Publications by authors named "Musaddique Hussain"

20 Publications

  • Page 1 of 1

RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss.

Cell Regen 2021 Mar 3;10(1). Epub 2021 Mar 3.

Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.

The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.
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http://dx.doi.org/10.1186/s13619-020-00071-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925793PMC
March 2021

COVID-19 and inhibitors of the renin-angiotensin-aldosterone system.

Expert Rev Anti Infect Ther 2020 Nov 26:1-2. Epub 2020 Nov 26.

Department of Pharmacology, School of Medicine, Zhejiang University , Hangzhou City, China.

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http://dx.doi.org/10.1080/14787210.2021.1851197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711737PMC
November 2020

Knowledge, attitude, preventive practices and perceived barriers to screening about colorectal cancer among university students of newly merged district, Kpk, Pakistan - A cross-sectional study.

J Oncol Pharm Pract 2021 Mar 9;27(2):359-367. Epub 2020 May 9.

Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.

Introduction: Colorectal cancer is the third most common type of cancer in the world and in Pakistan it ranks at fifth position. The present study was conducted to evaluate the knowledge, attitude, preventive practices and perceived barriers to screening about colorectal cancer among university students.

Method: A cross-sectional study was conducted after developing a self-administered questionnaire among the university students of newly merged districts of Kpk, Pakistan.

Result: A total of 302 students (232 male and 70 female) participated in the study. The knowledge score of the participants regarding the risk factors and warning signs of colorectal cancer was 59.9% and 40%. More than 90% of the participants were of the view that colorectal cancer diagnosis at initial stages can improve treatment and around 80% were in favor of undergoing regular physical examination to avoid colorectal cancer. Only 37.7% of the participants had intentionally collected information about colorectal cancer. The percentage of participants who intentionally participated in educational activities related to colorectal cancer was 33.1%. Furthermore, only 24.4% of the participant had ever taken part in colorectal cancer screening. The barriers toward colorectal cancer screening were fear of finding colorectal cancer and the anxiety of screening procedures. However, around 32% of the participants had no knowledge about colorectal cancer screening.

Conclusion: In view of the findings of this study, it can be suggested that community awareness programs that are focused towards screening of colorectal cancer may be initiated in the newly merged districts of Kpk, Pakistan. The implementation of such colorectal cancer screening program can help in its early detection and can potentially lower the associated mortality and morbidity risk with this disease.
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http://dx.doi.org/10.1177/1078155220922598DOI Listing
March 2021

Dengue control in Pakistan: prior planning is better than controlling too late.

BMJ 2019 12 12;367:l6912. Epub 2019 Dec 12.

Department of Pharmacology, Key Respiratory Drug Research Laboratory of China Food and Drug Administration, School of Medicine, Zhejiang University, Hangzhou City, 310058, China.

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http://dx.doi.org/10.1136/bmj.l6912DOI Listing
December 2019

Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway.

FASEB J 2019 11 30;33(11):11706-11720. Epub 2019 Jul 30.

Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.

Src homology domain 2-containing protein tyrosine phosphatase 2 (SHP2) participates in multiple cell functions including cell shape, movement, and differentiation. Therefore, we investigated the potential role of SHP2 in eosinophil recruitment into lungs in allergic airway inflammation and explored the underlying mechanism. Both SHP2 and Ras homolog family member A (RhoA) kinase were robustly activated in the airway eosinophils of children with allergic asthma and of a mouse model with allergic airway inflammation. Moreover, inhibition of SHP2 activity by its specific inhibitors reverses the dephosphorylation of p190-A Rho GTPase-activating protein and in turn attenuates RhoA/Rho-associated protein kinase (ROCK) signaling, resulting in the attenuation of eosinophil migration in response to platelet-activating factor stimulation. Specifically, deletion in myeloid cells did not affect the number and classification of circulating leukocytes but significantly attenuated the allergen-induced inflammatory cell, especially eosinophil, infiltration into lungs, and airway hyperreactivity. Notably, genetic interaction between and indicated that RhoA inactivation and deletion synergistically attenuated the allergen-induced eosinophil infiltration into lungs and airway hyperreactivity, whereas overexpression of active RhoA robustly restored the deletion-resultant attenuation of allergen-induced eosinophil recruitment into lungs and airway hyperreactivity as well. Thus, this study demonstrates that SHP2 RhoA/ROCK signaling regulates eosinophil recruitment in allergic airway inflammation and possibly in allergic asthma.-Xu, C., Wu, X., Lu, M., Tang, L., Yao, H., Wang, J., Ji, X., Hussain, M., Wu, J., Wu, X. Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway.
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http://dx.doi.org/10.1096/fj.201900698RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902720PMC
November 2019

A CRTH2 antagonist, CT-133, suppresses NF-κB signalling to relieve lipopolysaccharide-induced acute lung injury.

Eur J Pharmacol 2019 Jul 3;854:79-91. Epub 2019 Apr 3.

Department of Critical Care Medicine and Orthopedics, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou City, 310009, China. Electronic address:

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions that still have no definite pharmacotherapy. Hence, we investigate the potential effectiveness and underlying mechanism of CT-133, a newly developed selective antagonist of prostaglandin D2 receptor 2 (DP2) or of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), against lipopolysaccharide (LPS)-induced ALI. CT-133 (10 or 30 mg/kg) or dexamethasone (1 mg/kg, positive control) were intragastrically administered 1 h before and 12 h after intratracheal LPS instillation, and primary neutrophils and macrophages and RAW264.7 macrophages were used to investigate the role of CT-133 in regulation of their functions. LPS induced a significant secretion of PGD from primary macrophages, however, CT-133 dose-dependently and markedly decreased the infiltration of neutrophils and macrophages into lungs, reduced the IL-1β, TNF-α, IL-6, and KC levels in broncho-alveolar lavage (BAL) fluids, decreased the wet weight and myeloperoxidase activity of lungs, reduced Evans blue and albumin exudation into lungs, and improved the lung histopathological changes and hypoxemia. Moreover, CT-133 significantly suppressed the primary neutrophil migration toward the PGD and robustly inhibited the mRNA and protein expression of IL-1β, TNF-α, IL-6, and KC in primary and RAW264.7 macrophages in response to either LPS- or PGD stimulation. Finally, CT-133 significantly blocked the LPS-induced P65 activation in both RAW264.7 macrophages and mouse lungs. Thus, This is the first report that a CRTH2 antagonist, CT-133, is capable of significantly alleviating LPS-induced lung injury by probably down-regulating the NF-κB signalling.
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http://dx.doi.org/10.1016/j.ejphar.2019.03.053DOI Listing
July 2019

CRTH2 antagonist, CT‑133, effectively alleviates cigarette smoke-induced acute lung injury.

Life Sci 2019 Jan 22;216:156-167. Epub 2018 Nov 22.

Department of Pharmacology, Zhejiang University, School of Medicine, Hangzhou City 310058, China. Electronic address:

Aims: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D has been observed in CS-induced lung injury. Currently, no effective pharmacological therapies are available to treat ALI, and supportive therapies remain the mainstay of treatment. Therefore, we investigated the protective effect of CT‑133, a newly discovered selective CRTH2 antagonist, on CS-induced ALI in vivo and in vitro.

Main Methods: CT‑133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD-stimulated RAW 264.7 macrophages were used to evaluate the protective effect of CT‑133.

Key Findings: CT‑133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL‑1β, IL‑6, TNF‑α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT‑133 not only reversed the uncontrolled secretion of IL‑1β, IL-6, TNF‑α and KC from CSE- and PGD-stimulated RAW 264.7 macrophages but also augmented IL-10 production in both in vivo and in vitro studies. Additionally, CT‑133 alleviated in vitro neutrophil migration chemoattracted by PGD.

Significance: Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI.
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http://dx.doi.org/10.1016/j.lfs.2018.11.039DOI Listing
January 2019

High expression of Sonic hedgehog in allergic airway epithelia contributes to goblet cell metaplasia.

Mucosal Immunol 2018 09 4;11(5):1306-1315. Epub 2018 Jun 4.

Department of Pharmacology, Zhejiang University School of Medicine, 310058, Hangzhou, China.

Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH-neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM-pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the upregulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.
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http://dx.doi.org/10.1038/s41385-018-0033-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160330PMC
September 2018

Acute Respiratory Distress Syndrome: Bench-to-Bedside Approaches to Improve Drug Development.

Clin Pharmacol Ther 2018 09 27;104(3):484-494. Epub 2018 Feb 27.

Department of Pharmacology, Hangzhou City, 310058, China.

Despite 50 years of extensive research, no definite drug is currently available to treat acute respiratory distress syndrome (ARDS), and the supportive therapies remain the mainstay of treatment. To improve drug development for ARDS, researchers need to deeply analyze the "omics" approaches, reevaluate the suitable therapeutic targets, resolve the problems of inadequate animal modeling, develop the strategies to reduce the heterogeneity, and reconsider new therapeutic and analytical approaches for better designs of clinical trials.
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http://dx.doi.org/10.1002/cpt.1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162218PMC
September 2018

Pharmacological validation of the folkloric uses of Cyperus rotundus L. in different ailments: An in vivo and in vitro research.

Pak J Pharm Sci 2018 Jan;31(1):95-102

Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.

In vivo and in vitro research study was conducted on Cyperus rotundus to evaluate the sound mechanistic background in the treatment of gastrointestinal, bronchial and vascular disorders as well as in pain, emesis, pyrexia and bacterial infections. Results showed that crude extract of Cyperus rotundus (Cr.Cr) exhibited the dose-dependent spasmolytic effect in rabbit jejunum by inhibiting the spontaneous and K+ (80 mM)-induced contractions. Pretreatment of tissue with Cr. Cr caused the rightward shift of calcium concentration response curves, similar to verapamil. Cr. Cr also caused the relaxation of K+(80 mM)- and carbachol (1 µM)-induced contractions of trachea preparations, similar to that of verapamil. Moreover, Cr. Cr also relaxed the contraction induced by the K+ (80 mM) and phenylephrine (1 µM) of aorta preparations. Data show that C. rotundus possess the spasmolytic, bronchodilator and vasodilator activities possibly through calcium channels blockade; validating its folkloric use in diarrhea, dyspepsia, bronchitis, asthma and hypertension in addition to antibacterial, antiemetic, antipyretic and analgesic activities.
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January 2018

Cdc42 Is Essential for Both Articular Cartilage Degeneration and Subchondral Bone Deterioration in Experimental Osteoarthritis.

J Bone Miner Res 2018 05 15;33(5):945-958. Epub 2018 Feb 15.

Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.

Cdc42, a member of Rho family small guanosine triphosphatases (GTPases), is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilization of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages. Notably, genetic disruption of Cdc42, knockdown of Cdc42 expression or inhibition of Cdc42 activity significantly restored the increased numbers of mesenchymal stem cells, osteoprogenitors, osteoblasts, osteoclasts, and neovascularized vessels, the increased bone mass, and the activated Erk1/2, Smad1/5 and Smad2 in subchondral bone of DMM-operated mice. Mechanistically, Cdc42 mediates interleukin-1β-induced interleukin-6 production and subsequent Jak/Stat3 activation to regulate chondrocytic inflammation, and also lies upstream of Erk/Smads to regulate subchondral bone remodeling during transform growth factor-β1 signaling. Cdc42 is apparently required for both articular cartilage degeneration and subchondral bone deterioration of osteoarthritis, thus, interventions targeting Cdc42 have potential in osteoarthritic therapy. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3380DOI Listing
May 2018

Notch Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling.

Mol Pharmacol 2017 12 12;92(6):676-693. Epub 2017 Oct 12.

Department of Pharmacology and The Key Respiratory Drug Research Laboratory of China Food and Drug Administration, School of Medicine, Zhejiang University, Hangzhou City, China (M.H., C.X., M.A., Xim.W.); The Second People's Hospital of Wenling, Wenling City, Zhejiang Province, China (Y.Y.); and Department of Respiratory Medicine, the Affiliated Children Hospital, School of Medicine, Zhejiang University, Hangzhou City, China (M.L., Xil.W., L.T.)

Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.
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http://dx.doi.org/10.1124/mol.117.110254DOI Listing
December 2017

Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling.

Biochim Biophys Acta Mol Basis Dis 2017 12 1;1863(12):3226-3242. Epub 2017 Sep 1.

Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou City 310058, China; The Key Respiratory Drug Research Laboratory of China Food and Drug Administration, School of Medicine, Zhejiang University, Hangzhou City 310058, China. Electronic address:

Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/β-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/β-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/β-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling.
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http://dx.doi.org/10.1016/j.bbadis.2017.08.031DOI Listing
December 2017

Vitamin C deficiency exacerbates diabetic glomerular injury through activation of transforming growth factor-β signaling.

Biochim Biophys Acta Gen Subj 2017 Sep 23;1861(9):2186-2195. Epub 2017 Jun 23.

Department of Pharmacology, Zhejiang University Medical School, Hangzhou 310058, China. Electronic address:

Background: The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (VC) in diabetic humans and experimentally diabetic animals. Herein, we access the effects of VC deficiency on the diabetic kidney injury and explore the underlying mechanism.

Methods: l-gulonolactone oxidase conventional knockout (Gulo) mice genetically unable to synthesize VC were subjected to streptozotocin-induced diabetic kidney injury and the role of VC deficiency was evaluated by biochemical and histological approaches. Rat mesangial cells were cultured to investigate the underlying mechanism.

Results: Functionally, VC deficiency aggravates the streptozotocin-induced renal insufficiency, exhibiting the increased urine albumin, water intake, and urine volume in Gulo mice. Morphologically, VC deficiency exacerbates the streptozotocin-induced kidney injury, exhibiting the increased glomerular expansion, deposition of Periodic Acid-Schiff- and Masson-positive materials, and expression of α-smooth muscle actin, fibronectin and type 4 collagen in glomeruli of Gulo mice. Mechanistically, VC activates protein kinase B (Akt) to destabilize Ski and thereby induce the expression of Smad7, resulting in suppression of TGF-β/Smad signaling and extracellular matrix deposition in mesangial cells.

Conclusions: VC is essential for the renal function maintenance in diabetes.

General Significance: Compensation for the loss of VC could be an effective remedy for diabetic kidney injury.
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http://dx.doi.org/10.1016/j.bbagen.2017.06.018DOI Listing
September 2017

Inhibition of Myosin Light-Chain Kinase Enhances the Clearance of Lipopolysaccharide-Induced Lung Inflammation Possibly by Accelerating Neutrophil Apoptosis.

Shock 2017 09;48(3):377-386

*Department of Critical Care Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou City, China †Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou City, China ‡Department of Paediatrics, The First People's Hospital of Wenling City, Wenling City, China §Department of Respiratory Medicine, The Affiliated Children's Hospital, Zhejiang University School of Medicine, Hangzhou City, China.

Neutrophils are a population of inflammatory cells involved in acute lung injury (ALI), and lipopolysaccharide (LPS)-induced prolonged neutrophil survival and delayed neutrophil apoptosis hinder the alleviation of lung inflammation. Myosin light-chain kinase (MLCK) involved the RhoA/Rho kinase signaling pathway responsible for the cytoskeletal arrangement, and previous studies have revealed that inhibition of MLCK induces apoptosis in vitro and in vivo. In this study, glycogen-induced neutrophils isolated from rats or mice were incubated with ML-7, a MLCK-specific inhibitor, and LPS-induced ALI mice administrated with ML-7 were investigated, to demonstrate the roles of MLCK in neutrophil apoptosis as well as its possibility of contributing to the clearance of inflammation. We found that ML-7 dramatically promoted neutrophil apoptosis that possibly signal through the p38 to upregulate the expression of the apoptotic proteins caspase-9 and B-cell lymphoma 2 and to downregulate the expression of the antiapoptotic protein Bcl-2-associated X protein and myeloid cell leukemia-1. In mice, ML-7 accelerated the clearance of inflammation in LPS-induced ALI through attenuating neutrophil accumulation, histopathological changes, and pulmonary edema. ML-7 promoted elimination of inflammation possibly by accelerating neutrophil apoptosis and macrophage-mediated clearance. Moreover, ML-7 also reduced the LPS-induced production of proinflammatory cytokines interleukin-1β and tumor necrosis factor-α, and the activity of myeloperoxidase. Taken together, the present study uncovers a hitherto uncharacterized role of MLCK in neutrophil apoptosis that contributes to the alleviation of inflammation in response to LPS.
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http://dx.doi.org/10.1097/SHK.0000000000000863DOI Listing
September 2017

SUMOylation of large tumor suppressor 1 at Lys751 attenuates its kinase activity and tumor-suppressor functions.

Cancer Lett 2017 02 12;386:1-11. Epub 2016 Nov 12.

Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address:

Large tumor suppressor (Lats) plays a critical role in maintaining cellular homeostasis and is the core to mediate Hippo growth-inhibitory signaling pathway. SUMOylation is a reversible and dynamic process that regulates a variety of cell functions. Here, we show that SUMOylation of Lats1 affects its kinase activity specifically towards Hippo signaling. Small ubiquitin-like modifier (SUMO) 1 interacts with and directly SUMOylates Lats1, whereas loss of SUMOylation pathway function disrupts Lats1 SUMOylation. Among potential SUMOylation sites on hLats1, K751 and K830 are conversed and essential for maintaining the transcriptional output of Hippo signaling, whereas K751 mutation more significantly abolishes SUMO1-induced Lats1 SUMOylation than K830 mutation. Though Lats1 SUMOylation at K751 affects neither its subcellular distribution nor its interactions with YAP and TAZ, it significantly destabilizes the phosphorylated Lats1 (Thr1079 but not Ser909), resulting in the attenuation of Lats1 kinase activity and inhibition of Hippo signaling. Moreover, HepG2 hepatocellular carcinoma cells express significantly more SUMOylated Lats1 than LO2 normal human hepatic cells, and in HepG2 cells or HepG2 cells xenografts, Lats1 SUMOylation at K751 consistently attenuates Lats1 kinase activity and subsequently suppresses Hippo signaling, resulting in not only the promotion of cell proliferation and colony formation but also the suppression of cell apoptosis. Together, we demonstrate that Lats1 SUMOylation at K751 suppresses its kinase activity and subsequently attenuates its tumor-suppressor functions. Thus, this study provides additional insight into how Hippo signaling is regulated and highlights the potentially critical role of Lats1 SUMOylation in tumor development.
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http://dx.doi.org/10.1016/j.canlet.2016.11.009DOI Listing
February 2017

Anti-cholinergic and Ca-antagonist mechanisms explain the pharmacological basis for folkloric use of Sisymbrium irio Linn. in gastrointestinal, airways and vascular system ailments.

J Ethnopharmacol 2016 Dec 30;193:474-480. Epub 2016 Sep 30.

Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan. Electronic address:

Ethnopharmacological Relevance: Seeds of Sisymbrium irio Linn has been used traditionally in different regions of Pakistan for the treatment of gastrointestinal, airways and vascular system ailments. To insight the pharmacological basis, in vitro study was conducted in order to validate its folkloric uses.

Material And Methods: 70% aqueous-methanolic extract of seeds from S. irio (Si.MEs) was tested on isolated rabbit aorta, jejunum and trachea strip hanged in tissue bath having physiological solutions aerated with carbogen and their responses were measured and recorded via Power Lab.

Results: The Si.MEs exhibited the transient spasmogenic effect (0.01-1.0mg/mL) on spontaneous jejunum contractions, followed by the spasmolytic effect. The addition of atropine resulted in blocking in spasmogenic effect while the spasmolytic effect was originated, suggesting the presence of an antimuscarinic effect. Likewise verapamil, Si.MEs (0.03-5mg/mL) repressed the high concentration K(80mM)-induced contraction and also drifted the Ca concentration-response curves toward right (0.3-3.0mg/mL), possibly signifying the Ca channel blockade. Furthermore, Si.MEs exhibited nonspecific relaxant effect on carbachol (1µM)- and high concentration K(80mM)-induced tracheal contractions in a way comparable to dicyclomine, suggesting the coexistence of Ca-antagonistic and/or antimuscarinic properties. Additionally, Si.MEs also relaxed the phenylephrine(1µM)- and high concentration K(80mM)-induced aortic contraction (0.01-3mg/mL), suggesting blockade of Ca channel. Moreover, oral administration of Si.MEs, as high as 6g per kg, did not produce lethality among the treated groups of mice.

Conclusions: Aqueous-methanolic extract of seeds from S. irio (Si.MEs) exhibited the bronchodilator and gut modulator (spasmogenic and spasmolytic) activities, probably through dual blockade of muscarinic receptors and Ca channels, whereas, vasodilator effect may be due to Ca channels blockade.
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http://dx.doi.org/10.1016/j.jep.2016.09.028DOI Listing
December 2016

Diuretic and serum electrolyte regulation potential of aqueous methanolic extract of Solanum surattense fruit validates its folkloric use in dysuria.

BMC Complement Altern Med 2016 Jun 3;16:166. Epub 2016 Jun 3.

Department of Botany, University of Rajshahi, Rajshahi, 6205, Bangladesh.

Background: Solanum surattense Burm. (Solanaceae) is traditionally used for management of various ailments. The study was conducted for provision of pharmacological justification for folkloric uses of Solanum surattense in the treatment of dysuria.

Methods: Rats were randomly divided into 5 groups, each of (n = 6). Aqueous methanolic fruit extract of S. surattense were also administered intraperitoneally to the rats at doses of 50, 70 and 100 mg/kg. Furosemide (10 mg/kg i.p) was used as standard drug whereas controls were given saline solution (40 mL/kg i.p). The electrolytes in urine were measured using a flame photometer whereas serum sodium, potassium, calcium, bicarbonate and blood urea nitrogen (BUN) were determined by using an automatic analyzer. Urine osmolality was assayed by the micro-osmometer.

Results: The extract S. surattense induced diuretic effects in a dose-dependent manner as compared with control. Upon administration of extract (70 and 100 mg/kg), we observed the prominent (p < 0.01) increase in the urine volume and osmolality in comparison to control group. However, plant extract (100 mg/kg) significantly increase the urinary electrolyte excretion especially calcium (p < 0.05) to that of the furosemide whereas level of magnesium remains constant. Moreover, our results showed a decrease in serum levels of sodium, potassium, calcium and blood urea nitrogen (BUN), but concentration dependent increase in bicarbonate was found in the test groups. There was no substantial change in the pH of urine samples of the extract-treated groups.

Conclusion: These results indicate that S. surattense investigated exert its action by causing diuresis in the treatment of dysuria.
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http://dx.doi.org/10.1186/s12906-016-1148-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891924PMC
June 2016

Phosphodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway.

Cancer Lett 2016 08 11;378(1):38-50. Epub 2016 May 11.

Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China; Program of Molecular and Cellular Biology, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address:

Cancer stem cells (CSC) are critical for initiation, metastasis, and relapse of cancers, however, the underlying mechanism governing stemness of CSC remains unknown. Herein, we have investigated the roles of phosphodiesterase 5 (PDE5) in stemness of prostate cancer cells. Both PDE5 and WW domain-containing transcription regulator protein-1 (TAZ), a core effector of Hippo pathway, are highly expressed in the PC3-derived cancer stem cells (PCSC). Either TAZ knockdown or inhibition of PDE5 activity attenuated colony formation, altered expression patterns of stem cell markers, and enhanced cisplatin cytotoxicity, resulting in attenuation of stemness in PCSC. In addition, inhibition of PDE5 activity by its specific inhibitors activates cGMP-dependent protein kinase G (PKG), which in turn induces MST/LATS kinases, resulting in cytosolic degradation of TAZ and activation of Hippo pathway. Accordingly, knockdown of TAZ almost completely abolished PDE5 inhibitor-induced attenuation in stemness in cultured PCSC, whereas knockdown of TAZ not only abolished PDE5 inhibitor-induced attenuation in stemness but also facilitated PDE5 inhibitor-induced trans-differentiation in PCSC xenografts. Together, the present study has uncovered that PDE/cGMP/PKG signal targets to Hippo/TAZ pathway in maintaining stemness of PCSC, and suggested that PDE5 inhibitors in combination with chemotherapeutic agents could effectively prevent initiation, metastasis, and relapse of prostate cancer.
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http://dx.doi.org/10.1016/j.canlet.2016.05.010DOI Listing
August 2016

Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a.

J Biol Chem 2016 Mar 14;291(11):5611-5622. Epub 2016 Jan 14.

From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China,. Electronic address:

Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.
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http://dx.doi.org/10.1074/jbc.M115.700336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786702PMC
March 2016