Identification of small molecule inhibitors against Lin28/let-7 to suppress tumor progression and its alleviation role in LIN28-dependent glucose metabolism.

The reciprocal suppression of an RNA-binding protein LIN28 (human abnormal cell lineage 28) and miRNA Let-7 (Lethal 7) is considered to have a prime role in hepatocellular carcinoma (HCC). Though targeting this inhibition interaction is effective for therapeutics, it causes other unfavorable effects on glucose metabolism and increased insulin resistance. Hence, this study aims to identify small molecules targeting Lin28/let-7 interaction along with additional potency to improve insulin sensitivity. Of 22,14,996 small molecules screened by high throughput virtual screening, 6 molecules, namely 41354, 1558, 12437, 23837, 15710, and 8319 were able to block the LIN28 interaction with let-7 and increase the insulin sensitivity via interacting with PPARγ (peroxisome proliferator-activated receptors γ). MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) analysis is used to re-score the binding affinity of docked complexes. Upon further analysis, it is also seen that these molecules have superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties and form stable complexes with the targets for a significant period in a biologically simulated environment (Molecular Dynamics simulation) for 100 ns. From our results, we hypothesize that these identified 6 small molecules can be potential candidates for HCC treatment and the glucose metabolic disorder caused by the HCC treatment.

Study the anticancer efficacy of doxorubicin-loaded redox-responsive chitosan-derived nanoparticles in the MDA-MB-231 cell line.

This study focuses on the design and evaluation of redox-responsive nanoparticles (NPs) by synthesizing disulfide-containing N-phthaloyl chitosan-SS-methoxy poly(ethylene glycol) (NPC-SS-mPEG) and incorporating the anti-cancer drug doxorubicin into the NPs. The structural features of NPC-SS-mPEG were investigated using FTIR, NMR, XRD, and TGA/DTA analysis. DLS and TEM analysis confirmed the particle size and morphology of the NPs. The stability of the NPs was measured with the presence and absence of glutathione (GSH) in buffers pH 5 and 7.4. Furthermore, the release of DOX from the NPs was studied in GSH (10 mM) containing/absent medium at pH 5 and pH 7.4 which mimics the intracellular environment with redox potential. The results indicated a significantly increased release of DOX in the GSH containing medium pH 5 (82.9 ± 2.1 %) and pH 7.4 (67.37 ± 0.88 %) compared to the GSH free pH 7.4 (29.99 ± 1.01 %) and pH 5 medium (56.56 ± 1.7 %) at 60 h. The cytotoxicity study in the MDA-MB-231 breast cancer cell line by MTT assay indicated higher toxicity of redox-responsive NPs to cancer cells than free DOX. In concurrence with the cytotoxicity assay, in-vitro fluorescence staining assays (AO/EB, Hoechst, ROS generation) also confirmed that NPs loaded with DOX induce higher toxicity to cancer cells than free DOX. Taken together, the overall results confirmed the superiority of the redox response-mediated release of DOX in effectively controlling cancer progression.

Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach.

As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and Mpro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with Mpro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for Mpro and RdRp.

Microbiome and the inflammatory pathway in peri-implant health and disease with an updated review on treatment strategies.

Crestal bone preservation around the dental implant for aesthetic and functional success is widely researched and documented over a decade. Several etiological factors were put forth for crestal bone loss; of which biofilm plays a major role. Biofilm is formed by the colonization of wide spectra of bacteria inhabited around dental implants. Bacterial adherence affects the regulators of bone growth and an early intervention preserves the peri-implant bone. Primary modes of therapy stated in early literature were either prevention or treatment of infection caused by biofilm. This narrative review overviews the microbiome during different stages of peri-implant health, the mechanism of bone destruction, and the expression of the biomarkers at each stage. Microbial contamination and the associated biomarkers varied depending on the stage of peri-implant infection. The comprehensive review helps in formulating a research plan, both in diagnostics and treatment aspects in improving peri-implant health.

Formulation, biopharmaceutical evaluation and in-vitro screening of polyherbal phytosomes for breast cancer therapy.

Saudi Arabia has a rich culture of folk medicines and three such common herbs used by Saudi people for therapy of breast cancer are Turmeric (Kurkum) Curcuma longa, Chamomile (Babunaj) Matricaria chamomilla, and Aswaghantha (Aswaghadh) Withania somnifera. Hence, the present study aims to develop a polyherbal phytosome formulation by thin film hydration technique with a synergistic anti-cancer effect for the treatment of breast cancer. The phytosomes were standardized for their phytoconstituents by HPTLC and showed the best optimal properties with a mean vesicle diameter of less than 200 nm, zeta potential in the range of -24.43 to -35.70 mV, and relatively integrated structure with fairly uniform size on TEM. The in vitro MTT assay on MCF-7 breast cancer cell lines and MDA MB 231 breast adenocarcinoma cell lines was carried out. MTT assay on MCF-7 breast cancer cell lines indicated that plant extract-loaded phytosomes exhibited enhanced cytotoxic effects at IC50 values. of 55, 50, 45, 52, 42, 44, and 20 µg/mL compared to the extracts of C. longa, M. chamomilla, W. somnifera, and their combined extracts (80, 82, 74, 60, 70, 60, and 35 µg/mL respectively). Moreover, intracellular reactive oxygen species production was found to be higher for phytosomes treated cells at respective IC50 concentrations when compared to extracts. Overall, the developed polyherbal phytosomes were found to be effective and afford synergistic effects for breast cancer therapy.

Current Drug Targeting using siRNA-based Nano Therapeutics for Pulmonary Diseases.

The importance of siRNA in nano drug delivery systems to target important pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and others, is reviewed in this perspective. The great majority of lung illnesses are caused by protein misfolding. As a result, siRNA-based therapies are increasingly being used to target the gene. Given the difficulties of delivering bare siRNA, siRNA protection may ensure its efficacy in gene therapy. These issues could be solved with a nano-based siRNA delivery systems. In this context, a siRNA-based nanocarrier for major pulmonary disorders has been explored.

Ziziphus mauritiana Lam attenuates inflammation via downregulating NFκB pathway in LPS-stimulated RAW 264.7 macrophages & OVA-induced airway inflammation in mice models.

ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphus mauritiana Lam leaves were utilized in treating asthma, diabetes, inflammation, and hepatic diseases in Indian traditional medicine. The leaves were used as an edible vegetables in rural parts of India. AIM OF THE STUDY: The aim is to prove the anti-inflammatory activity of Ziziphus mauritiana Lam leaves against LPS-stimulated RAW 264.7 macrophages and OVA-induced airway inflammation in mice through its attenuation mechanism in the NFκB signalling pathway. MATERIALS AND METHODS: Terpenoids present in MEZ were quantified using U(H)PLC analysis. MEZ at 50 and 100 µg/mL were tested against LPS stimulated RAW 264.7 macrophages. The concentration of NO, ROS, and cytokines was quantified from the cell culture supernatants. OVA-induced asthma in mice was adopted for screening airway inflammation. MEZ at 250 and 500 mg/kg was tested for airway hyperresponsiveness, leukocyte counting, pro-inflammatory cytokines (IL-4, IL-5, IL-13 and TNF-α), lung histopathology, and various inflammatory gene expressions in lungs for NFκB signalling pathway in asthma. RESULTS: Terpenoids like betulin, betulinic acid, oleanolic acid, and ursolic acid were quantified from U(H)PLC analysis. MEZ at higher doses reduced the NO, ROS, and pro-inflammatory cytokines in LPS stimulated RAW 264.7 macrophages. MEZ at 500 mg/kg significantly reduced AHR and also decreased total and differential leukocytes. MEZ also reduced the expressions of ICAM, VCAM, and Muc5C genes. Histopathological analysis revealed MEZ significantly reduced the leukocyte infiltration and mucus hypersecretion in the lungs. MEZ suppressed lung inflammation by inhibition of p65 mediated IκB-α translocation in the NFκB signalling pathway. CONCLUSION: From these findings, MEZ significantly reduced airway inflammation by inhibiting NFκB mediated inflammatory pathway. Hence, this study proved that Ziziphus mauritiana Lam has anti-asthmatic potential in Indian traditional medicine.

Biopolymers and Osmolytes - A Focus towards the Prospects of Stability and Adjuvanticity of Vaccines.

'New-Gen Vaccines' are grabbing the attention of scientists as they are much suitable for an immune-compromised group of individuals as well as infants. The major drawbacks of these vaccines are lower immunogenicity and instability. The need for a convenient and safe adjuvant is still under exploration. On the other hand, thermal instability leads to the inactivation of the vaccine and becomes detrimental in many cases. Thus, there is a need to incorporate new kinds of excipients into vaccine formulation to enhance the potency/immunogenicity of vaccine antigens and also act as stabilizers. A limited or single excipient in providing the required dual-activity is vital to break the stereotypical usage of the well-entrenched adverse ingredients. In the proposed review, the efficiency of naturally occurring biocompatible carbohydrate polymers and osmolytes and their 'dual-role' is briefed. In addition, the information on the possible mechanisms of action of carbohydrate polymers in vaccines as adjuvants and stabilizers are also discussed.

Guar gum based oral films for hypertensive urgencies.

Guar gum (GG) is a natural film forming biopolymer used as a drug delivery media for Telmisartan (TS). TS is a poorly water-soluble anti-hypertensive agent with low bioavailability.The present work has been hypothesized by converting TS into nanocrystals by high shear homogenisation to enhance the solubility thereby the bioavailability is expected to get enhanced. TS-NC-GG-OF was formulated by solvent casting method using GG by varying the disintegrant ratio.Telmisartan nanocrystals showed particle size of 441.70 ± 35.28 nm, surface charge of -20.86 ± 0.55 mV and reduced crystalline pattern. The amount of TS present per mg ofnanocrystals is 0.33 mg. The developed TS-NC-GG-OF was circular, creamy white colour with desired physicochemical properties. The in vitro release studies performed by beaker model showed an immediate release pattern.This proof of concept specifies that the TS-NC-GG-OF may be a better choice for hypertensive emergencies using the natural excipient Guar gum.

Standardization, in-silico and in-vivo safety assessment of methanol extract of Ziziphus mauritiana Lam leaves.

Ziziphus mauritana Lam leaves were used to treat asthma, diabetes, pain, and inflammation in the Indian traditional system of medicine. The leaves of the Ziziphus mauritiana Lam were consumed as a vegetable in Indonesia and India. The present study aims to predict the pharmacokinetic properties of flavonoids identified & quantified through U(H)PLC and to evaluate the safety of methanol extract of Ziziphus mauritana Lam leaves (MEZ) in rats. A U(H)PLC-ESI-QTOF-MS/MS was performed to identify flavonoids present in MEZ and quantified using U(H)PLC method. The in-silico ADME properties of the flavonoids were analyzed using Schrodinger Maestro software. The acute oral toxicity study was performed by administering a single dose of MEZ (5000 mg/kg) in female rats and observed for 14 days. The sub-chronic studies were carried out by oral administration of MEZ at 500, 750, and 1000 mg/kg daily for 90 days. The changes in hematological parameters, clinical biochemistry, and histopathology were observed after the treatment period. Eight flavonoids rutin, kaempferol, luteolin, myricetin, catechin, and apigenin were identified from were identified in UPLC-QTOF-MS/MS analysis. These results showed the highest amount of luteolin (5.41 µg/ml) and kaempferol (4.02 µg/ml) present in MEZ. No signs of toxicity or mortality were observed in acute toxicity studies. In the sub-chronic studies, data showed that MEZ does not produce any changes in hematological and clinical biochemical parameters compared to control rats. MEZ (1000 mg/kg) significantly (p < 0.05) reduced total cholesterol, triglycerides, in male rats, which was more prominent on day 90. The histopathological analysis also revealed no changes in the vital organs. These results conclude that MEZ was considered safe and well-tolerated in rats.

Determination of Conformational and Functional Stability of Potential Plague Vaccine Candidate in Formulation.

Generally, protein-based vaccines are available in liquid form and are highly susceptible to instability under elevated temperature changes including freezing conditions. There is a need to create a convenient formulation of protein/peptides that can be stored at ambient conditions without loss of activity or production of adverse effects. The efficiency of naturally occurring biocompatible polymer dextran in improving the shelf-life and biological activity of a highly thermally unstable plague vaccine candidate protein called Low Calcium Response V antigen (LcrV), which can be stored at room temperature (30 ± 2 °C), has been evaluated. To determine the preferential interactions with molecular-level insight into solvent-protein interactions, analytical techniques such asspectroscopy, particle size distribution, gel electrophoresis, microscopy, and thermal analysis have been performed along with the evaluation of humoral immune response, invivo. The analytical methods demonstrate the structural stability of the LcrV protein by expressing its interaction with the excipients in the formulation. The invivo studies elicited the biological activity of the formulated antigen with a significantly higher humoral immune response (p-value = 0.047) when compared to the native, adjuvanted antigen. We propose dextran as a potential biopolymer with its co-excipient sodium chloride (NaCl) to provide protein compactness, i.e., prevent protein unfolding by molecular crowding or masking mechanism using preferential hydrophobic interaction for up to three weeks at room temperature (30 ± 2 °C).

Recent Progress in Stimuli-Responsive Intelligent Nano Scale Drug Delivery Systems: A Special Focus Towards pH-Sensitive Systems.

Stimuli-responsive nanocarriers are gaining much attention due to their versatile multifunctional activities, including disease diagnosis and treatment. Recently, clinical applications of nano-drug delivery systems for cancer treatment pose a challenge due to their limited cellular uptake, low bioavailability, poor targetability, stability issues, and unfavourable pharmacokinetics. To overcome these issues, researchers are focussing on stimuli-responsive systems. Nanocarriers elicit their role through endogenous (pH, temperature, enzyme, and redox) or exogenous (temperature, light, magnetic field, ultrasound) stimulus. These systems were designed to overcome the shortcomings such as non-specificity and toxicity associated with the conventional drug delivery systems. The pH variation between healthy cells and tumor microenvironment creates a platform for the generation of pH-sensitive nano delivery systems. Herein, we propose to present an overview of various internal and external stimuli-responsive behavior-based drug delivery systems. Herein, the present review will focus specifically on the significance of various pH-responsive nanomaterials such as polymeric nanoparticles, nano micelles, inorganic-based pH-sensitive drug delivery carriers such as calcium phosphate nanoparticles, and carbon dots in cancer treatment. Moreover, this review elaborates the recent findings on pH-based stimuli-responsive drug delivery systems with special emphasis on our reported stimuli-responsive systems for cancer treatment.

Combinatorial analysis of quercetin and resveratrol by HPTLC in Sesbania grandiflora/phyto-based nanoformulations.

A sensitive HPTLC method was developed for the simultaneous estimation of quercetin (QUR) and resveratrol (RES). The chromatographic separation was achieved using mobile phase toluene:chloroform:ethyl acetate:formic acid (3:2:4.9:0.1% v/v) and densitometric scan performed at 280 nm. The developed method was linear at 2-10 µg/mL with correlation coefficient of 0.9907 (QUR) and 0.9917 (RES). The method was validated for its precision, specificity, detection and quantification limits and % RSD was found to be less than 4.0%. The developed HPTLC method was evaluated in QUR and RES-loaded nanoformulation and Sesbania grandiflora leaf extract. The amount of QUR and RES present in the SG leaf extract was found to be 26.13 ± 0.7 µg/mg and 4.31 ± 0.8 µg/mg, respectively. The pH-dependent stability of RES has checked using the developed method. The above-developed method can be used to check the QUR/RES content in herbal/pharmaceutical formulation with scope towards industries.

Solubility Enhancement of Methotrexate by Solid Nanodispersion Approach for the Improved Treatment of Small Cell Lung Carcinoma.

AIMS: The present work aimed to develop MT loaded solid Nano dispersion by improving its solubility, half-life and bioavailability in biological system thereby this formulation may be afforded economically. BACKGROUND: Small cell lung carcinoma is a type of malignant tumor characterized by uncontrolled cell growth at lung tissues. The potent anti-cancer drug methotrexate (MT) chosen for the present work is poorly soluble in water (BCS type IV class) with short half-life and hepatotoxic effect. OBJECTIVE: With the concept of polymeric surfactant to improve the solubility along with wettability of drugs, the present work has been hypothesized to improve its solubility using polyvinyl pyrollidone (PVP K30) polymer and α- tocopheryl polyethylene glycol 1000 succinate (TPGS) surfactant, thereby the bioavailability is expected to get enhanced. By varying the PVP K30 and TPGS ratios different formulations were developed using emulsification process. METHODS: The developed MT loaded solid nanodispersion was further characterized for its particle size, charge, morphology, encapsulation efficiency and in-vitro release behavior etc. Results: The results of FT-IR spectrometric analysis indicated the compatibility nature of MTX, PVPK30 and TPGS. The developed formulations showed spherical morphology, particle size ranging from 59.28±24.2 nm to 169.33±10.85 nm with a surface charge ranging from -10.33 ± 2.81mV to -9.57 ± 1.2 mV. The in vitro release studies as performed by dialysis bag method showed a sustained release pattern as checked by UV Spectrophotometer. Residual solvent analysis for MTXNDs performed by HPLC indicates there is no residual DMSO in the formulation. Transmission electron microscopic image of MTXNDs revealed that the particles are spherical shaped with a solid core structure. Haemolytic assay indicates that the developed formulation is safe for intravenous administration. Cell culture studies in A549 cells indicates the enhanced cytotoxic effect for the developed formulation. CONCLUSION: This proof of study indicates that the developed formulation may have anticancer potential for SCLC treatment.

Anti-platelet Drug-loaded Targeted Technologies for the Effective Treatment of Atherothrombosis.

Atherothrombosis results from direct interaction between atherosclerotic plaque and arterial thrombosis and is the most common type of cardiovascular disease. As a long term progressive disease, atherosclerosis frequently results in an acute atherothrombotic event through plaque rupture and platelet-rich thrombus formation. The pathophysiology of atherothrombosis involves cholesterol accumulation endothelial dysfunction, dyslipidemia, immuno-inflammatory, and apoptotic aspects. Platelet activation and aggregation is the major cause for stroke because of its roles, including thrombus, contributing to atherosclerotic plaque, and sealing off the bleeding vessel. Platelet aggregates are associated with arterial blood pressure and cardiovascular ischemic events. Under normal physiological conditions, when a blood vessel is damaged, the task of platelets within the circulation is to arrest the blood loss. Antiplatelet inhibits platelet function, thereby decreasing thrombus formation with complementary modes of action to prevent atherothrombosis. In the present scientific scenario, researchers throughout the world are focusing on the development of novel drug delivery systems to enhance patient's compliance. Immediate responding pharmaceutical formulations become an emerging trend in the pharmaceutical industries with better patient compliance. The proposed review provides details related to the molecular pathogenesis of atherothrombosis and recent novel formulation approaches to treat atherothrombosis with particular emphasis on commercial formulation and upcoming technologies.

In vivo synergistic anti-tumor effect of lumefantrine combined with pH responsive behavior of nano calcium phosphate based lipid nanoparticles on lung cancer.

Conventional treatment options for lung cancer treatment were restricted due to non-specific nature and side effects, with this associated problem and to overcome this we had developed lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF- CaP- Ls) affording pH sensitive mechanism. Herein, the present study the in vivo anti-cancer property of LF-CaP-Ls was checked in mice models. Further, reduced lung cancer progression of lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF-CaP-Ls) treated mice were assessed by measuring the 5-methyltetrahydrofolate (MTHF) in serum. Moreover, LF-CaP-Ls showed substantially a anticancer effect compared to that of lumefantrine loaded lipid nanoparticles (LF-Ls) and free lumefantrine (LF) by exhibiting higher effects in lung tumor bearing mice model as confirmed by reduced tumor progression. Histopathological examination of lungs supported with H&E staining proved the reduced tumor vasculature and reduced inflammatory cells for LF-CaP-Ls compared to that of free LF and LF-Ls. Further, visual inspection with acetic acid test confirmed the reduced tumor progression for LF-CaP-Ls compared to that of free LF and LF-Ls. Altogether, the overall results suggested that the developed LF-CaP-Ls may acts as a better therapeutic molecule for lung cancer due to its maintenance of increased level of 5-MTHF levels, reduced tumor weight. Further, hematological and biochemical parameters were measured and supports our in-vivo therapeutic effect of LF-CaP-Ls.

Aerosolized hyaluronic acid decorated, ferulic acid loaded chitosan nanoparticle: A promising asthma control strategy.

Vibrating mesh nebulizers are recognized as the most efficient actuation technique over conventional inhalers for drug deposition. This study explored hyaluronic acid (HA) decorated, ferulic acid (FA) loaded chitosan (CS) nanoparticle (FACHA) aerosolized using vibrating mesh nebulizer as strategic combination of drug, nanocarrier and delivery device for effective asthma control. FACHA exhibited spherical morphology with suitable size (164.2 ± 9.7 nm), zeta potential (24.0 ± 0.5 mV), entrapment efficiency (EE%) (65.0 ± 1.5), loading capacity (LC%) (18.5 ± 0.4) and mass median aerodynamic diameter (MMAD) of 1.81 ± 0.15 µm, ascertaining efficient drug deposition. In vivo inhalation toxicity assessment confirmed safety, while, FACHA prophylaxis mitigated inflammation, airway hypersensitivity and remodelling in ovalbumin (OVA) induced mice models. The results thus accentuated the role of pro-pulmonary surface chemistry conferred by HA functionalization that improved 1) thermal stability (thermogravimetric analysis - TGA) and 2) therapeutic efficacy of FA, by facilitating better interaction and transportation across mucus barrier, which otherwise suffers poor bioavailability and rapid metabolism.

Multi potent aromatic nano colloid: synthesis, characterization and applications.

In this study the aromatic nanocolloids (CANCs) are synthesized using the noble metal silver by using Citronella extract and confirmed through physio chemical analysis. The synthesised CANCs were evaluated for its antimicrobial activity and antibiofilm activity against pathogenic biofilm forming E. coli. In addition, synthesized CANCs were evaluated for the expression of virulent genes encoding AmpC and CTX-M-15. The results confirmed that CANCs showed effective antimicrobial activity through its bacteriostatic, bactericidal and quorum quencher activity and downregulated CTX-M-15 gene. CANCs were validated as alternate to the commercial fungicides to control plant pathogenic fungi such as A. niger MTCC (281), Fusarium graminearum MTCC (2089) and F. udum MTCC (2204). Furthermore, analysis of CANCs on breast cancer (MCF-7) cells under in vitro condition showed that the cytotoxicity of CANCs is dose dependent. Thus, the multifunctional CANCs can be utilized as potential antimicrobial, antifungal and anticancer agent.

Novel Nanocarriers for the Treatment of Wound Healing.

The sequence of biochemical and cellular responses restoring the integrity of the subcutaneous tissue of the skin is termed as wound healing. Inflammatory cytokine suppression and inflammatory transduction cascades are the major targets for wound healing. Formulations for wound healing should promote neovascularization and angiogenic pathways by increasing the expression of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor. Medication used for wound healing promotes antiinflammatory associated with anti-bacterial action. In order to boost the effectiveness of current medical treatments, the cutting-edge nanotechnology offers many novel therapies. This review summarized and discussed wound healing, types of wounds, natural materials used for wound healing, metallic nanoparticles and current nano drug delivery systems used for wound healing with special emphasis on the angiogenesis role in the healing of wounds.

Mechanistic investigation of PPARγ-facilitated anti-asthmatic effects of Galangin (Norizalpinin): Insights from in silico and in vivo analyses.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifaceted ligand-activated transcription factor that regulates inflammatory responses in asthma pathophysiology. The present study corroborates PPARγ-mediated anti-asthmatic action of the flavonoid, galangin (norizalpinin). In silico molecular interactions reveal that galangin formed three H-bonds (Glu291, Leu340 and Ser342) and a π-sigma bond (Arg288) with PPARγ, contributing to the binding affinity and stability of the complex. In vivo studies explore the role of galangin as a propitious PPARγ agonist in mitigating airway inflammation, thereby excluding ligand-independent action of PPARγ. Accordingly, oral administration of galangin significantly ameliorated airway hyperresponsiveness, inflammation and goblet cell hyperplasia by the suppression of IL-4, 5, 13, 17, TNF-α, NO, ROS, EPO, IgE and increase of IFN-γ in ovalbumin-induced allergic asthma model. PPARγ expression (mRNA and protein) studies were performed to elucidate a possible mechanism by which galangin modulates. Furthermore, to eliminate PPARγ-independent effects of galangin, a specific PPARγ antagonist (GW9662) was administered, which dramatically reversed the effects of galangin on PPARγ up-regulation, confirming the pleiotropic role of galangin as a PPARγ agonist in asthma therapeutics. Taken together, our findings communicate that PPARγ plays as a master regulator in the anti-asthmatic action of galangin.