Publications by authors named "Maryam Mazhar"

10 Publications

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Dopamine receptor D2 antagonization normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis.

J Hepatol 2021 Oct 11. Epub 2021 Oct 11.

Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610064, China. Electronic address:

Background & Aims: Fibrosis in the liver is the main histological determinant of non-alcoholic steatohepatitis (NASH), a disease that parallels the worldwide surge in metabolic syndromes. Currently, there is no effective treatment for liver fibrosis. While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling "context-specific" contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases.

Methods: We used murine liver fibrosis and minipig NASH models, liver biopsies from cirrhotic patients, single-cell RNA sequencing (scRNA-Seq) and a G-protein-coupled receptor (GPCR) ligand screening system.

Results: YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The fibrogenic role of macrophage YAP was evidenced via boosting type I interferon and attenuating liver fibrosis in mice specifically lacking Yap1 in myeloid cells. scRNA-Seq further showed that defecting YAP pathway in macrophages diminished a fibrogenic vascular endothelial cell subset exhibiting pro-fibrotic molecular signatures such as CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, DRD2 antagonist blocked fibrosis and restored hepatic architecture.

Conclusions: DRD2 antagonization selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGFVCAM1 endothelial cells, promoting liver regeneration over fibrosis in both rodent and large animal models.

Lay Summary: Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that myeloid-specific YAP deficiency attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonization selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, showing the potential for the GPCR targeting-based NASH therapies.
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http://dx.doi.org/10.1016/j.jhep.2021.09.032DOI Listing
October 2021

Implication of ferroptosis in aging.

Cell Death Discov 2021 Jun 28;7(1):149. Epub 2021 Jun 28.

National Traditional Chinese Medicine Clinical Research Base, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.

Life is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.
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http://dx.doi.org/10.1038/s41420-021-00553-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257567PMC
June 2021

Research progress of traditional Chinese medicine against COVID-19.

Biomed Pharmacother 2021 May 3;137:111310. Epub 2021 Feb 3.

National Traditional Chinese Medicine Clinical Research Base, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China; Drug Research Center of Integrated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China. Electronic address:

Background: Currently, the number of confirmed cases and deaths of COVID-19 worldwide continues to rise, receiving great concern from the international community. However, there is no specific and widely accepted effective vaccines. The experience in controlling the outbreak in China has proven the effectiveness of traditional Chinese medicine (TCM).

Objectives: This review aims to evaluate the role of TCM in COVID-19 treatment, hoping to provide references for prevention and control of global pandemic.

Data Sources: China National Knowledge Infrastructure, Web of Science, Baidu Scholar, ScienceDirect, Elsevier and PubMed were used to search literatures published from December 2019 to December 2020 by entering the keywords "Traditional Chinese medicine", "COVID-19″, "Severe acute respiratory syndrome coronavirus 2″, "Pathogenesis", "Syndrome differentiation", "Prescriptions" and their combinations. Hence, we have performed an extensive review of research articles, reviews and primary scientific studies to identify TCM against COVID-19.

Results: Among clinical treatments of COVID-19, several TCM prescriptions and characteristic therapies have been effectively suggested, the underlying mechanisms of which are mainly involved in antiviral, anti-inflammatory, immunomodulatory and organ-protective effects of multi-components acting on multi-targets at multi-pathways.

Conclusions: This review may provide meaningful and feasible information that can be considered for the treatment of COVID-19 pandemic globally.
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http://dx.doi.org/10.1016/j.biopha.2021.111310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857050PMC
May 2021

Research Advance on Qingfei Paidu Decoction in Prescription Principle, Mechanism Analysis and Clinical Application.

Front Pharmacol 2020 27;11:589714. Epub 2021 Jan 27.

National Traditional Chinese Medicine Clinical Research Base, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.

Since the sudden epidemic of coronavirus disease 2019 (COVID-19), the State Administration of Traditional Chinese Medicine immediately organized experts to formulate and screen the effective prescriptions of traditional Chinese medicine according to the characteristics of the novel coronavirus infection. Qingfei Paidu decoction (QFPDD) has been proven to be effective in multi-provincial clinical trials, and has been selected as a general prescription for the treatment of COVID-19 in different stages that was later promoted to be used nationwide. This review highlights the latest advances of QFPDD, focusing on the TCM theory, mechanism analysis, clinical application of QFPDD and its future perspectives. Moreover, an in-depth discussion of some valuable issues and possible development for future research on QFPDD is also discussed, aiming to provide a novel guide to combat the global epidemic COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.589714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873690PMC
January 2021

SARS-CoV-2 microbiome dysbiosis linked disorders and possible probiotics role.

Biomed Pharmacother 2021 Jan 11;133:110947. Epub 2020 Nov 11.

Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China. Electronic address:

In December 2019, a pneumonia outbreak of unknown etiology was reported which caused panic in Wuhan city of central China, which was later identified as Coronavirus disease (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the Chinese Centre for Disease Control and Prevention (CDC) and WHO. To date, the SARS-CoV-2 spread has already become a global pandemic with a considerable death toll. The associated symptoms of the COVID-19 infection varied with increased inflammation as an everyday pathological basis. Among various other symptoms such as fever, cough, lethargy, gastrointestinal (GI) symptoms included diarrhea and IBD with colitis, have been reported. Currently, there is no sole cure for COVID-19, and researchers are actively engaged to search out appropriate treatment and develop a vaccine for its prevention. Antiviral for controlling viral load and corticosteroid therapy for reducing inflammation seems to be inadequate to control the fatality rate. Based on the available related literature, which documented GI symptoms with diarrhea, inflammatory bowel diseases (IBD) with colitis, and increased deaths in the intensive care unit (ICU), conclude that dysbiosis occurs during SARS-COV-2 infection as the gut-lung axis cannot be ignored. As probiotics play a therapeutic role for GI, IBD, colitis, and even in viral infection. So, we assume that the inclusion of studies to investigate gut microbiome and subsequent therapies such as probiotics might help decrease the inflammatory response of viral pathogenesis and respiratory symptoms by strengthening the host immune system, amelioration of gut microbiome, and improvement of gut barrier function.
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http://dx.doi.org/10.1016/j.biopha.2020.110947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657099PMC
January 2021

Hippo/YAP Pathway Plays a Critical Role in Effect of GDNF Against Aβ-Induced Inflammation in Microglial Cells.

DNA Cell Biol 2020 Jun 7;39(6):1064-1071. Epub 2020 Apr 7.

The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.

Neuroinflammation is a critical mechanism responsible for the progression of Alzheimer's disease (AD). Recent studies reveal that Hippo/Yes-associated protein (YAP) signaling pathway is highly associated with a series of inflammation-related disorders. Glial cell line-derived neurotrophic factor (GDNF), with its neurotrophic and anti-apoptotic functions for nervous system, has been demonstrated to decrease the expression of proinflammatory mediators. Here we investigated whether Hippo/YAP signaling may affect amyloid-β (Aβ)-induced proinflammatory cytokine production in microglial cells and explored its relationship with the anti-inflammation function of GDNF. The results showed that Aβ induced a decrease in the expression of YAP in microglia cells. YAP agonist XMU-MP-1 or its overexpression in microglial cells caused decreased expression of proinflammatory cytokines, whereas YAP antagonist Verteporfin or knockdown of YAP had the opposite effect. Treatment with GDNF resulted in upregulation of YAP expression and reduced the production of proinflammatory cytokines. Meanwhile YAP knockdown weakened the function of GDNF in microglial cells. In conclusion, Hippo/YAP pathway plays a critical role in effect of GDNF against Aβ-induced inflammatory response in microglia. Targeting GDNF or Hippo/YAP signaling may be promising therapeutic approach for the treatment of AD.
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http://dx.doi.org/10.1089/dna.2019.5308DOI Listing
June 2020

Quercetin modulates iron homeostasis and iNOS expression of splenic macrophages in a rat model of iron deficiency anemia.

Chin J Nat Med 2018 Aug;16(8):580-589

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; H.E.J. Research Institute for Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address:

Iron deficiency anemia is one of the most common micronutrient deficient conditions around the globe with various consequences, including the weakened immune system. Quercetin is widely distributed bioflavonoid; it has been debated for its dual roles in iron regulation. Quercetin-iron interaction in the body is a complex mechanism which has not been completely understood. The present study aimed to investigate the effect of quercetin on iron supplementation in iron deficiency anemia and on iNOS expression in splenic macrophages. The rat model of iron deficiency anemia was induced by feeding low iron diet to weanling rats for 20 days. The animals were then administered with ferrous sulfate, quercetin, and their combination for 30 days. Blood parameters, histopathological analysis, iron storage, CD68, iNOS and SLC40 expression in rat spleen were investigated. Our results showed that quercetin regulated iron absorption, despite SLC40 down-expression, indicating possible alternate route of iron transport, and that quercetin modulated iNOS production in splenic macrophages.
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http://dx.doi.org/10.1016/S1875-5364(18)30095-5DOI Listing
August 2018

Rutin and rutin-conjugated gold nanoparticles ameliorate collagen-induced arthritis in rats through inhibition of NF-κB and iNOS activation.

Int Immunopharmacol 2018 Jun 18;59:310-317. Epub 2018 Apr 18.

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address:

Numerous studies have suggested that nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) are important mediators of inflammatory response in human and animal models of arthritis. Besides, oxidative stress markers, nitric oxide (NO) and peroxide (PO) are also major contributors in the pathogenesis of rheumatoid arthritis (RA). Over expression of these inflammatory mediators leads to the extracellular matrix degradation, and excessive cartilage and bone resorption, ultimately leading to the irreversible damage to joints. The aim of the present study was to investigate the anti-arthritic mechanism of bioflavonoids, rutin and rutin-conjugated gold nanoparticles (R-AuNPs) by determining their role in the modulation of NF-κB and iNOS expression in collagen-induced arthritis (CIA) model of rats. Arthritis was induced by the subcutaneous administration of bovine type II collagen. Treatment was started with rutin, indomethacin + rutin (I + R) and R-AuNPs on the day of CIA induction. The severity of arthritis was determined by measuring the arthritic score on alternate days until mean arthritic score of 4 was observed. The NO and PO levels were also analyzed in serum samples. NF-κB and iNOS expression levels were determined in spleen tissue samples by real time RT-PCR and immunohistochemistry. Marked reduction in the arthritic score as well as in the NO and PO levels was observed in the treated groups. A significant downregulation in the NF-κB and iNOS expression levels was also observed in the treatment groups compared to the arthritic control group. Collectively, the findings suggest potential clinical role of rutin and R-AuNPs in the treatment of rheumatoid arthritis.
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http://dx.doi.org/10.1016/j.intimp.2018.04.017DOI Listing
June 2018

N-(2-Hydroxyphenyl)acetamide: a Novel Suppressor of RANK/RANKL Pathway in Collagen-Induced Arthritis Model in Rats.

Inflammation 2017 Aug;40(4):1177-1190

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.

RANKL and RANK are potential contributors of inflammatory cascade in human and animal model of arthritis. The current study aims to investigate the effect of N-(2-hydroxyphenyl)acetamide (NA-2) on regulation of RANKL pathway in collagen-induced arthritis (CIA) model in rats. CIA was induced using bovine type II collagen in female Wistar rats. The clinical parameters, level of pro-inflammatory and oxidative stress markers were measured to determine the progression of the disease. The mRNA level of RANKL and RANK and downstream mediators of inflammation i.e. c-fos, c-jun, NF-κB and Akt were analysed in spleen tissue using real-time PCR. Immunohistochemical analysis of iNOS, pAkt and c-Fos was also done in spleen tissue. Treatment with NA-2 and indomethacin showed increase in body weight and significant reduction in paw volume and arthritic score (p < 0.0001). Marked reduction in the level of oxidative stress markers, NO, PO and GSH (p < 0.0001), and pro-inflammatory markers, IL-1β (p < 0.0001) and TNF-α (p < 0.01), was also observed. Likewise, NA-2 and indomethacin treatment also significantly suppressed the mRNA expression of RANKL, RANK, c-fos, c-jun, NF-κB (p < 0.0001) and Akt (p < 0.01) and protein expression of iNOS, pAkt and c-Fos (p < 0.0001) compared to the arthritic control group. Our findings suggest that NA-2 is an antiarthritic agent acting in a pleiotropic manner in CIA rats by not only reducing the clinical signs of arthritis, inflammatory cytokines and free radical production but also attenuating the RANK/RANKL signaling pathway.
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http://dx.doi.org/10.1007/s10753-017-0561-1DOI Listing
August 2017

Eosin fluorescence: A diagnostic tool for quantification of liver injury.

Photodiagnosis Photodyn Ther 2017 Sep 9;19:37-44. Epub 2017 Apr 9.

Laboratory of Germplasm Innovation and Molecular Breeding, Department of Vegetable Sciences, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310029, PR China.

Hepatitis is one of the most common life threatening diseases. The diagnosis is mainly based on biochemical analysis such as liver function test. However, histopathological evaluation of liver serves far better for more accurate final diagnosis. The goal of our study was to evaluate the eosin fluorescence pattern in CCl-induced liver injury model compared with normal and different treatment groups. For this purpose, liver tissues were stained with H/E and examined under bright field microscope but the fluorescence microscopy of H/E stained slides provided an interesting fluorescence pattern and was quite helpful in identifying different structures. Interesting fluorescence patterns were obtained with FITC, Texas Red and Dual channel filter cubes that were quite helpful in identifying different morphological features of the liver. During the course of hepatic injury, liver cells undergo necrosis, apoptosis and overall cellular microenvironment is altered due to the modification of proteins and other intracellular molecules. Intensified eosin fluorescence was observed around the central vein of injured liver compared to normal indicating enhanced binding of eosin to the more exposed amino acid residues. To conclude, eosin fluorescence pattern varies with the health status of a tissue and can be used further for the diagnosis and quantification of severity of various liver diseases.
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http://dx.doi.org/10.1016/j.pdpdt.2017.03.016DOI Listing
September 2017
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