NeuroImmune pharmacology and therapeutics最新文献

{"title":"Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα","authors":"S. Raha, Ramesh K Paidi, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0027","DOIUrl":"https://doi.org/10.1515/nipt-2023-0027","url":null,"abstract":"\u0000 Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"14 30","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140240491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective mushrooms","authors":"M. M. Abdelmoaty, Rana Kadry, R. Mosley, H. Gendelman","doi":"10.1515/nipt-2024-0004","DOIUrl":"https://doi.org/10.1515/nipt-2024-0004","url":null,"abstract":"\u0000 \u0000 \u0000 Alternative medicines commonly supplement or, at times, replace standard medical treatment. One area of increasing attention is disease-modifying medicines for neurodegenerative diseases. However, few such alternatives have been investigated thoroughly with an eye towards understanding mechanisms of action for clinical use. Medicinal mushrooms have important health benefits and pharmacological activities with anti-inflammatory, antioxidant, antibacterial, antiviral, immunomodulatory, digestive, cytoprotective, homeostatic, and neuroprotective activities. Edible mushrooms are known to play roles in preventing age-related diseases. Several studies have revealed that polysaccharides, terpenes, and phenolic compounds are chemical components derived from mushrooms with pharmacological activities. Due to limited effective protocols for mushroom protein extraction for proteomic studies, information about these medicinally related proteins and their biological functions remains enigmatic.\u0000 \u0000 \u0000 \u0000 Herein, we have performed proteomic studies of two mushroom species Laricifomes officinalis (agarikon) and Grifola frondosa (maitake).\u0000 \u0000 \u0000 \u0000 These studies serve to uncover a foundation for putative proteome-associated neuroprotective processes. The recovered proteins from both species show multiple cell-specific signaling pathways including unfolded protein response, and mitochondrial protein import as well as those linked to BAG2, ubiquitination, apoptosis, microautophagy, glycolysis, SNARE, and immunogenic cell signaling pathways.\u0000 \u0000 \u0000 \u0000 This study uncovered mushroom proteome-associated proteins which serve to better understand the structural and functional properties of mushrooms used as alternative medicines for broad potential health benefits.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"27 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140261737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction","authors":"J. Proulx, In-Woo Park, K. Borgmann","doi":"10.1515/nipt-2023-0020","DOIUrl":"https://doi.org/10.1515/nipt-2023-0020","url":null,"abstract":"\u0000 \u0000 \u0000 Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one’s risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction.\u0000 \u0000 \u0000 \u0000 Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression.\u0000 \u0000 \u0000 \u0000 Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression.\u0000 \u0000 \u0000 \u0000 Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"11 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139958777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nebulization of low-dose aspirin ameliorates Huntington’s pathology in N171-82Q transgenic mice","authors":"S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0026","DOIUrl":"https://doi.org/10.1515/nipt-2023-0026","url":null,"abstract":"\u0000 Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" 53","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139788038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nebulization of low-dose aspirin ameliorates Huntington’s pathology in N171-82Q transgenic mice","authors":"S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0026","DOIUrl":"https://doi.org/10.1515/nipt-2023-0026","url":null,"abstract":"\u0000 Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"412 27","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139847619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virology, pathogenesis, epidemiology and clinical management of HTLV-1 infection. Proceedings of the 30th HTLV European research network (HERN 2023)","authors":"C. de Mendoza, Graham Taylor, A. Gessain, Andrea K. Thoma-Kress, Charles R. M. Bangham, Jan Vesterbacka, Roberto Accolla, Ali Bazarbachi, Jan van Weyenbergh, Lucy Cook, Jorge Casseb, Juan Carlos Ramos, Carolina Rosadas, Beatrice Macchi, O. Cassar, V. Soriano","doi":"10.1515/nipt-2023-0025","DOIUrl":"https://doi.org/10.1515/nipt-2023-0025","url":null,"abstract":"Abstract The 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15–16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity","authors":"P. Halcrow, Darius N. K. Quansah, Nirmal Kumar, Rebecca L. Solloway, Kayla M. Teigen, Kasumi A. Lee, Braelyn Liang, Jonathan D. Geiger","doi":"10.1515/nipt-2023-0021","DOIUrl":"https://doi.org/10.1515/nipt-2023-0021","url":null,"abstract":"Abstract Objectives Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pKa values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are “master regulators of iron homeostasis”, and neurodegeneration is linked to ferrous iron (Fe2+)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe2+, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death. Methods Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC50 values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe2+ in sufficient levels to increase cytosolic and mitochondria Fe2+ and ROS levels and cell death. Results Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe2+ levels in endolysosomes, (3) increased Fe2+ and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine. Conclusions Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe2+ interorganellar signaling may improve pharmacotherapeutics.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"9 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The S1 subunits of SARS-CoV-2 variants differentially trigger the IL-6 signaling pathway in human brain endothelial cells and downstream impact on microglia activation","authors":"Michael Stangis, Daniel Adesse, Bhavya Sharma, Eduardo Castro, Kush Kumar, Neil Kumar, Masha Minevich, Michal Toborek","doi":"10.1515/nipt-2023-0024","DOIUrl":"https://doi.org/10.1515/nipt-2023-0024","url":null,"abstract":"Abstract Objectives Cerebrovascular complications are prevalent in COVID-19 infection and post-COVID conditions; therefore, interactions of SARS-CoV-2 with cerebral microvascular cells became an emerging concern. Methods We examined the inflammatory responses of human brain microvascular endothelial cells (HBMEC), the main structural element of the blood–brain barrier (BBB), following exposure to the S1 subunit of the spike protein of different SARS-CoV-2 variants. Specifically, we used the S1 subunit derived from the D614 variant of SARS-CoV-2, which started widely circulating in March of 2020, and from the Delta variant, which started widely circulating in early 2021. We then further examined the impact of the HBMEC secretome, produced in response to the S1 exposure, on microglial proinflammatory responses. Results Treatment with S1 derived from the D614 variant and from the Delta variant resulted in differential alterations of the IL-6 signaling pathway. Moreover, the HBMEC secretome obtained after exposure to the S1 subunit of the D614 variant activated STAT3 in microglial cells, indicating that proinflammatory signals from endothelial cells can propagate to other cells of the neurovascular unit. Overall, these results indicate the potential for different SARS-CoV-2 variants to induce unique cellular signatures and warrant individualized treatment strategies. The findings from this study also bring further awareness to proinflammatory responses involving brain microvasculature in COVID-19 and demonstrate how the surrounding microglia react to each unique variant derived response.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139380067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","authors":"Jason R. Thonhoff, Ericka Greene, Stanley H. Appel","doi":"10.1007/978-3-031-68237-7_40","DOIUrl":"https://doi.org/10.1007/978-3-031-68237-7_40","url":null,"abstract":"","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"1 1","pages":"705-718"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147897819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy for Neurodegenerative Movement Disorders","authors":"R. Lee Mosley, Maamoon Saleh, Katherine E. Olson","doi":"10.1007/978-3-031-68237-7_52","DOIUrl":"https://doi.org/10.1007/978-3-031-68237-7_52","url":null,"abstract":"","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"1 1","pages":"943-973"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147893849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}