Showing papers by "Swapan K. Ray published in 2022"

Premarin Reduces Neurodegeneration and Promotes Improvement of Function in an Animal Model of Spinal Cord Injury

Abstract: Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso–Beattie–Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.

Specific microRNAs for Modulation of Autophagy in Spinal Cord Injury

Abstract: The treatment of spinal cord injury (SCI) is currently a major challenge, with a severe lack of effective therapies for yielding meaningful improvements in function. Therefore, there is a great opportunity for the development of novel treatment strategies for SCI. The modulation of autophagy, a process by which a cell degrades and recycles unnecessary or harmful components (protein aggregates, organelles, etc.) to maintain cellular homeostasis and respond to a changing microenvironment, is thought to have potential for treating many neurodegenerative conditions, including SCI. The discovery of microRNAs (miRNAs), which are short ribonucleotide transcripts for targeting of specific messenger RNAs (mRNAs) for silencing, shows prevention of the translation of mRNAs to the corresponding proteins affecting various cellular processes, including autophagy. The number of known miRNAs and their targets continues to grow rapidly. This review article aims to explore the relationship between autophagy and SCI, specifically with the intent of identifying specific miRNAs that can be useful to modulate autophagy for neuroprotection and the improvement of functional recovery in SCI.

Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities

Abstract: Glioblastoma multiforme (GBM) is a brain tumor notorious for its propensity to recur after the standard treatments of surgical resection, ionizing radiation (IR), and temozolomide (TMZ). Combined with the acquired resistance to standard treatments and recurrence, GBM is an especially deadly malignancy with hardly any worthwhile treatment options. The treatment resistance of GBM is influenced, in large part, by the contributions from two main degradative pathways in eukaryotic cells: ubiquitin-proteasome system (UPS) and autophagy. These two systems influence GBM cell survival by removing and recycling cellular components that have been damaged by treatments, as well as by modulating metabolism and selective degradation of components of cell survival or cell death pathways. There has recently been a large amount of interest in potential cancer therapies involving modulation of UPS or autophagy pathways. There is significant crosstalk between the two systems that pose therapeutic challenges, including utilization of ubiquitin signaling, the degradation of components of one system by the other, and compensatory activation of autophagy in the case of proteasome inhibition for GBM cell survival and proliferation. There are several important regulatory nodes which have functions affecting both systems. There are various molecular components at the intersections of UPS and autophagy pathways that pose challenges but also show some new therapeutic opportunities for GBM. This review article aims to provide an overview of the recent advancements in research regarding the intersections of UPS and autophagy with relevance to finding novel GBM treatment opportunities, especially for combating GBM treatment resistance.