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.

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.

Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market.

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.

ER stress induces upregulation of transcription factor Tbx20 and downstream Bmp2 signaling to promote cardiomyocyte survival.

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.

Anti-Hypertensive Activity of Some Selected Unani Formulations: An Evidence-Based Approach for Verification of Traditional Unani Claims Using LC-MS/MS for the Evaluation of Clinically Relevant Blood Parameters in Laboratory Rats.

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.

Quality Related Safety Evaluation of a South African Traditional Formulation (PHELA®) as Novel Anti-Biofilm Candidate.

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.

Nano-emulgel: Emerging as a Smarter Topical Lipidic Emulsion-based Nanocarrier for Skin Healthcare Applications.

BACKGROUND: In recent decades, enormous efforts for different drug discovery processes have led to a number of drug molecules available today to overcome different challenges of the health care system. Unfortunately, more than half of these drugs are listed in either BCS (biopharmaceutical classification system) class II/ IV or both are eliminated from the development pipeline due to their limited clinical use. A nanotechnological approach bears much hope and lipoidal fabrication is found to be suitable for the delivery of such drugs. Nanoemulsion based gel i.e. nanoemulgel out of different nanolipoidal formulations has been found to be a suitable approach to successful drug delivery through topical routes. In past few years many herbal and synthetic active pharmaceutical ingredients (APIs) has been patented as nano sized emulsified gel for various therapeutic activities. METHODS: Nanoemulgel is basically an emulsion-based topical gel formulation, where nanosized emulsion globules can be prepared with the help of high energy or low energy methods and further converted into nanoemulgel by adding a suitable gelling agent. Nanoemulgel fabrication enlists various kinds of polymeric materials, surfactants and fatty substances of natural, synthetic and semi-synthetic nature with a globule size range from 5 to 500 nm. RESULTS: Nanoemulgel can be applicable to various acute and chronic diseases through topical routes. CONCLUSION: Nanoemulgel preparations of many recently approved drugs are being used successfully in different areas of health care and have re-defined the significance of topical route of delivery as compared to other routes. However, along with various improvements in the current state of the delivery system, the safety factor needs to be taken into account by toxicological studies of the materials used in such formulations.