharmacokinetic parameters using validated LC-ESI-MS/MS bioanalytical method and pharmacodynamic assessment.

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.

Prospective Evaluation of Fractional Carbon Dioxide Laser Treatment of Mature Burn Scars, Post-traumatic Scars, and Post-acne Scars.

BACKGROUND: Annually, around 100 million patients worldwide acquire scars, some of which can cause significant problems. Various treatment interventions, such as topical scar creams, steroids, laser therapy, and surgery, have been developed to manage these scars. This study was conducted to evaluate the effectiveness of fractional CO2 laser treatment by assessing outcomes using the Patient Observer Scar Assessment Scale (POSAS) and clinical photographs. MATERIALS AND METHODS: A total of 47 patients were included in the study, divided into three groups: a post-acne scar group with 14 patients, a post-burn scar group with 17 patients, and a post-traumatic scar group with 16 patients. Detailed histories were taken, and clinical examinations were performed and recorded on a prepared proforma. Aesthetic outcomes were evaluated based on clinical photographs, and total patient and observer scores were recorded using POSAS at baseline, and after one and three months. POSAS comprises two components: the observer scale (POSAS-O) and the patient scale (POSAS-P). Fractional CO2 laser treatments were performed in each group, with sessions repeated every four weeks for three consecutive sessions. Data were analyzed using the paired t-test for before-and-after comparisons in each study group. Welch's ANOVA test was used for comparisons among the three groups at a significance level of p=0.05, using MS Excel (Microsoft Corporation, Redmond, Washington) and IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York). RESULTS: The mean age for men was 26.38 ± 8.19 years and for women 22.21 ± 6.38 years. The study comprised 34 female patients (72.34%) and 13 male patients (27.66%). The mean POSAS observer and patient scales were recorded and compared for all three types of scars from baseline to three months. The mean percentage change in POSAS-O and POSAS-P (total score) in relation to different scar sites was recorded. The most significant difference in mean percentage change, statistically significant (p-value < 0.05), was observed for facial scars, followed by scars on the neck, and was minimal for scars on the hand, in both observer and patient groups. Even a single session of fractional CO2 laser therapy had profound effects on the overall quality of scars. CONCLUSION: Fractional carbon dioxide laser therapy improves the quality of scars and produces significant improvements in skin texture, with better effects on post-traumatic scars than on post-burn and post-acne scars. Future studies are needed to better understand the mechanism of action and to optimize the doses and timing of therapy.

Significance of TRAIL/Apo-2 ligand and its death receptors in apoptosis and necroptosis signalling: Implications for cancer-targeted therapeutics.

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.

Chemo-profiling and exploring therapeutic potential of Momordica dioica Roxb. ex Willd. for managing metabolic related disorders: In-vitro studies, and docking based approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Momordica dioica Roxb. ex Willd. (M. dioica Roxb.) a nutritious and therapeutic property rich crop of Cucurbitaceae plant family. In various folklore medicine including Ayurveda fruits are used to treat several metabolic related disorders i.e., hyperglycemia, hyperlipidemia, diabetes, obesity etc. Furthermore, traditionally it is used to treat fever, inflammation, ulcer, skin diseases, haemorrhoids, hypertension and also employed as cardioprotective, hepatoprotective, analgesic, diuretic. AIM OF THE STUDY: This study focuses to explore the therapeutic potential of Momordica dioica Roxb. ex Willd. through in-vitro and in-silico approach for managing hyperlipidemia, hyperglycemia and related metabolic disorders along with its phytochemical profiling for quality evaluation and validation of traditional claim. MATERIALS AND METHODS: The present study was carried out on hydroalcohol extract of dried leaf and fruit of Momordica dioica. In-vitro antioxidant potential using DPPH and Nitric oxide scavenging assay along with in-vitro enzyme inhibitory potential against α-amylase, α-glucosidase, and pancreatic lipase enzymes was studied. The bioactive metabolites were identified from the most potent bioactive extract by analysis with LC-QTOF-MS and also studied their role to lessen the metabolic related disorder through in-silico approaches. RESULTS: The results confirmed that the fruit extract is more active to possess antioxidant and prominent enzyme inhibition potential compared to the leaf. Sixteen identified metabolites in M. dioica Roxb. fruits may be responsible for the therapeutic potential related to metabolic related disorder. The in-silico study of the identified phytomolecules against α-amylase, α-glucosidase and pancreatic lipase showed significant docking scores ranging from -9.8 to -5.5, -8.3 to -4.8 and -8.3 to -6 respectively. CONCLUSION: The current study illustrated that M. dioica Roxb., a traditionally important plant is potential against metabolic related disorders. Phytocomponents present in the fruit extract may be responsible for antioxidant as well as the enzymes' inhibitory potential. Thus, fruits of M. dioica Roxb. will be useful as alternative therapeutics for treatment of hyperlipidemia, hyperglycemia and related metabolic disorders.

A novel chitosan-PEG hydrogel embedded with in situ silver nanoparticles of Clerodendrum glandulosum Lindl. extract: evaluation of its in vivo diabetic wound healing properties using an image-guided machine learning model.

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.

Comparative Analysis of Tenecteplase versus Alteplase in Acute Ischemic Stroke: A Multicentric Observational Study from Eastern India.

BACKGROUND: Tenecteplase is used as an alternative to alteplase and is considered noninferior for thrombolysis in acute ischemic stroke. OBJECTIVES: To compare the effectiveness and adverse effects of tenecteplase and alteplase in the real-world management of acute ischemic stroke. MATERIALS AND METHODS: In this retrospective observational study, we collected data from acute ischemic stroke patients admitted in six hospitals in West Bengal, India, and were thrombolysed with tenecteplase or alteplase between July 2021 and June 2022. Demographic data, baseline parameters, hospital course, and 3-month follow-up data were collected. The percentage of patients achieving a score of 0-2 in the modified Ranking scale at 3 months, rate of symptomatic intracranial hemorrhage, and all-cause mortality within 3 months were the main parameters of comparison between the two thrombolytic agents. RESULTS: A total of 162 patients were initially included in this study. Eight patients were excluded due to unavailability of follow-up data. Among the remaining patients, 71 patients received tenecteplase and 83 patients received alteplase. There was no statistically significant difference between tenecteplase and alteplase with respect to the percentage of patients achieving functional independence (modified Rankin scale score 0-2) at 3 months (53.5% vs. 60.2%, P = 0.706), rate of symptomatic intracranial hemorrhage (5.6% vs. 10.8%, P = 0.246), and all-cause mortality at 3 months (11.3% vs. 15.7%, P = 0.628). CONCLUSION: The effectiveness of tenecteplase is comparable to alteplase in the real-world management of acute ischemic stroke. Symptomatic intracranial hemorrhage and all-cause mortality rates are also similar in real-world practice.

Ayurvedic herbal formulations Haridra Khanda and Manjisthadi Kwath (brihat) in the management of allergic rhinitis: A pharmacological study.

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.