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Mahaboobkhan Rasool

Bio: Mahaboobkhan Rasool is an academic researcher from VIT University. The author has contributed to research in topic(s): Arthritis & RANKL. The author has an hindex of 28, co-authored 88 publication(s) receiving 2297 citation(s). Previous affiliations of Mahaboobkhan Rasool include University of Madras & Management and Science University.
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Journal ArticleDOI
Abstract: Fibroblast-like synoviocytes (FLS) are the critical effector cells primarily involved in rheumatoid arthritis (RA) disease pathogenesis. Interleukin (IL)-6, a proinflammatory cytokine most abundantly expressed in the rheumatoid synovium, promotes Janus kinase (JAK)/signal transducer and transcriptional activator (STAT) signaling cascade activation in RA-FLS, thus leading to its aggressive phenotype, invasiveness, and joint destruction. Momelotinib (CYT387) is a selective small-molecule inhibitor of JAK1/2 and is clinically approved to treat myelofibrosis. However, the therapeutic efficacy of CYT387 in FLS mediated RA pathogenesis is less known. In the present study, we investigated the modulatory effect of CYT387 on IL6/JAK/STAT signaling cascade in FLS induced RA pathogenesis. CYT387 treatment inhibited IL-6 induced high proliferative and migratory potential of FLS cells isolated from adjuvant-induced arthritic (AA) rats. CYT387 reduced the expression of PRMT5, survivin, and HIF-1α mediated by IL-6/sIL-6R in AA-FLS in a dose-dependent manner. The IL-6/sIL-6R induced expression of angiogenic factors such as VEGF and PIGF in AA-FLS cells was found downregulated by CYT387 treatment. Importantly, CYT387 significantly reduced IL-6/sIL-6R dependent activation of JAK1 and STAT3 and increased SOCS3 expression in AA-FLS cells. Next, the S3I-201 mediated blockade of STAT3 activation supported the inhibitory effect of CYT387 on IL-6/JAK1/STAT3 signaling cascade in AA-FLS. Overall, this study proves that CYT387 inhibits proliferation, migration, and pathogenic disease potential of FLS isolated from adjuvant-induced arthritic (AA) rats via targeting IL-6/JAK1/STAT3 signaling cascade.

Journal ArticleDOI
TL;DR: The isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.
Abstract: While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B in vitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50 = 0.43 ± 0.11 and 0.54 ± 0.19 μM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30 mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.

3 citations

Journal ArticleDOI
17 Sep 2021
Abstract: Majoon Chobchini, a polyherbal Unani compound, has been used holistically in India to treat rheumatoid arthritis. However, the potential mechanism underlying the antiarthritic efficacy of Majoon Chobchini has not been elucidated so far. This study was aimed to explore the underlying molecular mechanism and scientifically validate the therapeutic basis of Majoon Chobchini in rheumatoid arthritis (RA). The anti-arthritic efficacy of Majoon Chobchini was demonstrated in vivo using complete Freund's adjuvant-induced arthritic rat model and adjuvant-induced arthritic fibroblast-like synoviocytes (AA-FLS). The expression of pro-inflammatory mediators and enzymes was evaluated in the serum and synovial tissues of adjuvant-induced arthritis (AIA) rats. In-vitro, AA-FLS, and bone marrow macrophages (BMMs) were co-cultured to evaluate the formation and activity of osteoclasts using TRAP staining analysis and pit formation assay, respectively. RANKL and OPG levels were detected using western blotting and qRT-PCR analysis. Furthermore, the involvement of JAK-STAT-3 signaling in the therapeutic efficacy of Majoon Chobchini was evaluated both in vivo and in vitro. Majoon Chobchini significantly reversed the physical symptoms in AIA rats with reduced expression of pro-inflammatory cytokines and enzymes. Notably, Majoon Chobchini alleviated cartilage degradation and bone erosion in AIA rats via inhibiting the activation of the JAK-STAT-3 signaling pathway in the AIA rats. Consistent with its effect in vivo, Majoon Chobchini decreased osteoclast inducing potential of AA-FLS and thus attenuated osteoclast formation and bone resorption in vitro. Taken together, our findings suggest that the JAK/STAT-3 signaling inhibition may underlie the mechanism through which Majoon Chobchini provides relief against RA symptoms.

Journal ArticleDOI
31 Mar 2021-Cytokine
Abstract: Interleukin (IL)-17A signaling pathway plays a critical role in the initiation and progression of rheumatoid arthritis (RA) and represents a viable target for RA therapy Cyanidin, a flavonoid compound, is a novel inhibitor of IL-17A/IL-17RA (receptor subunit A) interaction in several inflammatory diseases However, the therapeutic efficacy of cyanidin on IL-17A cytokine signaling induced monocyte migration and fibroblast-like synoviocytes (FLS) released RANKL mediated osteoclastogenesis in RA has not yet been deciphered In the present study, cyanidin impeded IL-17A induced migration of monocytes isolated from adjuvant-induced arthritic (AA) rats At the molecular level, cyanidin blocked the activation of p38MAPK signaling in response to IL-17A Importantly, cyanidin downregulated IL-17A induced expression of HSP27, CXCR4, and CCR7 in AA monocytes via modulating IL-17/p38 MAPK signaling axis Alternatively, cyanidin significantly suppressed the formation of matured osteoclasts and bone resorption in a coculture system consisting of IL-17 treated AA-FLS and rat bone marrow-derived monocytes/macrophages Further, cyanidin significantly inhibited the expression of RANKL and increased the expression of OPG in AA-FLS via blunted activation of IL-17A/STAT-3 signaling cascade Interestingly, cyanidin impaired IL-17A induced overexpression of IL-17RA Taken together, our study proposes a novel therapeutic function of cyanidin towards targeted inhibition of IL-17A/IL-17RA signaling mediated disease severity and bone erosion in RA

1 citations

Journal ArticleDOI
TL;DR: It is suggested that miR-532-3p attenuates the pro-inflammatory nature of macrophages by targeting ASK1/p38 MAPK signaling pathway and can be used as a molecular intervention for treating inflammatory diseases.
Abstract: Inflammation is a complex biological process which alters the normal physiological function of the immune system resulting in an abnormal microenvironment that leads to several clinical complications. The process of inflammation is mediated through various intracellular signaling factors inside the cells. Apoptosis signal–regulating kinase 1 (ASK1) is an inflammation-derived kinase that controls the activation of other family of kinases such as p38 mitogen–activated protein kinases (p38 MAPKs), which mediates various the inflammatory processes. In this study, we cultured THP-1 macrophage cells to undergo inflammatory proliferation with LPS (1 μg/ml) and TNFα (10 ng/ml) stimulation. Initial in silico analysis was utilized to predict novel microRNAs (miRNAs) that target ASK1 signaling and its expression levels in LPS and TNFα stimulated THP-1 cells were estimated. Among the miRNAs, miR-532-3p showcased the highest binding affinity towards ASK1 kinase. We witnessed that transient transfection of miR-532-3p diminished the levels of ASK1 and downstream phosphorylation/translocation of p38 MAPK. Furthermore, direct targeting of ASK1 resulted in regulation of uncontrolled release of cytokines (TNFα, IL-6, and IL-23) and chemokines (GM-CSF and MIP-2α). Overall, we suggest that miR-532-3p attenuates the pro-inflammatory nature of macrophages by targeting ASK1/p38 MAPK signaling pathway and can be used as a molecular intervention for treating inflammatory diseases.

1 citations

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Journal ArticleDOI
Abstract: Ethnopharmacological relevance The fruits of Phyllanthus emblica Linn or Emblica officinalis Gaertn (Phyllanthaceae), (FPE) commonly known as Indian gooseberry or Amla, gained immense importance in indigenous traditional medicinal systems, including Ayurveda, for its medicinal and nutritional benefits. It is used to cure several diseases such as common cold, fever, cough, asthma, bronchitis, diabetes, cephalalgia, ophthalmopathy, dyspepsia, colic, flatulence, hyperacidity, peptic ulcer, erysipelas, skin diseases, leprosy, hematogenesis, inflammation, anemia, emaciation, hepatopathy, jaundice, diarrhea, dysentery, hemorrhages, leucorrhea, menorrhagia, cardiac disorders, and premature greying of hair. Aim of the study In the present review, we presented a comprehensive analysis of the ethnopharmacology, bioactive composition, and toxicity of P. emblica to identify the gap between research and the current applications and to help explore the trends and perspectives for future studies. Materials and methods We collected the literature published before April 2021 on the phytochemistry, pharmacology, and toxicity of FPE. Literature in English from scientific databases such as PubMed, ScienceDirect, Wiley, Springer, and Google Scholar, books. These reports were analyzed and summarized to prepare this review. The plant taxonomy was verified by “The Plant List” database ( ). Results and conclusion s: FPE have been used as a rich source of vitamin C, minerals, and amino acids. Several bioactive molecules were isolated and identified from FPE such as tannins, flavonoids, saponins, terpenoids, alkaloids, ascorbic acid etc. The in vitro and in vivo pharmacological studies on FPE revealed its antimicrobial, antioxidant, anti-inflammatory, anti-diabetic, anticancer, radioprotective, hepatoprotective, immunomodulatory, hypolipidemic, anti-venom, wound healing, HIV-reverse transcriptase effect. Toxicological studies on fruits indicated the absence of any adverse effect even at a high dose after oral administration. Conclusions Although FPE showed remarkable therapeutic activities against several diseases such as diabetes, cancer, inflammation, hepatitis B virus, and malaria, there were several drawbacks in some previous reports including the lack of information on the drug dose, standards, controls, and mechanism of action of the extract. Further in-depth studies are required to explain the mechanism of action of the extracts to reveal the role of the bioactive compounds in the reported activities.

Journal ArticleDOI
Edward J. Calabrese1Institutions (1)
Abstract: This paper identifies and provides the first detailed assessment of hormetic dose responses by bone marrow stem cells (BMSCs) from a broad range of animal models and humans with particular emphasis on cell renewal (proliferation), cell differentiation and enhancing resilience to inflammatory stress. Such hormetic dose responses are commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., caffeine, dexamethasone, nicotine), dietary supplements (e.g., curcumin, Ginkgo biloba, green tea extracts. resveratrol, sulforaphane), endogenous agents (e.g., hydrogen sulfide, interleukin 10), environmental contaminants (e.g., arsenic, PFOS) and physical stressor agents (e.g., EMF, shockwaves). Hormetic dose responses reported here for BMSCs are similar to those induced with other stem cell types [e.g., adipose-derived stem cells (ADSCs), dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), neuro stem cells (NSCs), embryonic stem cells (ESCs)], indicating a substantial degree of generality for hormetic responses in stem cells. The paper assesses both the underlying mechanistic foundations of BMSC hormetic responses and their potential therapeutic implications.

Journal ArticleDOI
Abstract: This research aimed to evaluate the curative impact of nobiletin (NOB) on paraquat (PQ) induced mitochondrial impairment in rats' hepatic tissues. Twenty-four male rats were divided into control, PQ, PQ + NOB, and NOB treated groups. The alanine aminotransferase levels, aspartate aminotransferase, and alkaline phosphatase were increased in the experimental animals after exposure with PQ. A significant decrease in the level of catalase, glutathione peroxidase, superoxide dismutase, glutathione, thiobarbituric acid reactive substances, and reactive oxygen species were recorded in rats exposed to PQ. The mitochondrial TCA cycle enzyme activities, including isocitrate-dehydrogenase, succinate-dehydrogenase, alpha-ketoglutarate dehydrogenase, and malate-dehydrogenase, were reduced in PQ exposed rats. The activities of mitochondrial enzymes including NADH dehydrogenase, coenzyme Q-cytochrome reductase, succinic-coenzyme Q and cytochrome c-oxidase were significantly decreased after the PQ-exposure. PQ administration also reduced the mitochondrial membrane potential. However, the administration of mitochondria with NOB can decrease the toxic effect of the PQ in isolated mitochondria. NOB treatment potentially reduced the damaging effects of the PQ in the mitochondria isolated from hepatic tissues. Thus, the current study revealed that the NOB could attenuate PQ-induced mitochondrial damage in rats' hepatic tissues.

Journal ArticleDOI
Gui-Yang Xia1, Gui-Yang Xia2, Shijie Cao2, Lixia Chen1  +1 moreInstitutions (2)
Abstract: Covering: March 2010 to December 2020. Previous review: Nat. Prod. Rep., 2011, 28, 705This review summarizes the latest progress and perspectives on the structural classification, biological activities and mechanisms, metabolism and pharmacokinetic investigations, biosynthesis, chemical synthesis and structural modifications, as well as future research directions of the promising natural withanolides. The literature from March 2010 to December 2020 is reviewed, and 287 references are cited.

Journal ArticleDOI
Yunxiang Cao1, Jian Liu1, Chuanbing Huang1, Yanhong Tao1  +3 moreInstitutions (1)
Abstract: Rheumatoid arthritis (RA) is an autoimmune disease with increased M1 macrophages. The classical activated M1 macrophages produce various cytokines to control inflammation. Wilforlide A is a natural product that displays anti-inflammatory activities. However, the effect of Wilforlide A on RA progression and the potential mechanisms are unclear. Herein, the collagen-induced arthritis (CIA) mouse was used as an experimental model of RA. The administration of Wilforlide A reduced clinical scores, joint swelling and histological damage in ankle joints of RA mice. The secreted pro-inflammatory factors (MCP1, GM-CSF and M-CSF) and M1 biomarker iNOS in synovium were inhibited by Wilforlide A. In vitro, macrophages deriving from THP-1 cells were stimulated with LPS/IFN-γ to mimic M1 polarization. Similarly, Wilforlide A blocked macrophages polarizing towards M1 subsets. The in vitro results demonstrated that Wilforlide A suppressed LPS/IFN-γ-induced TLR4 upregulation, IκBα degradation and NF-κB p65 activation. In addition, TAK242 (a TLR4 inhibitor) treatment caused a similar inhibitory effect on M1 polarization with Wilforlide A, whereas it was less than the combination of TAK242 and Wilforlide A. Therefore, this work supports that Wilforlide A ameliorates M1 macrophage polarization in RA, which is partially mediated by TLR4/NF-κB signaling pathway inactivation.

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Author's H-index: 28

No. of papers from the Author in previous years