Livogrit prevents Amiodarone-induced toxicity in experimental model of human liver (HepG2) cells and Caenorhabditis elegans by regulating redox homeostasis.

Treatment with cationic amphiphilic drugs like Amiodarone leads to development of phospholipidosis, a type of lysosomal storage disorder characterized by excessive deposition of phospholipids. Such disorder in liver enhances accumulation of drugs and its metabolites, and dysregulates lipid profiles, which subsequently leads to hepatotoxicity. In the present study, we assessed pharmacological effects of herbal medicine, Livogrit, against hepatic phospholipidosis-induced toxicity. Human liver (HepG2) cells and in vivo model of Caenorhabditis elegans (N2 and CF1553 strains) were used to study effect of Livogrit on Amiodarone-induced phospholipidosis. In HepG2 cells, Livogrit treatment displayed enhanced uptake of acidic pH-based stains and reduced phospholipid accumulation, oxidative stress, AST, ALT, cholesterol levels, and gene expression of SCD-1 and LSS. Protein levels of LPLA2 were also normalized. Livogrit treatment restored Pgp functionality which led to decreased cellular accumulation of Amiodarone as observed by UHPLC analysis. In C. elegans, Livogrit prevented ROS generation, fat-6/7 gene overexpression, and lysosomal trapping of Amiodarone in N2 strain. SOD-3::GFP expression in CF1553 strain normalized by Livogrit treatment. Livogrit regulates phospholipidosis by regulation of redox homeostasis, phospholipid anabolism, and Pgp functionality hindered by lysosomal trapping of Amiodarone. Livogrit could be a potential therapeutic intervention for amelioration of drug-induced phospholipidosis and prevent hepatotoxicity.

Melanogrit potentiates melanogenesis by escalating cellular tyrosinase activity and MITF levels via pERK inhibition.

Vitiligo is characterized by the development of white patches on the skin either due to the loss of functional melanocytes or perturbations in the melanogenesis pathway. In the present study, we investigated the therapeutic potential of herbo-mineral formulation, Melanogrit in neutralizing the white patches in the skin. The study utilized UPLC/MS-QToF technique to determine the diversified phytochemical profile in Melanogrit. The murine B16F10 cells when treated with Melanogrit underwent morphological changes, including increased angularity, enlarged cell size, and greater dendritic protrusions. To establish an equivalent model to study melanogenesis, we carefully optimized the dosage of α-melanocyte stimulating hormone (αMSH) in B16F10 cells as an alternative to using melanocyte-keratinocyte cocultures. The study determined a sub-optimal dose of αMSH (0.2 nM) in B16F10 cells that does not manifest any measurable effects on melanogenesis. In contrast, Melanogrit when used in conjunction with 0.2 nM αMSH, induced a dose-dependent increase in extracellular and intracellular melanin levels. Melanogrit transcriptionally up-regulated the decisive genes of the melanogenesis pathway, MITF, TYR, and TRP1, which was evident from the increased cellular tyrosine activity. Our findings also demonstrated that Melanogrit ameliorated the MITF protein levels by inhibiting pERK; notably without involving GSK3ß in the process. Taken together, our findings strongly suggest that Melanogrit has the potential to stimulate melanogenesis, making it a promising candidate for clinical applications in the treatment of white skin patches that develop in vitiligo patients.

Renogrit attenuates Vancomycin-induced nephrotoxicity in human renal spheroids and in Sprague-Dawley rats by regulating kidney injury biomarkers and creatinine/urea clearance.

Vancomycin, is widely used against methicillin-resistant bacterial infections. However, Vancomycin accumulation causes nephrotoxicity which leads to an impairment in the filtration mechanisms of kidney. Traditional herbal medicines hold potential for treatment of drug-induced nephrotoxicity. Herein, we investigated protective properties of plant-based medicine Renogrit against Vancomycin-induced kidney injury. Phytometabolite analysis of Renogrit was performed by UHPLC. Spheroids formed from human proximal tubular cell (HK-2) were used for in vitro evaluation of Vancomycin-induced alterations in cell viability, P-gp functionality, NAG, KIM-1 levels, and mRNA expression of NGAL and MMP-7. The in vivo efficacy of Renogrit against Vancomycin-induced nephrotoxicity was further evaluated in Sprague-Dawley (SD) rats by measurement of BUN, serum creatinine, and their respective clearances. Moreover, eGFR, kidney-to-body weight ratio, GSH/GSSG ratio, KIM-1, NAG levels and mRNA expression of KIM-1 and osteopontin were also analyzed. Changes in histopathology of kidney and hematological parameters were also observed. Renogrit treatment led to an increase in cell viability, normalization of P-gp functionality, decrease in levels of NAG, KIM-1, and reduction in mRNA expression of NGAL and MMP-7. In Vancomycin-challenged SD rats, Renogrit treatment normalized altered kidney functions, histological, and hematological parameters. Our findings revealed that Renogrit holds a clinico-therapeutic potential for alleviating Vancomycin-associated nephrotoxicity.

Divya-WeightGo combined with moderate aerobic exercise remediates adiposopathy, insulin resistance, serum biomarkers, and hepatic lipid accumulation in high-fat diet-induced obese mice.

Obesity has become an unprecedented epidemic worldwide owing to a prolonged imbalance between energy intake and expenditure. Available therapies primarily suppress energy intake but often fail to produce sustained fat loss, necessitating a more efficacious strategy to combat obesity. In this study, a polyherbal formulation, Divya-WeightGo (DWG) has been investigated for its anti-obesity activity using in-vitro and in-vivo assays. Ultra-high performance liquid chromatography (UHPLC) analysis revealed the presence of phytocompounds including gallic acid, methyl gallate, corilagin, ellagic acid, pentagalloyl glucose, withaferin A and hydroxycitric acid, proven to aid in weight loss. The exposure of 3T3-L1 cells to DWG at cytosafe concentrations inhibited lipid and triglyceride accumulation and downregulated the expression of several adipogenic and lipogenic markers like PPARy, C/EBPα, C/EBPß, SREBP-1c, FASN and DGAT1. DWG reduced LPS-induced pro-inflammatory cytokine release and NF-κB activity in THP-1 cells. The in-vivo anti-obesity activity of DWG, both alone and in combination with moderate aerobic exercise, was assessed in a high fat diet-induced obese mouse model. DWG mitigated the obesity associated increased body weight gain, feed efficiency ratio, glucose intolerance, diminished insulin sensitivity, dyslipidemia, altered liver function profile, lipid accumulation and adiposopathy in obese mice, alone as well as in combination intervention, with better efficacy in the combination approach. Thus, the findings of this study suggest that DWG could be a promising therapeutic avenue to treat obesity through attenuation of lipid and fat accumulation in liver and adipose tissues and could be utilized as an adjunct with lifestyle interventions to combat obesity and associated complications.

Wintertime aerosol properties of urban desert region of western India: Implications in regional climate assessment.

This study assessed the inter-relation between physiochemical and optical characteristics of aerosols measured at a desert-urban region affected by anthropogenic sources and desert dust during October 2020 to January 2021. Based on horizontal visibility and measured PM2.5 concentration, clear (37 %), light (33 %) and high (31 %) pollution periods were identified. Elemental and organic carbon (50 ± 15 µgm-3; 31 %) and secondary inorganics (53 ± 21 µgm-3; 33 %) dominated the PM2.5 mass (160 ± 4 µgm-3) during high pollution period with low dust (14 ± 7 µgm-3; 8 %) content. Interestingly, the clear pollution period was also influenced by carbonaceous fraction (19 ± 8 µgm-3; 32 %) and secondary inorganics (19 ± 5 µgm-3; 32 %), but the PM2.5 concentrations (59 ± 9 µgm-3) were ∼ one-third as compared to high pollution period. High scattering coefficients were observed which were comparable to highly polluted Indian city like Delhi. An exponential increase in non-absorbing material was observed and showed clear influence on light absorption capacity of EC and dust due to coating/mixing. High absorption Ångström exponent (AAE) >0.6 was observed for the ratio of non-absorbing to light absorbing components (LAC) in the range of 1-2.5 and EC/PM2.5 fraction of 7-14 %. While further increase in non-absorbing to absorbing components ratio > 4 and low amount of EC (<4 %) tend to decrease AAE below 0.4. Higher mass absorption cross-section (>30 m2g-1 of EC) was observed when 4-10 % EC fraction of PM2.5 associated with 1.5-3.5 times non-absorbing components to total absorbing components. Likewise, absorption enhanced by three to five folds compared to uncoated EC for low EC fraction (3-6 %) in PM2.5, but high non-absorbing to absorbing component ratio (>2.5). Interestingly, absorption was minimally amplified for nominal coating fraction associated with significant core materials or vice-versa. These findings have implications not only in regional climate assessment but also for other regions with comparable geography and source-mixes.

Anti-oxidant response of lipidom modulates lipid metabolism in Caenorhabditis elegans and in OxLDL-induced human macrophages by tuning inflammatory mediators.

Atherosclerosis is the main pathological process of several cardiovascular diseases. It may begin early in life and stay latent and asymptomatic for an extended period before its clinical manifestation. The formation of foamy macrophages due to dysregulated lipid metabolism is a key event in the development and progression of atherosclerotic plaque. The current pharmacotherapy for atherosclerosis is not able to address multiple aetiologies associated with the disease. Lipidom, an herbal prescription medicine, has anti-oxidant, lipid lowering and anti-inflammatory properties that lead to multifaceted treatment benefits against chronic inflammation, dyslipidaemia, and oxidative stress. The present study aimed to characterize the pharmacological effects of Lipidom using various experimental models. The phytochemical analysis of Lipidom was performed on ultra-high performance liquid chromatography (UHPLC) platform. Lipidom was evaluated for cytosafety, IL-1ß and MCP-1 release, modulation of NLRP3 pathway, NFκB activity, ROS generation, lipid accumulation and gene expression in THP1 macrophages. Furthermore, Lipidom evaluation was also performed in the N2, CF1553, and TJ356 strains of Caenorhabditis elegans (C. elegans). The evaluation of brood size, adult (%), lipid accumulation, triglyceride levels, SOD-3 GFP signal, MDA formation, DAF-16 nuclear translocation, and gene expression was performed in C. elegans. Lipidom treatment significantly reduced the inflammatory mediators, lipid accumulation, oxidative stress, and normalized genes involved in the development of foamy macrophages. Lipidom treated C. elegans showed a significant decline in lipid accumulation and oxidative stress. Taken together, Lipidom treatment showed a multifaceted approach in the modulation of several mediators responsible for the development and progression of atherosclerotic plaque.

Anu Taila, an herbal nasal-drop, delays spore germination in Cunninghamella bertholletiae by reducing cAMP-PKA dependent ROS in mucorale pathogen and extrinsic ROS in human host cells.

The rare, fastest-germinating, frequently invasive mucorale, Cunninghamella bertholletiae, is intractable due to its imprecise etiology. Cunninghamella bertholletiae spores can infect both immunocompromised and immunocompetent individuals to cause mucormycosis. Sub-optimal drug-susceptibility further limits its treatment options. The classical nasal drop, Anu Taila, is reported to be effective against the rather prevalent mucorales, Mucor spp., making its anti-mucormycotic effect against C. bertholletiae worth testing. The inhibitory effect of Anu Taila against C. bertholletiae was manifested as microstructural alterations of the spores and their delayed germination. Anu Taila reduced the germination-promoting reactive oxygen species (ROS) levels in both the pathogen, C. bertholletiae, and the human host lung epithelial A549 cells. Expressions of structural (chitin synthase, trehalose synthase) and functional (cAMP-PKA) markers of spore germination were regulated by Anu Taila. cAMP-PKA expression and ROS generation are well-correlated, implicating the role of Anu Taila in delaying C. bertholletiae spore germination by targeting cAMP-PKA-mediated ROS generation. In conclusion, this study demonstrates that Anu Taila can create an opportunity for the host immune system to tackle the onset of C. bertholletiae infection by delaying its pathogenesis. This can be further leveraged to reinforce the host immune system through combinatorial treatment to prevent the establishment of the mucormycosis infection.

Anti-hyperglycemic contours of Madhugrit are robustly translated in the Caenorhabditis elegans model of lipid accumulation by regulating oxidative stress and inflammatory response.

Background: The prevalence of diabetes has considerably increased in recent years. In the long run, use of dual therapy of anti-diabetic agents becomes mandatory to attain euglycemia. Also, the incidences of diabetes-related co-morbidities have warranted the search for new therapeutic approaches for the management of the disease. Traditional herbo-mineral, anti-diabetic agents like Madhugrit are often prescribed to mitigate diabetes and related complications. The present study aimed to thoroughly characterize the pharmacological applications of Madhugrit. Methods: Phytometabolite characterization of Madhugrit was performed by ultra-high performance liquid chromatography. Evaluation of cell viability, α-amylase inhibition, glucose uptake, inflammation, and wound healing was performed by in vitro model systems using AR42J, L6, THP1, HaCaT cells, and reporter cell lines namely NF-κB, TNF-α, and IL-1ß. The formation of advanced glycation end products was determined by cell-free assay. In addition, the therapeutic potential of Madhugrit was also analyzed in the in vivo Caenorhabditis elegans model system. Parameters like brood size, % curling, glucose and triglyceride accumulation, lipid deposition, ROS generation, and lipid peroxidation were determined under hyperglycemic conditions induced by the addition of supraphysiological glucose levels. Results: Madhugrit treatment significantly reduced the α-amylase release, enhanced glucose uptake, decreased AGEs formation, reduced differentiation of monocyte to macrophage, lowered the pro-inflammatory cytokine release, and enhanced wound healing in the in vitro hyperglycemic (glucose; 25 mM) conditions. In C. elegans stimulated with 100 mM glucose, Madhugrit (30 µg/ml) treatment normalized brood size, reduced curling behavior, decreased accumulation of glucose, triglycerides, and lowered oxidative stress. Conclusions: Madhugrit showed multimodal approaches in combating hyperglycemia and related complications due to the presence of anti-diabetic, anti-inflammatory, anti-oxidant, wound healing, and lipid-lowering phytoconstituents in its arsenal. The study warrants the translational use of Madhugrit as an effective medicine for diabetes and associated co-morbidities.

Herbo-mineral formulation, Divya-Swasari-Vati averts SARS-CoV-2 pseudovirus entry into human alveolar epithelial cells by interfering with spike protein-ACE 2 interaction and IL-6/TNF-α /NF-κB signaling.

The herbo-mineral formulation, Divya-Swasari-Vati (DSV), is a well-known Ayurvedic medication for respiratory ailments. In a recent pre-clinical study, DSV rescued humanized zebrafish from SARS-CoV-2 S-protein-induced pathologies. This merited for an independent evaluation of DSV as a SARS-CoV-2 entry inhibitor in the human host cell and its effectiveness in ameliorating associated cytokine production. The ELISA-based protein-protein interaction study showed that DSV inhibited the interactions of recombinant human ACE 2 with three different variants of S proteins, namely, Smut 1 (the first reported variant), Smut 2 (W436R variant) and Smut 3 (D614G variant). Entry of recombinant vesicular stomatitis SARS-CoV-2 (VSVppSARS-2S) pseudovirus, having firefly luciferase and EGFP reporters, was assessed through luciferase assay and fluorescent microscopy. DSV exhibited dose-dependent inhibition of VSVppSARS-2S pseudovirus entry into human lung epithelial A549 cells and also suppressed elevated levels of secreted pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) induced by viral infection mimicking Poly I:C-, S-protein- and VSVppSARS-2S pseudovirus. In human immune cells, DSV also moderated TNF-α-mediated NF-κB induction, in a dose-dependent manner. The observed anti-viral effect of DSV against SARS-CoV-2 is attributable to the presence of different metabolites Summarily, the observations from this study biochemically demonstrated that DSV interfered with the interaction between SARS-CoV-2 S-protein and human ACE 2 receptor which consequently, inhibited viral entry into the host cells and concomitant induction of inflammatory response.

Livogrit Prevents Methionine-Cystine Deficiency Induced Nonalcoholic Steatohepatitis by Modulation of Steatosis and Oxidative Stress in Human Hepatocyte-Derived Spheroid and in Primary Rat Hepatocytes.

The prevalence of nonalcoholic steatohepatitis (NASH), characterized by fatty liver, oxidative injury, and inflammation, has considerably increased in the recent years. Due to the complexity of NASH pathogenesis, compounds which can target different mechanisms and stages of NASH development are required. A robust screening model with translational capability is also required to develop therapies targeting NASH. In this study, we used HepG2 spheroids and rat primary hepatocytes to evaluate the potency of Livogrit, a tri-herbal Ayurvedic prescription medicine, as a hepatoprotective agent. NASH was developed in the cells via methionine and cystine-deficient cell culture media. Livogrit at concentration of 30 µg/mL was able to prevent NASH development by decreasing lipid accumulation, ROS production, AST release, NFκB activation and increasing lipolysis, GSH (reduced glutathione), and mitochondrial membrane potential. This study suggests that Livogrit might reduce the lipotoxicity-mediated ROS generation and subsequent production of inflammatory mediators as evident from the increased gene expression of FXR, FGF21, CHOP, CXCL5, and their normalization due to Livogrit treatment. Taken together, Livogrit showed the potential as a multimodal therapeutic formulation capable of attenuating the development of NASH. Our study highlights the potential of Livogrit as a hepatoprotective agent with translational possibilities.

Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.

BACKGROUND: The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis. METHODS: We generated myeloid cell-specific PKM2-/- mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2mye-KOLdlr-/-). Controls were littermate PKM2WTLdlr-/- mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high-fat Western diet for 14 weeks, starting at 8 weeks. RESULTS: PKM2 was upregulated in macrophages of Ldlr-/- mice fed a high-fat Western diet compared with chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2-/- mice associated with decreased MCP-1 (monocyte chemoattractant protein 1) levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2-/- mice fed the Western diet exhibited reduced expression of proinflammatory genes, including MCP-1, IL (interleukin)-1ß, and IL-12. Myeloid cell-specific PKM2-/- mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP (LDLR-related protein)-1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP-1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr-/- mice. CONCLUSIONS: Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.

Anu taila, an herbal nasal drop, suppresses mucormycosis by regulating host TNF-α response and fungal ergosterol biosynthesis.

AIM: The intractable, mucormycosis, caused by Mucorales primarily targets immunocompromised individuals. The first-line therapy, intravenous liposomal amphotericin B and surgical debridement of necrotic tissue, is contraindicative in individuals with compromised kidneys. This invokes a pressing need to identify safer treatment options. METHODS AND RESULTS: The antifungal effect of the classical nasal drop, Anu taila, against Mucor spp. was investigated through microbiological, cytological, analytical chemical (HPLC and GS-MS/MS) and scanning electron microscopic (SEM) approaches. Anu taila-pretreated spores germinated late, resulting in reduced infectivity, observed as milder monocytic immune response. Conversely, Anu taila-pretreated human THP-1 cells exhibited an improved immune response against Mucor spores, through TNF-α. Repeated Anu taila application rapidly abolished fungal microarchitectures than amphotericin B, evident from swift replacement of hyphae, sporangiophores and sporangia with fused biomass, in the SEM images. HPLC analysis showed that Anu taila treatment significantly reduced overall ergosterol content in Mucor biomass. Anu taila also downregulated sterol-C5-desaturase-coding ERG3 gene, crucial for ergosterol biosynthesis and resultant structural integrity, in Mucor spp. CONCLUSION: Taken together, Anu taila was found effective against Mucor spp., with both prophylactic and curative implications, which is attributable to the phytochemical composition of this classical nasal drop. SIGNIFICANCE AND IMPACT STATEMENT: The potential remedial effects of a classical nasal drop against an obdurate and challenging fungal infection are identified.

Enteric-Coated Cologrit Tablet Exhibit Robust Anti-Inflammatory Response in Ulcerative Colitis-like In-Vitro Models by Attuning NFκB-Centric Signaling Axis.

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the patients' colorectal area culminating in an inflamed 'leaky gut.' The majority of UC treatments only provide temporary respite leading to its relapse. Therefore, this study investigated the efficacy of the enteric-coated 'Cologrit' (EC) tablet in alleviating UC-like inflammation. Cologrit is formulated using polyherbal extracts that have anti-inflammatory qualities according to ancient Ayurveda scriptures. Phytochemical profiling revealed the presence of gallic acid, rutin, ellagic acid, and imperatorin in Cologrit formulation. Cologrit treatment decreased inflammation in LPS-induced transformed THP-1 macrophages, and TNF-α-stimulated human colorectal (HT-29) cells through the modulation of NFκB activity, IL-6 production, and NFκB, IL-1ß, IL-8, and CXCL5 mRNA expression levels. Cologrit also lessened human monocytic (U937) cell adhesion to HT29 cells. Methacrylic acid-ethylacrylate copolymer-coating of the enteric Cologrit tablets (EC) supported their dissolution, and the release of phytochemicals in the small intestine pH 7.0 environment in a simulated gastrointestinal digestion model. Small intestine EC digestae effectively abridged dextran sodium sulfate (2.5% w/v)-induced cell viability loss and oxidative stress in human colon epithelial Caco-2 cells. In conclusion, the enteric-coated Cologrit tablets demonstrated good small intestine-specific phytochemical delivery capability, and decreased UC-like inflammation, and oxidative stress through the regulation of TNF-α/NFκB/IL6 signaling axis.

Chyawanprash, An Ancient Indian Ayurvedic Medicinal Food, Regulates Immune Response in Zebrafish Model of Inflammation by Moderating Inflammatory Biomarkers.

The time-tested Ayurvedic medicinal food, Chyawanprash, has been a part of the Indian diet since ancient times. It is an extremely concentrated mixture of extracts from medicinal herbs and processed minerals, known for its immunity boosting, rejuvenating, and anti-oxidative effects. In this study, we have evaluated the anti-inflammatory potential of Patanjali Special Chyawanprash (PSCP) using the zebrafish model of inflammation. Zebrafish were fed on PSCP-infused pellets at stipulated doses for 13 days before inducing inflammation through lipopolysaccharide (LPS) injection. The test subjects were monitored for inflammatory pathologies like behavioral fever, hyperventilation, skin hemorrhage, locomotory agility, and morphological anomaly. PSCP exerted a strong prophylactic effect on the zebrafish that efficiently protected them from inflammatory manifestations at a human equivalent dose. Expression levels of pro-inflammatory cytokines, like interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1ß), were also reduced in the LPS-stimulated zebrafish fed on PSCP-infused pellets. Skin hemorrhage, hyperventilation, and loss of caudal fins are characteristics of LPS-induced inflammation in zebrafish. PSCP prophylactically ameliorated skin hemorrhage, restored normal respiration, and prevented loss of caudal fin in inflamed zebrafish. Under in vitro conditions, PSCP reduced IL-6 and TNF-α secretion by THP-1 macrophages in a dose-dependent manner by targeting NF-κB signaling, as evident from the secreted embryonic alkaline phosphatase (SEAP) reporter assay. These medicinal benefits of PSCP can be attributed to its constitutional bioactive components. Taken together, these observations provide in vivo validation of the anti-inflammatory property and in vitro insight into the mode-of-action of Chyawanprash, a traditionally described medicinal food.

Assessment of PM10 and PM2.5 over Ghaziabad, an industrial city in the Indo-Gangetic Plain: spatio-temporal variability and associated health effects.

This study examined the PM10 and PM2.5 concentration, associated mortality, and transport pathways in Ghaziabad which is an industrial city in the Indo-Gangetic Plain. To achieve this, PM (both PM10 and PM2.5) and meteorological parameters were measured from June 2018 to May 2019 at 2 locations and analyzed together with data from a 3rd location in Ghaziabad. The highest daily average PM10 and PM2.5 concentrations were ~ 1000 µg m-3 and ~ 450 µg m-3, respectively. At each of the three locations, the annual mean PM10 concentrations were ~ 260 ± 150 µg m-3 while the PM2.5 concentrations were 140 ± 90 µg m-3. Nonparametric Spearman rank correlation analysis between meteorological parameters and PM concentrations indicated that ventilation coefficient was anti-correlated with PM concentration during the post-monsoon and winter seasons (the most polluted seasons) with rank correlation values of approximately - 0.50. Multiple linear regression (MLR) revealed that the variability in local meteorological parameters account for ~ 50% variability (maximum) in PM10 mass during the monsoon and PM2.5 during the post-monsoon season. For long-range sources, cluster and concentrated weighted trajectory (CWT) analyses utilizing regional meteorology showed the impact of transported PM from sources in Arabian sea through western India in monsoon and from parts of South Asia through Northwestern IGP and neighboring cities in Uttar Pradesh in other seasons. Finally, mortality estimates show that the number of deaths attributable to ambient PM2.5 in Ghaziabad were ~ 873 per million individuals which was ~ 70% higher than Delhi.

Integrin α9 regulates smooth muscle cell phenotype switching and vascular remodeling.

Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3ß, and nuclear ß-catenin, with reduced transcriptional activation of ß-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.

DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways.

Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs.