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Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice:involvement of Alda-1-induced ALDh2 activation-mediated suppression of reactive aldehyde mechanisms

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Neural Regeneration Research 2022年第1期17卷 185-193页

作者： Mushfiquddin Khan Fei Qiao Pavan Kumar S.M.Touhidul Islam Avtar K.Singh Jeseong Won Inderjit Singh Department of Pediatrics Medical University of South CarolinaCharlestonSCUSA Department of Pathology and Laboratory Medicine Medical University of South CarolinaCharlestonSCUSA ralph h.johnson va medical center CharlestonSCUSA

Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-hNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane *** aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion *** scavenging of reactive aldehydes results in limited improved motor and sensory *** this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDh2)to detoxify 4-hNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDh2,was used as a therapeutic tool to suppress the 4-hNE *** was induced by an impactor at the T9–10 vertebral *** animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive *** function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal ***2 activity was measured by enzymatic assay.4-hNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/*** resulted in a sustained and prolonged overload of 4-hNE,which parallels with the decreased activity of ALDh2 and low functional ***-1 treatment of SCI decreased 4-hNE load and enhanced the activity of ALDh2 in both the acute and the chronic phases of ***,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory ***,the results provide evidence that enhancing the ALDh2 activity by Alda-1 treatment of SCI mice suppresses the 4-hNE load that attenuates neuroinfl

关键词： 4-hydroxy-trans-2-nonenal Alda-1 ALDh2 Basso Mouse Scale score functional recovery mitochondrial function neuroinflammation neuroprotection pain spinal cord injury

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hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment

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World Journal of Stem Cells 2015年第2期7卷 253-265页

作者： Ying Xiong Lindsay T Mc Donald Dayvia L Russell Ryan R Kelly Katie R Wilson Meenal Mehrotra Adam C Soloff Amanda C LaRue Research Services Ralph H Johnson Veterans Affairs Medical Center Department of Pathology and Laboratory Medicine Ralph H Johnson Veterans Affairs Medical Center the hollings Cancer center Medical University of South CarolinaRalph H Johnson Veterans Affairs Medical Center Department of Microbiology and Immunology Ralph H Johnson Veterans Affairs Medical Center

The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.

关键词： hematopoietic stem cell Cancer associatedadipocyte Mesenchymal stromal cell Tumor progression Cancer associated fibroblast Plasticity Metastasis Fibrocyte

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Regulation of enolase activation to promote neural protection and regeneration in spinal cord injury

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Neural Regeneration Research 2023年第7期18卷 1457-1462页

作者： hannah MMcCoy Rachel Polcyn Naren LBanik Azizul haque Department of Microbiology and Immunology Medical University of South CarolinaCharlestonSCUSA Department of Neurosurgery Medical University of South CarolinaCharlestonSCUSA ralph h.johnson Veterans Administration medical center CharlestonSCUSA

Spinal cord injury(SCI)is a debilitating condition characterized by damage to the spinal cord resulting in loss of function,mobility,and sensation with no *** and Drug Administration-approved ***,a multifunctional glycolytic enzyme upregulated after SCI,promotes pro-and anti-inflammatory events and regulates functional recovery in *** is normally expressed in the cytosol,but the expression is upregulated at the cell surface following cellular injury,promoting glial cell activation and signal transduction pathway ***-induced microglia activation triggers pro-inflammatory mediators at the injury site,activating other immune cells and metabolic events,i.e.,Rho-associated kinase,contributing to the neuroinflammation found in *** surface expression also activates cathepsin X,resulting in cleavage of the C-terminal end of neuron-specific enolase(NSE)and non-neuronal enolase(NNE).Fully functional enolase is necessary as NSE/NNE C-terminal proteins activate many neurotrophic processes,i.e.,the plasminogen activation system,phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B,and mitogen-activated protein kinase/extracellular signal-regulated *** here suggest an enolase inhibitor,ENOblock,attenuates the activation of Rho-associated kinase,which may decrease glial cell activation and promote functional recovery following ***,ENOblock inhibits cathepsin X,which may help prevent the cleavage of the neurotrophic C-terminal protein allowing full plasminogen activation and phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase *** combined NSE/cathepsin X inhibition may serve as a potential therapeutic strategy for preventing neuroinflammation/degeneration and promoting neural cell regeneration and recovery following *** role of cell membrane-expressed enolase and associated metabolic events should be investigated to determine if the same strategies can be applied to other neu

关键词： cathepsin X ENOblock enolase glia mitogen-activated protein kinase/extracellular signal-regulated kinase neurodegeneration neuroinflammation phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B Rho-associated protein kinase spinal cord injury

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Long-term differences in urinary, bowel and sexual function among men treated with surgery versus radiation for prostate cancer

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Asian Journal of Andrology 2013年第4期15卷 443-444页

作者： Justin D Ehett James S Rosoff Sandip M Prasad Department of Urology Medical University of South Carolina Charleston SC 29425 USA and Section of Urology Ralph H. Johnson VA Medical Center Charleston SC 29401 USA

surgery and radiation have both been shown to increase the longterm diseasespecific survival rate for men with din icaUy localized prostate cancer. Although both modalities have demonstrated favor able effects on cancer control, questions regarding quality of life （QoL） and func tional outcomes remain incompletely answered. To date, no randomized prospective trials have been performed comparing the two treatment modalities and so indirect compar isons of longterm functional outcomes have served as a substitute to aid in patient coun seling and decisionmaking. As there is a pau city of longterm data comparing functional outcomes after radical prostatectomy and external beam radiation therapy, a recent art icle by Resnick et al.,1 has attempted to pro vide additional information about this topic in terms of continence, erectile function and bowel function. Utilizing the Prostate Cancer Outcomes Study cohort, a populationbased cohort of men diagnosed with prostate cancer in the pro statespecific antigen （PSA） era, the authors compared rates of urinary incontinence, erect ile dysfunction, and bowel urgency at 2, 5 and 15 years after primary therapy. They showed that men undergoing prostatectomy had higher rates of incontinence and erectile dys function at 2 and 5 years, but these rates were similar to those in the radiotherapy group at 15 years. More specifically, men were approxi mately five times more likely to have urinary continence issues if they underwent prostatec tomv versus radiotherapy and almost three anda half times more likely to develop erectile dys function in the short to intermediateterm following primary treatment. As expected, rates of bowel urgency were higher in the radio therapy group at 2 and 5 years, but not sig nificantly different from the surgery group at 15 years. In addition, the authors note that the rate of incontinence and erectile function pro gressively worsened over time, regardless of primary treatment modality. At 15 years of foll

关键词： Long-term bowel sexual function

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Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

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Neural Regeneration Research 2023年第5期18卷 940-946页

作者： Ali Myatich Azizul haque Christopher Sole Naren L.Banik Department of Microbiology and Immunology Medical University of South CarolinaCharlestonSCUSA Department of Neurosurgery Medical University of South CarolinaCharlestonSCUSA ralph h.johnson Veterans Administration medical center CharlestonSCUSA Department of health and human Performance The CitadelCharlestonSCUSA

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. however, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

关键词： axonal damage clemastine myelination neuronal death oligodendrocytes skeletal muscle spinal cord injury

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Implications of enolase in the RANKL-mediated osteoclast activity following spinal cord injury

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BIOCELL 2021年第6期45卷 1453-1457页

作者： RAMShA ShAMS NAREN LBANIK AZIZUL hAQUE Department of Microbiology and Immunology Medical University of South CarolinaCharlestonSC 29425USA Department of Neurosurgery Medical University of South CarolinaCharlestonSC 29425USA ralph h.johnson Veterans Administration medical center CharlestonSC 29401USA

Spinal Cord Injury(SCI)is a debilitating condition characterized by damage to the spinal cord,resulting in loss of function,mobility,and *** increasingly prevalent in the US,no FDA-approved therapy exists due to the unfortunate complexity of the condition,and the difficulties of SCI may be furthered by the development of SCI-related complications,such as *** demonstrates two crucial stages for consideration:the primary stage and the secondary *** the primary stage is suggested to be immediate and irreversible,the secondary stage is proposed as a promising window of opportunity for therapeutic ***,a metabolic enzyme upregulated after SCI,performs non-glycolytic functions,promoting inflammatory events via extracellular degradative actions and increased production of inflammatory cytokines and ***-specific enolase(NSE)serves as a biomarker of functional damage to neurons following SCI,and the inhibition of NSE has been demonstrated to reduce signs of secondary injury of SCI and to ameliorate *** Viewpoint article involves enolase activation in the regulation of RANK-RANKL pathway and summarizes succinctly the mechanisms influencing osteoclast-mediated resorption of bone in *** laboratory proposes that inhibition of enolase activation may reduce SCI-induced inflammatory response and decrease osteoclast activity,limiting the chances of skeletal tissue loss in SCI.

关键词： Enolase RANK RANKL Osteoporosis Neuronal death Spinal cord injury

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hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

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Neural Regeneration Research 2017年第5期12卷 696-701页

作者： Mushfiquddin Khan hamza Khan Inderjit Singh Avtar K.Singh Department of Pediatrics Medical University of South Carolina Charleston SC USA College of Medicine University of South Carolina Columbia SC USA Department of Pathology and Laboratory Medicine Medical University of South Carolina Charleston SC USA ralph h. johnson va medical center Charleston SC USA

Mild traumatic brain injury（TBI）, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide（NO）, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. hypoxia inducible factor-1 alpha（hIF-1α）, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of hIF-1α is regulated by NO via the mechanism of S-nitrosylation of hIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione（GSNO） and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes hIF-1α. Exogenously administered GSNO was found not only to stabilize hIF-1α and to induce hIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

关键词： traumatic brain injury hypoxia inducible factor-1 alpha S-nitrosoglutathione neurorepair functional recovery

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Mediastinal pancreatic pseudocyst with hemorrhage and left gastric artery pseudoaneurysm,managed with left gastric artery embolization and placement of percutaneous trans-hepatic pseudocyst drainage

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Gastroenterology Report 2016年第3期4卷 241-245,I0003页

作者： Parag Brahmbhatt Jason McKinney John Litchfield Mehul Panchal Thomas Borthwick Mark Young Lance Klosterman Division of Gastroenterology and hepatology East Tennessee State UniversityJohnson CityTNUSA Department of Medicine M.P.Shah Medical CollegeJamnagarGujaratIndia Department of Gastroenterology James H.Quillen VA Medical CenterJohnson CityTNUSA Department of Radiology James H.Quillen VA Medical centerJohnson CityTNUSA

Mediastinal pancreatic pseudocyst(MPP)is a rare,but known,complication of both acute and chronic *** pseudocysts are associated with alcoholic *** advances in endoscopic techniques have shown promising results,with reduced chances of infection and recurrence than with percutaneous drainage,but limited availability restricts widespread *** gastric artery pseudoaneurysm with mediastinal pseudocyst has not been described in the literature to *** report a successful resolution of hemorrhagic MPP with embolization of pseudoaneurysm and percutaneous trans-hepatic pseudocyst drainage.

关键词： mediastinal pancreatic pseudocyst dysphagia percutaneous pseudocyst drainage

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Development of donor specific antibodies after SARS-CoV-2 vaccination:What do we know so far?

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World Journal of Meta-Analysis 2024年第2期12卷 1-4页

作者： Ahmed Daoud Karim Soliman Maria Aurora Posadas Salas Sakshi vaishnav Genta Uehara AhmedAbdelkader Tibor Fulop Michael J Casey Department of Medicine Division of NephrologyMedical University of South CarolinaCharlestonSC 29425United States Department of Medicine Cairo University Medical SchoolCairo 11211Egypt Department of Medicine Medical ServicesRalph H.Johnson VA Medical CenterCharlestonSC 29425United States Department of Medicine Division of NephrologyMedical ServicesRalph H.Johnson VA Medical CenterCharlestonSC 29425United States

vaccination against Coronavirus disease-19(COVID-19)was pivotal to limit spread,morbidity and *** aim is to find out whether vaccines against COVID-19 lead to an immunological response stimulating the production of de novo donor specific antibodies(DSAs)or increase in mean fluorescence intensity(MFI)of pre-existing DSAs in kidney transplant recipients(KTRs).This study involved a detailed literature search through December 2nd,2023 using PubMed as the primary *** search strategy incorporated a combination of relevant medical Subject headings terms and keywords:"COVID-19","SARS-CoV-2 vaccination","Kidney,Renal Transplant",and"Donor specific antibodies".The results from related studies were collated and analyzed.A total of 6 studies were identified,encompassing 460 KTRs vaccinated against *** responses were detected in 8 KTRs of which 5 had increased MFIs,1 had de novo DSA,and 2 were categorized as either having de novo DSA or increased *** were 48 KTRs with pre-existing DSAs prior to vaccination,but one study(Massa et al)did not report whether pre-existing DSAs were associated with post vaccination *** the remaining 5 studies,35 KTRs with pre-existing DSAs were identified of which 7 KTRs(20%)developed de novo DSAs or increased ***,no immunological response was detected in 452(98.3%)*** study affirms prior reports that COVID-19 vaccination is safe for KTRs,especially if there are no pre-existing ***,if KTRs have pre-existing DSAs,then an increased immunological risk may be *** findings need to be taken cautiously as they are based on a limited number of patients so further studies are still needed for confirmation.

关键词： COVID-19 SARS-CoV-2 vaccination Kidney Renal transplant Donor specific antibodies

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hypertension and obesity in living kidney donors

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World Journal of Transplantation 2021年第6期11卷 180-186页

作者： Mahmoud M Mohamed Ahmed Daoud Syed Quadri Michael J Casey Mariah Aurora Posadas Salas Vinaya Rao Tibor Fülöp Karim M Soliman Department of Medicine Division of NephrologyUniversity of TennesseeMemphisTN 38163United States Department of Medicine Division of NephrologyCairo UniversityCairo 11562Egypt Department of Medicine Division of NephrologyMedical University of South CarolinaCharlestonSC 29425United States Medicine Service Ralph H.Johnson VA Medical CenterCharlestonSC 29401United States

Over the past few decades,the shortage in the kidney donor pool as compared to the increasing number of candidates on the kidney transplant waitlist led to loosening of kidney donors’acceptance *** and obesity represent risk factors for chronic kidney disease,both in native kidneys and those in kidney transplant *** great progress has been made in kidney transplantation from living donors to benefit the recipient survival and quality of life,progress has been slow to fully risk-characterize the *** review critically reassesses the current state of understanding regarding the risk of endstage kidney disease in those donors with obesity,hypertension or *** risk assessment tools need to be developed urgently to fully understand the risk glomerular filtration rate compensation failure in the remaining kidney of the donors.

关键词： Living donor Kidney Obesity hypertension Living kidney donors

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