Publications by authors named "Syed Shadab Raza"

39 Publications

Sanguinarine mediated apoptosis in Non-Small Cell Lung Cancer via generation of reactive oxygen species and suppression of JAK/STAT pathway.

Biomed Pharmacother 2021 Dec 28;144:112358. Epub 2021 Oct 28.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar. Electronic address:

Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies.
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http://dx.doi.org/10.1016/j.biopha.2021.112358DOI Listing
December 2021

Dose dependent safety implications and acute intravenous toxicity of aminocellulose-grafted-polycaprolactone coated gelatin nanoparticles in mice.

Int J Biol Macromol 2021 Dec 20;192:1150-1159. Epub 2021 Oct 20.

Chemical Biology Unit, Institute of Nano Science and Technology (INST), Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Punjab Pin 140306, India. Electronic address:

Polymeric nanoparticles (NPs) are the most widely researched nanoformulations and gained broad acceptance in nanotherapeutics for targeted drug delivery and theranostics. However, lack of regulations, guidelines, harmonized standards, and limitations with their employability in clinical circumstances necessitates an in-depth understanding of their toxicology. Here, we examined the in-vivo toxicity of core-shell polymeric NPs made up of gelatin core coated with an outer layer of aminocellulose-grafted polycaprolactone (PCL-AC) synthesized for drug delivery purposes in inflammatory disorders. Nanoparticles were administered intravenously in Swiss albino mice, in multiple dosing (10, 25, and 50 mg/kg body weight) and outcomes of serum biochemistry analysis and histopathology evaluation exhibited that the highest 50 mg/kg administration of NPs altered biochemistry and histopathology aspects of vital organs, while doses of 10 and 25 mg/kg were safe and biocompatible. Further, mast cell (toluidine blue) staining confirmed that administration of the highest dose enhanced mast cell infiltration in tissues of vital organs, while lower doses did not exhibit any of these alterations. Therefore, the results of the present study establish that the NPs disposal in-vivo culminates into alterations in organ structure and function consequences such that lower doses are quite biocompatible and do not demonstrate any structural or functional toxicity while some toxicological effects start appearing at the highest dose.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.10.028DOI Listing
December 2021

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.

Biomed Pharmacother 2021 Nov 15;143:112142. Epub 2021 Sep 15.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar. Electronic address:

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.
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http://dx.doi.org/10.1016/j.biopha.2021.112142DOI Listing
November 2021

Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway - Implications For Neurotransplantations.

Stem Cell Rev Rep 2021 Dec 6;17(6):2347-2358. Epub 2021 Sep 6.

Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Era University, Sarfarazganj, Lucknow, 226003, India.

Stem cell therapies are becoming increasingly popular solutions for neurological disorders. However, there is a lower survival rate of these cells after transplantation. Oxidative stress is linked to brain damage, and it may also impact transplanted stem cells. To better understand how transplanted cells respond to oxidative stress, the current study used HO. We briefly illustrated that exogenous HO treatment exaggerated oxidative stress in the human dental pulp and mesenchymal stem cells. 2',7'-Dichlorofluorescin diacetate (DCFDA), MitoSOX confirms the reactive oxygen species (ROS) involvement, which was remarkably subsided by the ROS inhibitors. The findings showed that HO activates autophagy by enhancing pro-autophagic proteins, Beclin1 and Atg7. Increased LC3II/I expression (which co-localized with lysosomal proteins, LAMP1 and Cathepsin B) showed that HO treatment promoted autophagolysosome formation. In the results, both Beclin1 and Atg7 were observed co-localized in mitochondria, indicating their involvement in mitophagy. The evaluation of Erk1/2 in the presence and absence of Na-Pyruvate, PEG-Catalase, and PD98059 established ROS-Erk1/2 participation in autophagy regulation. Further, these findings showed a link between apoptosis and autophagy. The results conclude that HO acts as a stressor, promoting autophagy and mitophagy in stem cells under oxidative stress. The current study may help understand better cell survival and death approaches for transplanted cells in various neurological diseases. The current study uses human Dental Pulp and Mesenchymal Stem cells to demonstrate the importance of HO-driven autophagy in deciding the fate of these cells in an oxidative microenvironment. To summarise, we discovered that exogenous HO treatment causes oxidative stress. Exogenous HO  treatment also increased ROS production, especially intracellular HO. HO stimulated the ErK1/2 signaling pathway and autophagy. Erk1/2 was found to cause autophagy. Further, the function of mitophagy appeared to be an important factor in the HO-induced regulation of these two human stem cell types. In a nutshell, by engaging in autophagy nucleation, maturation, and terminal phase proteins, we elucidated the participation of autophagy in cell dysfunction and death.
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http://dx.doi.org/10.1007/s12015-021-10212-zDOI Listing
December 2021

Aminocellulose - grafted polycaprolactone-coated core-shell nanoparticles alleviate the severity of ulcerative colitis: a novel adjuvant therapeutic approach.

Biomater Sci 2021 Sep 21;9(17):5868-5883. Epub 2021 Jul 21.

Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector-81, Sahibzada Ajit Singh Nagar, Punjab Pin - 140306, India.

Ulcerative colitis (UC) is an idiopathic inflammatory condition of colorectal regions. Existing therapies for UC face grave lacunae including off-target and other harmful side effects, extensive first-pass metabolism, rapid clearance, limited or poor drug absorption and various other limitations, resulting in lower bioavailability. These conditions demand advanced delivery strategies to inflammatory colonic conditions so that drugs can counter stomach acid, avail protective strategies at this pH and selectively deliver drugs to the colon. Therefore, this approach was undertaken to develop and characterize nanoparticles for the delivery of drugs glycyrrhizic acid as well as budesonide in UC. Biocompatible and biodegradable aminocellulose-conjugated polycaprolactone containing budesonide was covered onto gelatinous nanoparticles (NPs) loaded with GA. Nanoparticles were prepared by the solvent evaporation technique, which showed particle size of ∼230 nm, spherical shape, almost smooth morphological characters under transmission, scanning and atomic force microscopy. These NPs also improved disease activities like occult blood in the stool, length of the colon and fecal properties. The nanoparticle therapy appreciably decreased colonic mast cellular infiltration, significantly maintained mucin protection, ameliorated histological features of the colon. Furthermore, markers of inflammation such as iNOS, COX-2, IL1-β, TNF-α, NO, and MPO were also appreciably ameliorated with the therapy of dual drug-loaded nanoparticles. Overall, these results establish that dual drug-loaded core-shell NPs exhibit superior therapeutic properties over the free or naïve forms of GA and budesonide in acute colon inflammation and present advantages that may be assigned to their ability to significantly inhibit colon inflammatory conditions.
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http://dx.doi.org/10.1039/d1bm00877cDOI Listing
September 2021

Aminocellulose-grafted-polycaprolactone coated gelatin nanoparticles alleviate inflammation in rheumatoid arthritis: A combinational therapeutic approach.

Carbohydr Polym 2021 Apr 12;258:117600. Epub 2021 Jan 12.

Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab, 160062, India. Electronic address:

Rheumatoid arthritis (RA) is a chronic autoimmune disorder and serious cause of disability. Despite considerable advances in RA management, challenges like extensive drug metabolism and rapid clearance causes poor bioavailability. Core-shell nanocarriers for co-delivery of glycyrrhizic acid (GA) and budesonide against RA were developed. GA-loaded gelatin nanoparticles (NPs) were synthesized and coated with budesonide encapsulated aminocellulose-grafted polycaprolactone (PCL-AC). GA- and budesonide-loaded PCL-AC-gel NPs had diameter of 200-225 nm. Dual drug-loaded (DDL) NPs reduced joint swelling and erythema in rats while markedly ameliorating bone erosion evidenced by radiological analysis, suppressed collagen destruction, restored synovial tissue, bone and cartilage histoarchitecture with reduced inflammatory cells infiltration. NPs also reduced various inflammatory biomarkers such as TNF-α, IL-1β, COX-2, iNOS. Results of this study suggest that dual NPs exerted superior therapeutic effects in RA compared to free drugs which may be attributed to slow and sustained drug release and NPs' ability to inhibit inflammatory mediators.
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http://dx.doi.org/10.1016/j.carbpol.2020.117600DOI Listing
April 2021

Enema based therapy using liposomal formulation of low molecular weight heparin for treatment of active ulcerative colitis: New adjunct therapeutic opportunity.

Mater Sci Eng C Mater Biol Appl 2021 Feb 6;121:111851. Epub 2021 Jan 6.

Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India. Electronic address:

Ulcerative colitis (UC) is an idiopathic bowel disease involving chronic inflammation and ulcers in colon and implicates severe epithelial damage with disruption in colon homeostasis. Presently existing treatments possess serious concerns like off target effects and adverse reactions, drug inactivation, poor absorption and other complications resulting in poor bioavailability. In context of high risk of thrombotic events in UC patients, heparin can offer appreciable benefits in UC management due to its remarkable anti-coagulating properties, its ability to intervene inflammatory pathways and acceleration of wound healing process. However, oral administration of heparin being impractical due to harsh gastric acidic environment and heparin degradation, conventional heparin administration is done via intravenous route. Present study was designed to formulate, characterize and evaluate sustained release heparin formulation in mice model of experimental colitis. Heparin liposomes (HLp) were formulated by solvent evaporation and extrusion process and possessed hydrodynamic diameter of 242 ± 4.3 nm. Size, shape and surface morphology was confirmed by TEM, SEM and AFM micrographs while encapsulation efficiency and loading of heparin in optimized HLp were 59.61% and 12.27%, respectively. HLp enema administration ameliorated gross disease indices like body weight, colon length, stool consistency, fecal occult blood. Further, anti-inflammatory efficacy of HLp was established in histopathological analysis where HLp appreciably restored protective mucin layer, colon epithelial mucosal histoarchitecture and considerably attenuated mast cell infiltration in colon epithelia. Overall, results of this study indicate that HLp demonstrated an appreciable therapeutic efficacy in experimental colitis and these results are attributed to their ability to suppress inflammation.
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http://dx.doi.org/10.1016/j.msec.2020.111851DOI Listing
February 2021

Sivelestat-loaded nanostructured lipid carriers modulate oxidative and inflammatory stress in human dental pulp and mesenchymal stem cells subjected to oxygen-glucose deprivation.

Mater Sci Eng C Mater Biol Appl 2021 Jan 6;120:111700. Epub 2020 Nov 6.

Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Sarfarazganj, Lucknow 226003, Uttar Pradesh, India; Department of Stem Cell Biology and Regenerative Medicine, Era University, Sarfarazganj, Lucknow 226003, Uttar Pradesh, India. Electronic address:

Stroke remains the leading cause of morbidity and mortality. Stem cell-based therapy offers promising hope for survivors and their families. Despite the clinical translation of stem cell-based therapies in stroke patients for almost two decades, results of these randomized controlled trials are not very optimistic. In these lines, an amalgamation of nanocarriers based drug delivery with stem cells holds great promise in enhancing stroke recovery. In the present study, we treated oxygen-glucose deprivation (OGD) exposed dental pulp stem cells (DPSCs) and mesenchymal stem cells (MSCs) with sivelestat-loaded nanostructured lipid carriers (NLCs). Various physicochemical limitations associated with sivelestat drug applications and its recent inefficacy in the clinical trials necessitates the development of novel delivery approaches for sivelestat. Therefore, to improve its efficacy on the survival of DPSCs and MSCs cell types under OGD insult, the current NLCs were formulated and characterized. Resulting NLCs exhibited a hydrodynamic diameter of 160-180 nm by DLS technique and possessed good PDI values of 0.2-0.3. Their shape, size and surface morphology were corroborated with microscopic techniques like TEM, SEM, and AFM. FTIR and UV-Vis techniques confirmed nanocarrier's loading capacity, encapsulation efficiency of sivelestat, and drug release profile. Oxidative stress in DPSCs and MSCs was assessed by DHE and DCFDA staining, and cell viability was assessed by Trypan blue exclusion test and MTT assay. Results indicated that sivelestat-loaded NLCs protected the loss of cell membrane integrity and restored cell morphology. Furthermore, NLCs successfully defended human DPSCs and MSCs against OGD-induced oxidative and inflammatory stress. In conclusion, modulation of oxidative and inflammatory stress by treatment with sivelestat-loaded NLCs in DPSCs and MSCs provides a novel strategy to rescue stem cells during ischemic stroke.
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http://dx.doi.org/10.1016/j.msec.2020.111700DOI Listing
January 2021

Experimental Rodent Models of Vascular Dementia: A Systematic Review.

CNS Neurol Disord Drug Targets 2021 ;20(7):657-672

Department of Epidemic Disease Research, Institute for Research & Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.

Vascular Dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of Vascular Cognitive Impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small Vessel Disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Cerebral Amyloid Angiopathy (CAA), which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as Diabetes Mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.
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http://dx.doi.org/10.2174/1871527319666210108123438DOI Listing
January 2021

Enteric-coated gelatin nanoparticles mediated oral delivery of 5-aminosalicylic acid alleviates severity of DSS-induced ulcerative colitis.

Mater Sci Eng C Mater Biol Appl 2021 Feb 6;119:111582. Epub 2020 Oct 6.

Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India. Electronic address:

Ulcerative colitis (UC) is an inflammatory condition involving ulcers in colon and rectum. Conventional treatments for colitis confront serious limitations like off target systemic side effects, drug degradation and inactivation, restricted absorption and other complications culminating in poor bioavailability. These limitations necessitate localized drug delivery to inflamed colon such that drug can bypass abrasive gastric surroundings, availing protection form gastric acid and has selective access to colonic mucosa. Therefore, present study was designed to formulate Eudragit-S100 coated 5-amino salicylic acid (5-ASA)-loaded gelatin nanoparticles (NPs) for localized delivery of 5-ASA for treatment of ulcerative colitis. NPs were formulated by nanoprecipitation and solvent evaporation method, had hydrodynamic diameter of 225-250 nm, smooth and spherical surface morphology under TEM, SEM and AFM. Oral administration of NPs ameliorated disease activity indices like fecal occult bleeding, colon length and stool consistency. NPs treatment significantly reduced mast cells infiltration in colon, restored protective mucin layer and appreciably reinstated colonic histoarchitecture. Furthermore, inflammatory biomarkers like TNF-α, IL1-β, COX-2, iNOS, myeloperoxidase and nitrite levels were also significantly reduced by NPs treatment. Overall, results of this study indicate that 5-ASA NPs possessed superior therapeutic efficacy over free 5-ASA in experimental colitis and these results are attributed to their ability to significantly suppress inflammation.
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http://dx.doi.org/10.1016/j.msec.2020.111582DOI Listing
February 2021

Recent developments in unraveling signaling mechanisms underlying drug resistance due to cancer stem-like cells.

Curr Opin Pharmacol 2020 10 6;54:130-141. Epub 2020 Nov 6.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar. Electronic address:

Resistance in cancer cells to therapeutic measures is challenging and requires a rigorous delineation of the underlying mechanisms. Emerging findings reflect the characteristics of tumor cells to do the reprogramming of signaling machinery in order to overturn the therapeutic responses. Recent evidence shows that the tumor acquires drug resistance due to the presence of cancer stem cells (CSCs). Hence the understanding that how tumor cells reprogram their signaling mechanisms converging towards the stemness of CSCs is imperative for novel and effective therapy. This review outlines the current updates on how CSC-associated signaling pathways and its enhanced stemness trigger the development of drug resistance. Furthermore, we also discussed the strategies with a combinational approach that can simultaneously target both CSC-induced stemness and the resistance-related signaling pathways, which may provide an optimal outcome to overcome the problem of drug resistance in cancer therapy.
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http://dx.doi.org/10.1016/j.coph.2020.09.012DOI Listing
October 2020

Comparative acute intravenous toxicity study of triple polymer-layered magnetic nanoparticles with bare magnetic nanoparticles in Swiss albino mice.

Nanotoxicology 2020 12 10;14(10):1362-1380. Epub 2020 Oct 10.

Institute of Nano Science and Technology, Habitat Centre, Mohali, India.

Iron-oxide nanoparticles are one of the most commercialized nanomaterials and have gained widespread acceptance in nanotherapeutics due to their ability for targeted drug delivery, bioimaging, and various other preclinical and clinical theranostic biomedical applications. However, the absence of regulations, guidelines, and harmonized standards as well as limitations associated with their use in clinical settings in the context of their safety and toxicity profiling necessitates in-depth understanding of their toxicological paradigms. Here we examine the toxicity of modified superparamagnetic iron oxide nanoparticles in Swiss albino mice in terms of body weight changes, organ coefficients, generalized and organ-specific biochemical, and various histological staining parameters after administration of bare (uncoated) magnetic nanoparticles (MNPs) and triple polymer-coated magnetic nanoparticles (MNP-AC-G2-pPEG). Both types of nanoparticles were administered intravenously, in three doses (5, 10, and 25 mg/kg body weight) and results of biochemical and histopathological assessment revealed that the highest dose of bare (uncoated) MNPs significantly altered biochemical and histoarchitectural aspects in vital organs, while coated NPs (MNP-AC-G2-pPEG) was found safe in almost all doses. Furthermore, results of toluidine blue (for mast cells) and Prussian blue (for iron deposition) staining also established that the highest dose administration of bare MNPs in animals significantly enhanced mast cell infiltration and iron deposition in tissue sections of most vital organs, while coated NPs did not demonstrate any such adverse effects. Overall, outcomes of this study aid in establishing that administration of uncoated (bare) magnetic NPs results in structural and functional toxicological modifications while the coating of these NPs with biocompatible and biodegradable polymers can significantly bring down the toxicity of these NPs.
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http://dx.doi.org/10.1080/17435390.2020.1829144DOI Listing
December 2020

Lipid-based nanocarrier-mediated targeted delivery of celecoxib attenuate severity of ulcerative colitis.

Mater Sci Eng C Mater Biol Appl 2020 Nov 20;116:111103. Epub 2020 May 20.

Institute of Nano Science and Technology, Habitat Centre, Phase - 10, Sector 64, Mohali, Punjab 160062, India. Electronic address:

Ulcerative colitis is a chronic mucosal inflammatory condition that adversely affects colon and rectum. Celecoxib is a selective inhibitor of inducible cyclooxygenase-2 (COX-2) and is prescribed for the management of pain and other inflammatory disorders. The physicochemical properties of celecoxib limit its clinical potency. Here we developed nanostructured lipid carriers (NLCs) using Generally Recognized as Safe and US-FDA approved compounds for encapsulating celecoxib. Present study was aimed to evaluate efficacy of eudragit-S100-coated celecoxib-loaded NLCs against DSS-induced colitis in mice. NLCs were formulated by hot-melt method and possessed the average particle size of 250.90 nm and entrapment efficiency (%) was 59.89%. Furthermore, size, shape and morphology of NLCs were confirmed using TEM, SEM and AFM. The blank NLCs were cytocompatible against hTERT-BJ cells up to a dose of 200 μg/ml. Treatment with celecoxib-loaded NLCs alleviated severity of colitis as demonstrated by disease activity index, colon length, fecal occult blood test, and histopathological analysis. Moreover, treatment with celecoxib-loaded NLCs reduced disintegration of goblets cells and restores sulfomucin in colon. Celecoxib-nanoformulation markedly reduced colonic inflammation as evidenced by decreased immunohistochemical expression of COX-2 and iNOS. The observations of study suggest that lipid-based colon specific delivery of celecoxib may be used for management of colitis.
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http://dx.doi.org/10.1016/j.msec.2020.111103DOI Listing
November 2020

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Semin Cancer Biol 2020 Jul 25. Epub 2020 Jul 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.003DOI Listing
July 2020

Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma.

Int J Mol Sci 2020 Jul 15;21(14). Epub 2020 Jul 15.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host's immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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http://dx.doi.org/10.3390/ijms21145002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403981PMC
July 2020

'Primed' Mesenchymal Stem Cells: a Potential Novel Therapeutic for COVID19 Patients.

Stem Cell Rev Rep 2021 02;17(1):153-162

Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow, 226003, India.

The COVID19 pandemic, designated as a public health crisis by the World Health Organization (WHO), is rapidly spreading around the world impacting the health and economy of almost all the countries. The data of hospitalized COVID19 patients, especially those with serious illness, indicate the involvement of immunopathological complications. As no effective treatment is currently available, we propose 'Primed' Mesenchymal Stem Cells (MSCs) as a therapeutic alternative to tackle devastating epidemic. The individual response to MSCs treatment is heterogeneous. During the treatment of infectious pathology, the effectiveness of the treatment may vary based on the disease scenario. Interestingly, when transplanted in vivo, MSCs are governed by the locally regulated microenvironment, suggesting that the restorative variability could be tailored by choosing a priming regimen to specifically correct a given pathology. Therefore, in our opinion, the priming of MSCs could be a novel approach to improve the responses of COVID19 patients.
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http://dx.doi.org/10.1007/s12015-020-09999-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317273PMC
February 2021

Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches.

Cancers (Basel) 2020 May 6;12(5). Epub 2020 May 6.

National Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar.

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer.
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http://dx.doi.org/10.3390/cancers12051172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281705PMC
May 2020

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Mol Cancer 2020 03 12;19(1):57. Epub 2020 Mar 12.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
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http://dx.doi.org/10.1186/s12943-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069174PMC
March 2020

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized.
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http://dx.doi.org/10.3390/cancers12020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072613PMC
February 2020

Zinc Gluconate-Loaded Chitosan Nanoparticles Reduce Severity of Collagen-Induced Arthritis in Wistar Rats.

ACS Biomater Sci Eng 2019 Jul 12;5(7):3380-3397. Epub 2019 Jun 12.

Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India.

Rheumatoid arthritis (RA) is the most prevalent autoimmune disease affecting about 1% world population. Zinc (Zn) is necessary for the maintenance of bone homeostasis and the level of Zn was reported to be decreased in RA patients and collagen-induced arthritic rats. Effective delivery of Zn has been reported using zinc gluconate but oral absorption of Zn from zinc gluconate (ZG) is very low in humans. Zn supplementation reduces disease severity in patients suffering from chronic, refractory RA and exerts mild and transient side effects. The aim of this study was to synthesize and characterize zinc gluconate-loaded chitosan nanoparticles (ZG-Chit NPs) and to evaluate and compare therapeutic efficacy of ZG-Chit NPs and zinc gluconate against collagen-induced RA in Wistar rats. The nanoparticles were formulated by ionic gelation method and the hydrodynamic diameter was 106.5 ± 79.55 nm as measured using DLS. The particle size, shape, and surface morphology was further confirmed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. These nanoparticles showed good cytocompatibility against foreskin fibroblasts (BJ) and L929 cells. Arthritic rats were treated with ZG (20 mg/kg body weight, intraperitoneally) and equivalent doses of ZG-Chit NPs. The treatment of both ZG and ZG-Chit NPs reduced the severity of arthritis as evidenced by reduced joint swelling, erythema, and edema but ZG-Chit NPs exhibited superior efficacy. Furthermore, it was found that ZG and ZG-Chit NPs attenuate biomarkers of inflammation (C-reactive protein, myeloperoxidase, nitric oxide, TNF-α, and IL-1β) and oxidative stress (articular elastase, lipid peroxidation, catalase, glutathione, and superoxide dismutase). The results of the histopathology further confirmed that ZG-Chit NPs markedly suppressed infiltration of inflammatory cells as compared to ZG at the ankle joint tissue. Immunohistochemical analysis also revealed that treatment with ZG-Chit NPs resulted in reduced pro-inflammatory marker (TNF-α, IL-6, and iNOS) expression and enhanced SOD1 expression. Overall, this study suggests that ZG and ZG-Chit NPs suppressed the severity of arthritis plausibly mediated by attenuation of inflammation and oxidative stress and more importantly ZG-Chit NPs exhibited superior efficacy as compared to ZG.
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http://dx.doi.org/10.1021/acsbiomaterials.9b00427DOI Listing
July 2019

Gelatin-Coated Polycaprolactone Nanoparticle-Mediated Naringenin Delivery Rescue Human Mesenchymal Stem Cells from Oxygen Glucose Deprivation-Induced Inflammatory Stress.

ACS Biomater Sci Eng 2019 Feb 24;5(2):683-695. Epub 2018 Dec 24.

Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India.

Ischemic stroke involves pro-inflammatory species, which implicates inflammation in the disease mechanism. Recent studies indicate that the prevalence of therapeutic choice such as stem cell transplantation has seen an upsurge in ischemic stroke. However, after transplantation the fate of transplanted cells is largely unknown. Human mesenchymal stem cells (MSCs), due to their robust survival rate upon transplantation in brain tissue, are being widely employed to treat ischemic stroke. In the present study, we have evaluated naringenin-loaded gelatin-coated polycaprolactone nanoparticles (nar-gel-c-PCL NPs) to rescue MSCs against oxygen glucose deprived insult. Naringenin, due to its strong anti-inflammatory effects, remains a therapeutic choice in neurological disorders. Though, the low solubility and inefficient delivery remain challenges in using naringenin as a therapeutic drug. The present study showed that inflammation occurred in MSCs during their treatment with oxygen glucose deprivation (OGD) and was well overturned by treatment with nar-gel-c-PCL NPs. In brief, the results indicated that nar-gel-c-PCL NPs were able to protect the loss of cell membrane integrity and restored neuronal morphology. Then nar-gel-c-PCL NPs successfully protected the human MSCs against OGD-induced inflammation as evident by reduced level of pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-1β) and other inflammatory biomarkers (COX2, iNOS, and MPO activity). Therefore, the modulation of inflammation by treatment with nar-gel-c-PCL NPs in MSCs could provide a novel strategy to improve MSC-based therapy, and thus, our nanoformulation may find a wide therapeutic application in ischemic stroke and other neuro-inflammatory diseases.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01081DOI Listing
February 2019

Chick Embryo: A Preclinical Model for Understanding Ischemia-Reperfusion Mechanism.

Front Pharmacol 2018 21;9:1034. Epub 2018 Sep 21.

Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India.

Ischemia-reperfusion (I/R)-related disorders, such as stroke, myocardial infarction, and peripheral vascular disease, are among the most frequent causes of disease and death. Tissue injury or death may result from the initial ischemic insult, primarily determined by the magnitude and duration of the interruption in blood supply and then by the subsequent reperfusion-induced damage. Various and models are currently available to study I/R mechanism in the brain and other tissues. However, thus far, no I/R model has been reported for understanding the I/R mechanisms and for faster drug screening. Here, we developed an Hook model of I/R by occluding and releasing the right vitelline artery of a chick embryo at 72 h of development. To validate the model and elucidate various underlying survival and death mechanisms, we employed imaging (Doppler blood flow imaging), biochemical, and blotting techniques and evaluated the cell death mechanism: autophagy and inflammation caused by I/R. In conclusion, the present model is useful in parallel with established and I/R models to understand the mechanisms of I/R development and its treatment.
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http://dx.doi.org/10.3389/fphar.2018.01034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160536PMC
September 2018

Mechanisms underlying dental-derived stem cell-mediated neurorestoration in neurodegenerative disorders.

Stem Cell Res Ther 2018 09 26;9(1):245. Epub 2018 Sep 26.

Era Medical College & Hospital, Era University, Lucknow, Uttar Pradesh, 226003, India.

Background: Neurodegenerative disorders have a complex pathology and are characterized by a progressive loss of neuronal architecture in the brain or spinal cord. Neuroprotective agents have demonstrated promising results at the preclinical stage, but this has not been confirmed at the clinical stage. Thus far, no neuroprotective drug that can prevent neuronal degeneration in patients with neurodegenerative disorders is available.

Main Body: Recent studies have focused on neurorestorative measures, such as cell-based therapy, rather than neuroprotective treatment. The utility of cell-based approaches for the treatment of neurodegenerative disorders has been explored extensively, and the results have been somewhat promising with regard to reversing the outcome. Because of their neural crest origin, ease of harvest, accessibility, ethical suitability, and potential to differentiate into the neurogenic lineage, dental-derived stem cells (DSCs) have become an attractive source for cell-based neurorestoration therapies. In the present review, we summarize the possible use of DSC-based neurorestoration therapy as an alternative treatment for neurodegenerative disorders, with a particular emphasis on the mechanism underlying recovery in neurodegenerative disorders.

Conclusion: Transplantation research in neurodegenerative diseases should aim to understand the mechanism providing benefits both at the molecular and functional level. Due to their ease of accessibility, plasticity, and ethical suitability, DSCs hold promise to overcome the existing challenges in the field of neurodegeneration through multiple mechanisms, such as cell replacement, bystander effect, vasculogenesis, synaptogenesis, immunomodulation, and by inhibiting apoptosis.
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http://dx.doi.org/10.1186/s13287-018-1005-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158826PMC
September 2018

Edaravone ameliorates oxidative stress associated cholinergic dysfunction and limits apoptotic response following focal cerebral ischemia in rat.

Mol Cell Biochem 2012 Aug 22;367(1-2):215-25. Epub 2012 May 22.

Department of Medical Elementology and Toxicology (Fund for the Improvement of Science and Technology-DST and Special Assistance Programme-UGC Sponsored), Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India.

Stroke is a life-threatening disease with major cause of mortality and morbidity worldwide. The neuronal damage following cerebral ischemia is a serious risk to stroke patients. Oxidative stress and apoptotic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The objective of this study was to test the hypothesis that administration of edaravone (Edv) maintains antioxidant status in brain, improves the cholinergic dysfunction and suppresses the progression of apoptosis response in rat. To test this hypothesis, male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) of 2 h followed by reperfusion for 22 h. Edv was administered (10 mg/kg bwt) intraperitoneally 30 min before the onset of ischemia and 1 h after reperfusion. After reperfusion, rats were tested for neurobehavioral activities and were sacrificed for the infarct volume, estimation of oxidative damage markers. Edv treatment significantly reduced ischemic lesion volume, improved neurological deficits, contended oxidative loads, and suppressed apoptotic damage. In conclusion, treatment with Edv ameliorated the neurological and histological outcomes with elevated endogenous anti-oxidants status as well as reduced induction of apoptotic responses in MCA occluded rat. We theorized that Edv is among the pharmacological agents that reduce free radicals and its associated cholinergic dysfunction and apoptotic damage and have been found to limit the extent of brain damage following stroke.
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http://dx.doi.org/10.1007/s11010-012-1335-6DOI Listing
August 2012

Catechin hydrate ameliorates redox imbalance and limits inflammatory response in focal cerebral ischemia.

Neurochem Res 2012 Aug 9;37(8):1747-60. Epub 2012 May 9.

Neurotoxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India.

Epidemiologic studies have shown that foods rich in polyphenols, such as flavonoids, can lower the risk of ischemic disease; however, the mechanism of protection has not been clearly investigated. In this study, we hypothesized that pretreatment effect of catechin hydrate (CH) on functional outcome, neuronal damage and on secondary injuries in the ischemic brain of rats. To test this hypothesis, male Wistar rats were pretreated with CH (20 mg/kg b.wt) for 21 days and then subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. After 2 h MCAO/22 h reperfusion, neurological deficit, infarct sizes, activities of antioxidant enzymes and cytokines level were measured. Immunohistochemistry and western blot were used to analyse the expression of glial fibrillary acidic protein (GFAP), inducible nitric oxide (iNOS) and NF-kB in ischemic brain. The administration of CH showed marked reduction in infarct size, reduced the neurological deficits, suppressed neuronal loss and downregulate the iNOS, GFAP and NF-kB expression in MCAO rats. A significantly depleted activity of antioxidant enzymes and content of glutathione in MCAO group were protected significantly in MCAO group pretreated with CH. Conversely, the elevated level of thiobarbituric acid reactive species and cytokines in MCAO group was attenuated significantly in CH pretreated group when compared with MCAO group. The results indicated that CH protected the brain from damage caused by MCAO, and this effect may be through downregulation of NF-kB expression.
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http://dx.doi.org/10.1007/s11064-012-0786-1DOI Listing
August 2012

S-allyl cysteine mitigates oxidative damage and improves neurologic deficit in a rat model of focal cerebral ischemia.

Nutr Res 2012 Feb;32(2):133-43

Department of Medical Elementology and Toxicology (Fund for the Improvement of Science and Technology sponsored by DST and Special Assistance Programme sponsored by UGC), JamiaHamdard (Hamdard University), Hamdard Nagar, New Delhi-110062, India.

Oxidative stress and inflammatory damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The present study examined the hypothesis that S-allyl cysteine (SAC), organosulfur compounds found in garlic extract, would reduce oxidative stress-associated brain injury after middle cerebral artery occlusion (MCAO). To test this hypothesis, male Wistar rats were subjected to MCAO for 2 hours and 22-hour reperfusion. S-allyl cysteine was administered (100 mg/kg, b.wt.) intraperitoneally 30 minutes before the onset of ischemia and after the ischemia at the interval of 0, 6, and 12 hours. After 24 hours of reperfusion, rats were tested for neurobehavioral activities and were killed for the infarct volume, estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase). S-allyl cysteine treatment significantly reduced ischemic lesion volume, improved neurologic deficits, combated oxidative loads, and suppressed neuronal loss. Behavioral and biochemical alterations observed after MCAO were further associated with an increase in glial fibrillary acidic protein and inducible nitric oxide expression and were markedly inhibited by the treatment with SAC. The results suggest that SAC exhibits exuberant neuroprotective potential in rat ischemia/reperfusion model. Thus, this finding of SAC-induced adaptation to ischemic stress and inflammation could suggest a novel avenue for clinical intervention during ischemia and reperfusion.
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http://dx.doi.org/10.1016/j.nutres.2011.12.014DOI Listing
February 2012

Ocimum sanctum attenuates oxidative damage and neurological deficits following focal cerebral ischemia/reperfusion injury in rats.

Neurol Sci 2012 Dec 26;33(6):1239-47. Epub 2012 Jan 26.

Neurotoxicology Laboratory, Department of Medical Elementology and Toxicology (Fund for the Improvement of Science and Technology Sponsored by DST and Special Assistance Programme Sponsored by UGC), Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, 110062, India.

Stroke is an enormous public health problem with an imperative need for more effective therapy. Free radicals have been reported to play a role in the expansion of ischemic brain lesions, and the effect of free radical scavengers is still under debate. The present study investigated the neuroprotective effect of Ocimum sanctum (OS) to reduce brain injury after middle cerebral artery occlusion (MCAO). Male Wistar rats were subjected to MCAO for 2 h and reperfused for 22 h. The administration of OS (200 mg/kg bwt., orally) once daily for 15 days before MCAO showed marked reduction in infarct size, reduced the neurological deficits, and suppressed neuronal loss in MCAO rats. A significantly depleted activity of antioxidant enzymes and content of glutathione in MCAO group were protected significantly in MCAO group pretreated with OS. Conversely, the elevated level of thiobarbituric acid-reactive substances (TBARS) in MCAO group was attenuated significantly in OS-pretreated group when compared with MCAO group. Consequently, OS pretreatment may reduce the deterioration caused by free radicals, and thus may used to prevent subsequent behavioral, biochemical and histopathological changes that transpire during cerebral ischemia. This finding reflects that supplementation of OS intuitively by reasonable and understandable treatment effectively ameliorates the cerebral ischemia-induced oxidative damage.
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http://dx.doi.org/10.1007/s10072-012-0940-1DOI Listing
December 2012

Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson's disease.

Neurotox Res 2012 Jul 23;22(1):1-15. Epub 2011 Dec 23.

Neurotoxicology Laboratory, Department of Medical Elementology & Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, 110062, India.

This study was undertaken to investigate the neuroprotective effects of rutin (vitamin P) on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. Oxidative stress and inflammation is an important event, play a crucial role in neurodegenerative diseases. Rutin has been shown to have antioxidant and anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male Wistar rats were pre-treated with rutin (25 mg/kg bwt, orally) for 3 weeks and subjected to unilateral intrastriatal injection of 6-OHDA (10 μg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity, and were killed after 4 weeks of 6-OHDA infusion for the estimation of thiobarbituric acid reactive substances, glutathione, and its dependent enzymes (glutathione peroxidase and glutathione reductase), dopamine (DA) and its metabolite 3,4-dihydroxyphenyl acetic acid. The increase in 6-OHDA-induced rotations and deficits in locomotor activity and motor coordination and decrease in antioxidant level, DA content and its metabolite and increase in the number of dopaminergic D2 receptors in striatum were protected significantly with lesioned group pre-treated with rutin. These findings were further supported by the histopathological and immunohistochemical findings in the substantia nigra that showed that rutin protected neurons from deleterious effects of 6-OHDA. These results suggest that the consumption of rutin, which is novel vitamin, may have the possibility of protective effect against the neurological disorder such as PD.
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http://dx.doi.org/10.1007/s12640-011-9295-2DOI Listing
July 2012

Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke.

Brain Res 2011 Oct 27;1420:93-105. Epub 2011 Aug 27.

Neurotoxicology Laboratory, Department of Medical Elementology & Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi-110062, India.

Incidence of stroke is considered to be a major cause of death throughout the world. The middle cerebral artery occlusion (MCAO) for 2h followed by 22h of reperfusion model was used in male Wistar rats to study the protection of stroke by hesperidin. Hesperidin administration (50mg/kg b.wt.) once daily for 15days has improved the infarct size, reduced the neurological deficits in terms of behaviors, and protected the elevated level of thiobarbituric acid reactive species (TBARS). A significantly depleted activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) and content of glutathione (GSH) in MCAO group were protected significantly in MCAO group pretreated with hesperidin. Moreover, inflammatory mediators like TNF-α, IL-1β levels, expression of iNOS and glial fibrillary acidic protein (GFAP) were significantly attenuated in H+MCAO group as compared to MCAO group. In conclusion, prophylactic treatment with hesperidin ameliorated the functional and histological outcomes with elevated endogenous antioxidants status as well as reduced induction of proinflammatory cytokines in MCA occluded rat. We theorized that hesperidin is among the pharmacological agents that reduce free radicals and its associated inflammation and have been found to limit the extent of brain damage following stroke.
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http://dx.doi.org/10.1016/j.brainres.2011.08.047DOI Listing
October 2011
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