Role of mesenchymal stem cells and short chain fatty acids in allergy: A prophylactic therapy for future.

Allergic diseases are broadly classified as IgE-mediated type-I hypersensitivity immune reactions due to exposure to typically harmless substances known as allergens. These allergenic substances activate antigen presenting cells, which further triggers T-helper 2 cells immune response and class switch B-cells for synthesis of allergen-specific IgE, followed by classical activation of inflammatory mast cells and eosinophils, which releases preformed mediators involved in the cascade of allergic symptoms. However, the role of Mesenchymal stem cells (MSCs) in tissue repair ability and immunomodulation, makes them as an appropriate tool for treatment of various allergic diseases. Several clinical and preclinical studies show that MSCs could be a promising alternative therapy to allergic diseases. Further, short chain fatty acids, produced from gut microbes by breaking down complex fibre-rich foods, acts through G-coupled receptor mediated activation of MSCs, and their role as key players involved in amelioration of allergic inflammation needs further investigation. Therefore, there is a need for understating the role of SCFAs on the activation of MSCs, which might shed light on the development of new therapeutic regime in allergy treatment. In summary, this review focuses on the underlying of therapeutic role of MSCs in different allergic diseases and the prospects of SCFA and MSC therapy.

Drug utilization evaluation of pantoprazole in Kempegowda Institute of Medical Sciences (KIMS) hospital and research centre, India.

Objective: To evaluate the rational use of Pantoprazole by analyzing the appropriateness of prescription. Methodology: This cross-sectional study was performed within four months in 150 patients hospitalized in Kempegowda Institute of Medical Sciences Hospital and Research Centre, India. Demographic data, type and doses of Pantoprazole, including risk factors, and other relevant clinical data were recorded. Result: Out of 150 prescriptions prescribed with Pantoprazole 102 prescriptions were prescribed along with Non-steroidal anti-inflammatory drugs (NSAIDs) and 90 prescriptions were prescribed along with antibiotics. The majority (78.7%) of the patients were endorsed with Pantoprazole. Following national institute for health and care excellence (NICE) rules, fitting utilization of protein pump inhibitors (PPIs) was found in 64% whereas it was unseemly to use in 36% of cases. A large portion of the potential medication sedate associations was moderate. Characterized everyday dose/100-bed day of PPIs was seen as 0.929. Rabeprazole (20 mg, tablet) demonstrated the most extreme rate value variety of 672.32% while Pantoprazole (40 mg, infusion) indicated a base rate value variety of 18.72%. Conclusion: Prevalence of dosage shows that Pantoprazole was prescribed more for males in the age group of 60-70 years with the significant risk factor of smoker (18%) and alcoholic (9.3%). Among 150 prescriptions, 22.67% of prescriptions were irrationally prescribed. PPIs should be used only when there is documented evidence and when their use is clinically justified so that the appropriate prescription of PPIs will decrease the social insurance weight of the patient.

Investigation of Antifungal Properties of Synthetic Dimethyl-4-Bromo-1-(Substituted Benzoyl) Pyrrolo[1,2-a] Quinoline-2,3-Dicarboxylates Analogues: Molecular Docking Studies and Conceptual DFT-Based Chemical Reactivity Descriptors and Pharmacokinetics Evaluation.

Candida albicans, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein ß-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19.

Coronavirus disease-19 (COVID-19), a devastating respiratory illness caused by SARS-associated coronavirus-2 (SARS-CoV-2), has already affected over 64 million people and caused 1.48 million deaths, just 12 months from the first diagnosis. COVID-19 patients develop serious complications, including severe pneumonia, acute respiratory distress syndrome (ARDS), and or multiorgan failure due to exaggerated host immune response following infection. Currently, drugs that were effective against SARS-CoV are being repurposed for SARS-CoV-2. During this public health emergency, food nutraceuticals could be promising prophylactic therapeutics for COVID-19. Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.

Prevention of pesticide-induced neuronal dysfunction and mortality with nucleophilic poly-Oxime topical gel.

Organophosphate-based pesticides inhibit acetylcholinesterase (AChE), which plays a pivotal role in neuromuscular function. While spraying in the field, farmworkers get exposed to pesticides through the dermal route. Internalized pesticide inhibits AChE, which leads to neurotoxicity, cardiotoxicity, cognitive dysfunction, loss of endurance, and death in severe cases. Here, we present a nucleophilic pyridine-2-aldoxime-functionalized chitosan-based topical gel (poly-Oxime gel) that rapidly deactivates organophosphates, methyl parathion (MPT), on the skin of rats, which leads to reduced AChE inhibition in the blood and tissues. Testing the robustness of poly-Oxime gel, we report reduction in AChE inhibition following repeated dermal administration of MPT in the presence of poly-Oxime gel. Furthermore, poly-Oxime gel prevented MPT-induced neuromuscular dysfunction, loss of endurance, and locomotor coordination. We observe a 100% survival in rats following topical MPT administration in the presence of poly-Oxime gel. This prophylactic gel may therefore help farmworkers by limiting pesticide-induced toxicity and mortality.

Laser-facilitated epicutaneous immunotherapy to IgE-mediated allergy.

Allergen specific immunotherapy has been shown to be the only effective treatment for long-lasting clinical benefit to IgE-mediated allergic diseases, but a fewer than 5% of patients choose the treatment because of inconvenience and a high risk of anaphylaxis. Recently, epicutaneous allergen-specific immunotherapy (EPIT) has proven effective, yet with limitations owing to strong skin reactions. We demonstrate here safer and faster EPIT, named µEPIT, by delivering powdered allergen and adjuvants into many micropores in the epidermis. We fabricated a microarray patch fractionally coated with a powder mixture of ovalbumin (OVA) model allergen, CpG, and 1,25-dihydroxyvitamin D3 (VD3). Topical application of the patch onto laser-microperforated skin resulted in a high level of epidermal delivery while greatly minimizing allergen leakage into circulation system as compared to current subcutaneous immunotherapy (SCIT). Moreover, only three times of µEPIT over two weeks could sufficiently inhibit allergen-specific IgE responses in mice suffering OVA-induced airway hyperresponsivness (AHR), which was unattainable by eight times of SCIT over three weeks. Mechanistically, µEPIT preferably enhanced IgG2a production suggesting TH1-biased immune responses and induced a high level of T-regulatory (Treg) cells against repeated allergen sensitization. The immune tolerance was confirmed by marked reduction in airway wall thickness as well as eosinophil and neutrophil infiltration into the respiratory airway. The µEPIT represents a novel and painless technology to treat IgE-mediated allergic diseases with little local skin reaction and a minimal risk of anaphylaxis.

Bortezomib treatment diminishes hazelnut-induced intestinal anaphylaxis in mice.

Food allergy is a common health problem and can cause anaphylaxis. Avoidance of the offending food allergen is still the mainstay therapeutic approach. In this study, we investigated the role of plasma cell reduction by proteasome inhibition in a murine model of food allergy and examined the impact of this treatment on the systemic and local immune response. For this purpose, intestinal anaphylaxis was induced in BALB/c mice with the food allergen hazelnut, in conjunction with different adjuvants (alum and Staphylococcal enterotoxin B SEB) and different administration routes (oral and intraperitoneal). In both models, allergy symptoms were observed, but the clinical severity was more pronounced in the hazelnut-alum model than in the hazelnut-SEB model. Accordingly, allergen-specific immunoglobulin E (IgE) against hazelnut was detectable, and mast cell protease-1 in serum was increased after allergen provocation. Treatment with the proteasome inhibitor bortezomib reduced plasma cells and resulted in an abolishment of hazelnut allergen-specific IgE, which was associated with amelioration of clinical symptoms as well as a significant decrease in both CD19(+) and follicular B lymphocytes. Our data demonstrate the importance of allergen-specific IgE in food allergy and point to B cells as potential therapeutic targets for its treatment.

Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen-induced eczema model.

Proteasome inhibition (PI) has been reported to interfere with antibody-driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen-driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen-specific plasma cells/antibody-secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase-1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti-inflammatory effects are detectable in the skin, counter-regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.