Publications by authors named "Priya Jhelum"

10 Publications

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Therapeutic angiogenesis using zinc oxide nanoflowers for the treatment of hind limb ischemia in rat model.

Biomed Mater 2021 Mar 3. Epub 2021 Mar 3.

Biomaterials Group, LST Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, AP, Hyderabad, Andhra Pradesh, 500007, INDIA.

Critical limb ischemia (CLI) is considered as a severe type of peripheral artery diseases (PADs) which occurs due to the inadequate supply of blood to the limb extremities. CLI patients often suffer from extreme cramping pain, impaired wound healing, immobility, cardiovascular complications, amputation of the affected limb and even death. The conventional therapy for the treatment of CLI includes surgical revascularization as well as restoring angiogenesis using growth factor therapy. However, surgical revascularization is suitable for only a minor percentage of CLI patients and it is associated with high perioperative mortality rate. The use of growth factors is also limited in terms of their poor therapeutic angiogenesis potential as observed by the earlier clinical studies, which could be attributed to their poor bio-availability and non-specificity issues. Therefore, to outweigh the aforesaid disadvantages of the conventional strategies, there is an utmost need for the advancement of new alternative therapeutic biomaterials to treat CLI. Since past few decades, various research groups including ours have been involved in developing different pro-angiogenic nanomaterials. Among them, zinc oxide nanoflowers (ZONF), established in our laboratory, are considered as one of the potent nanoparticles to induce therapeutic angiogenesis. In our earlier studies, we have depicted that ZONF promote angiogenesis by inducing the formation of reactive oxygen species (ROS) and nitric oxide (NO) as well as activating Akt/MAPK/eNOS cell signaling pathways in the endothelial cells. Recently, we have also reported the therapeutic potential of ZONF to treat cerebral ischemia through their neuritogenic and neuroprotective properties, exploiting angio-neural cross talk. Considering the excellent pro-angiogenic properties of ZONF and importance of revascularization for the recovery of CLI, in this present study, we have comprehensively explored the therapeutic potential of ZONF in a rat hind limb ischemia model (established by ligating the femoral artery of hind limb), an animal model that mimics CLI in humans. The behavioural studies, laser Doppler perfusion imaging, histopathology, immunofluorescence as well as estimation of serum NO level depicted that the administration of ZONF could ameliorate the ischemic conditions in rats at a faster rate by promoting therapeutic angiogenesis to the ischemic sites. Altogether, the present study offers an alternative nanomedicine approach employing ZONF for the treatment of PADs.
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http://dx.doi.org/10.1088/1748-605X/abebd1DOI Listing
March 2021

Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination.

J Neurosci 2020 11 26;40(48):9327-9341. Epub 2020 Oct 26.

Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper-containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined whether chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron-mediated OL loss. We show that giving mice (male) CZ in the diet induces rapid loss of OL in the corpus callosum by 2 d, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small-molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders, such as multiple sclerosis and CNS injury. Cuprizone (CZ) is a copper chelator that induces demyelination. Although it is a widely used model to study demyelination and remyelination in the context of multiple sclerosis, the mechanisms mediating demyelination is not fully understood. This study shows, for the first time, that CZ induces demyelination via ferroptosis-mediated rapid loss of oligodendrocytes. This work shows that chelating copper with CZ leads to the expression of molecules that rapidly mobilize iron from ferritin (an iron storage protein), that triggers iron-mediated lipid peroxidation and oligodendrocyte loss (via ferroptosis). Such rapid mobilization of iron from cellular stores may also play a role in cell death in other neurologic conditions.
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http://dx.doi.org/10.1523/JNEUROSCI.1749-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687057PMC
November 2020

Potential Therapeutic Application of Zinc Oxide Nanoflowers in the Cerebral Ischemia Rat Model through Neuritogenic and Neuroprotective Properties.

Bioconjug Chem 2020 03 25;31(3):895-906. Epub 2020 Feb 25.

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.

Neuritogenesis, a complex process of the sprouting of neurites, plays a vital role in the structural and functional restoration of cerebral ischemia-injured neuronal tissue. Practically, there is no effective long-term treatment strategy for cerebral ischemia in clinical practice to date due to several limitations of conventional therapies, facilitating the urgency to develop new alternative therapeutic approaches. Herein, for the first time we report that pro-angiogenic nanomaterials, zinc oxide nanoflowers (ZONF), exhibit neuritogenic activity by elevating mRNA expression of different neurotrophins, following PI3K/Akt-MAPK/ERK signaling pathways. Further, ZONF administration to global cerebral ischemia-induced Fischer rats shows improved neurobehavior and enhanced synaptic plasticity of neurons via upregulation of Neurabin-2 and NT-3, revealing their neuroprotective activity. Altogether, this study offers the basis for exploitation of angio-neural cross talk of other pro-angiogenic nano/biomaterials for future advancement of alternative treatment strategies for cerebral ischemia, where neuritogenesis and neural repair are highly critical.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00030DOI Listing
March 2020

Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury.

PLoS Biol 2018 10 17;16(10):e2005264. Epub 2018 Oct 17.

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Quebec, Canada.

Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially modulate each other's functions. Importantly, microglia-mediated phagocytosis and inflammation are suppressed by infiltrating macrophages. In the context of spinal cord injury (SCI), preventing such communication increases microglial activation and worsens functional recovery. We suggest that macrophages entering the CNS provide a regulatory mechanism that controls acute and long-term microglia-mediated inflammation, which may drive damage in a variety of CNS conditions.
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http://dx.doi.org/10.1371/journal.pbio.2005264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205650PMC
October 2018

Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models.

Curr Neuropharmacol 2017 ;15(6):815-830

Chemical Biology, CSIR-Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad-500007, India.

Background: Understanding the complexities associated with the ischemic condition and identifying therapeutic targets in ischemia is a continued challenge in stroke biology. Emerging evidence reveals the potential involvement of epigenetic mechanisms in the incident and outcome of stroke, suggesting novel therapeutic options of targeting different molecules related to epigenetic regulation.

Objective: This review summarizes our current understanding of ischemic pathophysiology, describes various in vivo and in vitro models of ischemia, and examines epigenetic modifications associated with the ischemic condition.

Method: We focus on microRNAs, DNA methylation, and histone modifying enzymes, and present how epigenetic studies are revealing novel drug target candidates in stroke.

Conclusion: Finally, we discuss emerging approaches for the prevention and treatment of stroke and post-stroke effects using pharmacological interventions with a wide therapeutic window.
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http://dx.doi.org/10.2174/1570159X14666161213143907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652028PMC
April 2018

Insights into the epigenetic mechanisms involving histone lysine methylation and demethylation in ischemia induced damage and repair has therapeutic implication.

Biochim Biophys Acta Mol Basis Dis 2017 01 21;1863(1):152-164. Epub 2016 Sep 21.

CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India. Electronic address:

Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. Therapeutic interventions to minimize ischemia-induced neural damage are limited due to poor understanding of molecular mechanisms mediating complex pathophysiology in stroke. Recently, epigenetic mechanisms mostly histone lysine (K) acetylation and deacetylation have been implicated in ischemic brain damage and have expanded the dimensions of potential therapeutic intervention to the systemic/local administration of histone deacetylase inhibitors. However, the role of other epigenetic mechanisms such as histone lysine methylation and demethylation in stroke-induced damage and subsequent recovery process is elusive. Here, we established an Internal Carotid Artery Occlusion (ICAO) model in CD1 mouse that resulted in mild to moderate level of ischemic damage to the striatum, as suggested by magnetic resonance imaging (MRI), TUNEL and histopathological staining along with an evaluation of neurological deficit score (NDS), grip strength and rotarod performance. The molecular investigations show dysregulation of a number of histone lysine methylases (KMTs) and few of histone lysine demethylases (KDMs) post-ICAO with significant global attenuation in the transcriptionally repressive epigenetic mark H3K9me2 in the striatum. Administration of Dimethyloxalylglycine (DMOG), an inhibitor of KDM4 or JMJD2 class of histone lysine demethylases, significantly ameliorated stroke-induced NDS by restoring perturbed H3K9me2 levels in the ischemia-affected striatum. Overall, these results highlight the novel role of epigenetic regulatory mechanisms controlling the epigenetic mark H3K9me2 in mediating the stroke-induced striatal damage and subsequent repair following mild to moderate cerebral ischemia.
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http://dx.doi.org/10.1016/j.bbadis.2016.09.014DOI Listing
January 2017

Sirtuin 1 and 7 mediate resveratrol-induced recovery from hyper-anxiety in high-fructose-fed prediabetic rats.

J Biosci 2016 Sep;41(3):407-17

Chemical Biology, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.

Hyperglycaemia in diabetes is either caused by reduced availability of insulin (type 1 diabetes, T1D) or insulin resistance to the cells (type 2 diabetes, T2D). In recent years, the prevalence of T2D has increased to an alarming proportion, encompassing 95 percent of the total diabetic burden, probably due to economy-driven changes in lifestyle. Recent epidemiological studies show comorbid depression, anxiety and related mental illness. To explore the molecular mechanisms underlying this comorbid conditions, we used Sprague-Dawley rats on high-fructose diet for 8 weeks to induce prediabetic condition. Rats with this metabolic syndrome also showed hyper-anxiety when they were subjected to anxiety-related behavioural assays. Rats were administered with resveratrol, an activator of sirtuins, and metformin, a standard antidiabetic drug, simultaneously with fructose. We observed that resveratrol was more effective in protecting from both the metabolic (prediabetic) and affective (anxiety) disorders than metformin. Molecular studies showed that recovery was associated with the upregulation of few nuclear sirtuins that act epigenetically - Sirt 1 and 7, which were significantly attenuated in the striatum of prediabetic rats. In conclusion, our study showed that hyper-anxiety associated with prediabetic condition is ameliorated by resveratrol through modulation of sirtuins, which is more or less similar to metformin.
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http://dx.doi.org/10.1007/s12038-016-9627-8DOI Listing
September 2016

Sameerpannag Ras Mixture (SRM) improved neurobehavioral deficits following acute ischemic stroke by attenuating neuroinflammatory response.

J Ethnopharmacol 2017 Feb 22;197:147-156. Epub 2016 Jul 22.

Chemical Biology, CSIR - Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India. Electronic address:

Ethnopharmacological Relevance: Cerebral ischemic stroke is one of the leading causes of death and long-term disability worldwide. Unfortunately, due to the failure of most of drugs in clinical trials recently, attentions have moved towards the traditional system of medicines including Ayurveda. In Ayurveda, Sameerpannag Ras (SR) is a mineral and metallic origin based formulation which has been used for the treatment of arthritis and chronic systematic inflammatory disorder. The current study was designed to investigate the neuroprotective effects of Sameerpannag Ras Mixture (SRM), on the neurobehavioral dysfunction and associated neuroinflammation, induced by transient Internal Carotid Artery Occlusion (ICAO) in mice model.

Materials And Methods: In the present study, mice were treated with Sameerpannag Ras Mixture (SRM) at the dose of 40mg/kg body weight by oral gavages for 3 and 7days respectively, twice a day, after the induction of ICAO for 90min followed by reperfusion. The efficacy of SRM was examined by scoring neurological behavioral deficit using the standard neurological deficit score (NDS), grip strength and rotarod performance tests at different time intervals of post-ICAO.

Results: Post-ischemic treatment with Sameerpannag Ras Mixture (SRM) at 40mg/kg significantly reduced Neurological Deficit Score and improved the motor coordination at different time intervals post-ICAO. The analysis of RT-qPCR data showed that transient cerebral ischemia could induce the inflammatory response genes in the affected striatal region of ICAO group, as compared to sham group, on day3 and day7 post-ICAO. Interestingly, SRM treatment showed marked improvement in the ischemia-induced neurobehavioral deficits by attenuating ischemia-induced neuroinflammatory response at both gene and protein level.

Conclusion: The present study suggests that Sameerpannag Ras Mixture (SRM) treatment ameliorates behavioral outcomes after mild ischemia through the suppression of a number of inflammatory response genes involved in neuronal damage. This is the first report of the molecular mechanism underlying the significant neuroprotective action of the Ayurvedic drug, Sameerpannag Ras Mixture (SRM), using a mild stroke in mice model.
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http://dx.doi.org/10.1016/j.jep.2016.07.059DOI Listing
February 2017

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action.

Sci Rep 2015 Sep 21;5:14134. Epub 2015 Sep 21.

CSIR- Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, India.

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.
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http://dx.doi.org/10.1038/srep14134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585672PMC
September 2015