A5016667368- Spinal Cord Injury Research
- Nerve injury and regeneration
- Autophagy in Disease and Therapy
- Neurogenesis and neuroplasticity mechanisms
- Endoplasmic Reticulum Stress and Disease
- Protease and Inhibitor Mechanisms
- Circadian rhythm and melatonin
- Neuroscience of respiration and sleep
- Peptidase Inhibition and Analysis
- Neuroinflammation and Neurodegeneration Mechanisms
- Liver physiology and pathology
- Spinal Dysraphism and Malformations
- Cerebral Palsy and Movement Disorders
- Antimicrobial Peptides and Activities
- Viral Infectious Diseases and Gene Expression in Insects
- RNA Research and Splicing
- Neurogenetic and Muscular Disorders Research
- Adipose Tissue and Metabolism
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Metabolism, Diabetes, and Cancer
- NF-κB Signaling Pathways
- Veterinary Orthopedics and Neurology
- Intracerebral and Subarachnoid Hemorrhage Research
- Cell death mechanisms and regulation
University of Louisville
2016-2025
Neurological Surgery
2016-2025
Jawaharlal Nehru University
2002-2012
Activation of the unfolded protein response (UPR) is involved in pathogenesis numerous CNS myelin abnormalities; yet, its direct role traumatic spinal cord injury (SCI)-induced demyelination not known. The UPR an evolutionarily conserved cell defense mechanism initiated to restore endoplasmic reticulum homeostasis various cellular stresses including infection, trauma, and oxidative damage. However, if uncompensated, triggers apoptotic death. We demonstrate that three signaling branches PERK,...
Deficient myelination, the spiral wrapping of highly specialized membrane around axons, causes severe neurological disorders. Maturation oligodendrocyte progenitor cells (OPC) to myelinating oligodendrocytes (OL), sole providers central nervous system (CNS) myelin, is tightly regulated and involves extensive morphological changes. Here, we present evidence that autophagy, targeted isolation cytoplasm organelles by double-membrane autophagosome for lysosomal degradation, essential OPC/OL...
Autophagy mechanisms are well documented in neurons after spinal cord injury (SCI), but the direct functional role of autophagy oligodendrocyte (OL) survival SCI pathogenesis remains unknown. is an evolutionary conserved lysosomal-mediated catabolic pathway that ensures degradation dysfunctional cellular components to maintain homeostasis response various forms stress, including nutrient deprivation, hypoxia, reactive oxygen species, DNA damage, and endoplasmic reticulum (ER) stress. Using...
Expression and secretion of procathepsin D (pCD) increases proliferation, metastasis progression breast cancer but the structural moiety by which pCD exerts these effects is still ambiguous. Here, we present data on a series stable mutants to identify region that mediates this mitogenic effect. Mutations affecting activation peptide (AP) were studied together with catalytic glycosylation mutants. Mitogenic effect was evaluated using in vitro invasion proliferation assays vivo determining...
Manipulation of various components the endoplasmic reticulum (ER) stress response (ERSR) has led to functional recovery in diabetes, cancer, and several neurodegenerative diseases, indicating its use as a potential therapeutic intervention. One downstream pro-apoptotic transcription factors activated by ERSR is CCAAT enhancer binding protein (C/EBP) homologous (CHOP). Recently, we showed significant hindlimb locomotion function after moderate contusive spinal cord injury (SCI) mice null for...
The pentose phosphate pathway is the main source of NADPH, which by reducing oxidized glutathione, contributes to antioxidant defenses. Although oxidative stress plays a major role in white matter injury, significance NADPH for oligodendrocyte survival has not been yet investigated. It reported here that antimetabolite 6-amino-NADP (6AN) was cytotoxic cultured adult rat spinal cord precursor cells (OPCs) as well OPC-derived oligodendrocytes. 6AN-induced necrosis preceded increased production...
Cellular stressors inhibit general protein synthesis while upregulating stress response transcripts and/or proteins. Phosphorylation of the translation factor eIF2α by one several stress-activated kinases is a trigger for such signaling, known as integrated (ISR). The ISR regulates cell survival and function under stress. Here, germline knockout mice were used to determine contributions three major kinases, HRI/EIF2AK1, GCN2/EIF2AK4, PKR//EIF2AK2, pathogenesis moderate contusive spinal cord...
Abstract The transcription factor BMAL1/ARNTL is a non-redundant component of the clock pathway that regulates circadian oscillations gene expression. Loss BMAL1 perturbs organismal homeostasis and usually exacerbates pathological responses to many types insults by enhancing oxidative stress inflammation. Surprisingly, we observed improved locomotor recovery spinal cord white matter sparing in Bmal1 −/− mice after T9 contusive injury (SCI). While acute loss neurons oligodendrocytes was...
After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central that response PERK signaling, which ultimately initiates a pro-apoptotic if cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive consequences determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) chronic (6 weeks effects of conditionally deleting Perk from OLs prior While transcript expressed in many types...
Procathepsin D (pCD), a zymogen of lysosomal aspartic peptidase cathepsin D, overexpression is correlated with highly invasive malignancies, including breast cancer. Recently, different studies have shown the role secreted pCD as mitogen acting both in an autocrine and paracrine manner. The aim present study to examine anti-tumor effects elicited by decrease protein level ribozyme explore therapeutic potential this specific targeting. Using mFold program, we designed seven anti-pCD ribozymes...
Activation of the endoplasmic reticulum stress response (ERSR) is a hallmark various pathological diseases and/or traumatic injuries. Restoration ER homeostasis can contribute to improvement in functional outcome these diseases. Using genetic and pharmacological inhibition PERK-CHOP arm ERSR, we recently demonstrated improvements hindlimb locomotion after spinal cord injury (SCI) implicated oligodendrocyte survival as potential mechanism. Here, investigated contribution stress-inducible...
The present study evaluates anti-hyperglycemic activity of fractionated Momordica charantia (bitter gourd) seed extracts. Fasting blood glucose levels were evaluated before and after administration different fractions the extract. Among three tested, fraction Mc-3 (15 mg/kg b.wt.) showed maximum reduced in experimental diabetic rats significantly. activities key regulatory enzymes metabolism (hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase) determined...
Abstract The endoplasmic reticulum stress response (ERSR) is activated in various neurodegenerative diseases and/or after CNS traumatic injuries. ERSR comprised of three major arms, PERK, IRE‐1, and activating transcription factor‐6, with the latter two contributing to unfolded protein (UPR). PERK activity overlaps integrated (ISR) kinases, PKR, HRI, GCN2 which all signal through, eukaryotic initiation factor 2α, ATF4, CHOP. All initially attempt restore (ER) homeostasis, but if ER...
AbstractElevated level of procathepsin D (pCD), a zymogen lysosomal aspartic proteinase cathepsin D, is associated with highly invasive neoplasms that include breast cancer. Independent studies have established secreted pCD functions as growth factor acting both in an autocrine and paracrine manner. Therefore, to explore whether can be employed therapeutic target, the present study evaluates impact knockdown using RNA interference technology. Of three siRNA oligos tested, siRNA-3 exhibited...
Abstract The integrated stress response (ISR)-activated transcription factors ATF4 and CHOP/DDIT3 may regulate oligodendrocyte (OL) survival, tissue damage functional impairment/recovery in white matter pathologies, including traumatic spinal cord injury (SCI). Accordingly, OLs of OL-specific RiboTag mice, Atf4, Chop/Ddit3 their downstream target gene transcripts were acutely upregulated at 2, but not 10, days post-contusive T9 SCI coinciding with maximal loss tissue. Unexpectedly, another,...
Abstract Histone deacetylase (HDAC) inhibition mediated by small molecule HDAC inhibitors (HDACi) has demonstrated divergent effects including toxicity towards transformed cell lines, neuroprotection in neurological disease models, and of oligodendrocyte precursor (OPC) differentiation to mature oligodendrocytes (OL). However, it remains unknown if transient may promote OPC survival. Using mouse cortical primary cultures, we investigated the FDA approved pan‐HDACi suberoylanilide hydroxamic...