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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
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NeuroMolecular Medicine
Journal Prestige (SJR): 1.468
Citation Impact (citeScore): 3
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  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1559-1174 - ISSN (Online) 1535-1084
Published by Springer-Verlag Homepage  [2468 journals]
  • Effects of Chronic Hypertension on the Energy Metabolism of Cerebral
           Cortex Mitochondria in Normotensive and in Spontaneously Hypertensive Rats
           During Aging

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      Abstract: In this study the subcellular modifications undergone by cerebral cortex mitochondrial metabolism in chronic hypertension during aging were evaluated. The catalytic properties of regulatory energy-linked enzymes of Tricarboxylic Acid Cycle (TCA), Electron Transport Chain (ETC) and glutamate metabolism were assayed on non-synaptic mitochondria (FM, located in post-synaptic compartment) and on intra-synaptic mitochondria of pre-synaptic compartment, furtherly divided in “light” (LM) and “heavy” (HM) mitochondria, purified form cerebral cortex of normotensive Wistar Kyoto Rats (WKY) versus Spontaneously Hypertensive Rats (SHR) at 6, 12 and 18 months. During physiological aging, the metabolic machinery was differently expressed in pre- and post-synaptic compartments: LM and above all HM were more affected by aging, displaying lower ETC activities. In SHR at 6 months, FM and LM showed an uncoupling between TCA and ETC, likely as initial adaptive response to hypertension. During pathological aging, HM were particularly affected at 12 months in SHR, as if the adaptive modifications in FM and LM at 6 months granted a mitochondrial functional balance, while at 18 months all the neuronal mitochondria displayed decreased metabolic fluxes versus WKY. This study describes the effects of chronic hypertension on cerebral mitochondrial energy metabolism during aging through functional proteomics of enzymes at subcellular levels, i.e. in neuronal soma and synapses. In addition, this represents the starting point to envisage an experimental physiopathological model which could be useful also for pharmacological studies, to assess drug actions during the development of age-related pathologies that could coexist and/or are provoked by chronic hypertension. Graphical
      PubDate: 2024-02-23
       
  • Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers
           Neuroprotection in an MPTP-induced Parkinson’s Disease Model

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      Abstract: Abstract Parkinson’s disease (PD) is a neurodegenerative disorder that results in motor impairment due to dopaminergic neuronal loss. The pathology of PD is closely associated with neuroinflammation, which can be characterized by astrocyte activation. Thus, targeting the inflammatory response in astrocytes might provide a novel therapeutic approach. We conducted a luciferase assay on an in-house chemical library to identify compounds with anti-inflammatory effects capable of reducing MPP+-induced NF-κB activity in astrocytes. Among the compounds identified, EI-16004, a novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides, exhibited a significant anti-inflammatory effect by significantly reducing MPP+-induced astrocyte activation. Biochemical analysis and docking simulation indicated that EI-16004 inhibited the MPP+-induced phosphorylation of p65 by attenuating ERK phosphorylation, and EI-16004 reduced pro-inflammatory cytokine and chemokine levels in astrocytes. In vivo studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in male C57BL/6 mice showed that EI-16004 ameliorated motor impairment and protected against dopaminergic neuronal loss, and EI-16004 effectively mitigated the MPTP-induced astrocyte activation in striatum (STR) and substantia nigra (SN). These results indicate EI-16004 is a potential neuroprotective agent for the prevention and treatment of astrocyte-mediated neuroinflammatory conditions in PD.
      PubDate: 2024-01-30
       
  • Targeting Pericytes for Functional Recovery in Ischemic Stroke

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      Abstract: Abstract Pericytes surrounding endothelial cells in the capillaries are emerging as an attractive cell resource, which can show a large variety of functions in ischemic stroke, including preservation of the blood–brain barrier, regulation of immune function, and support for cerebral vasculature. These functions have been fully elucidated in previous studies. However, in recent years, increasing evidence has shown that pericytes play an important role in neurological recovery after ischemic stroke due to their regenerative function which can be summarized in two aspects according to current discoveries, one is that pericytes are thought to be multipotential themselves, and the other is that pericytes can promote the differentiation of oligodendrocyte progenitor cells (OPCs). Considering the neuroprotective treatment for stroke has not been much progressed in recent years, new therapies targeting pericytes may be a future direction. Here, we will review the beneficial effects of pericytes in ischemic stroke from two directions: the barrier and vascular functions and the regenerative functions of pericytes.
      PubDate: 2023-12-01
       
  • A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and
           Intolerance to Riboflavin Deficiency

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      Abstract: Abstract AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.
      PubDate: 2023-12-01
       
  • Pathophysiological Links Between Obesity and Dementia

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      Abstract: Abstract Obesity is a major global health concern, with prevalence rates rapidly rising due to increased availability of highly processed foods rich in fats and/or sugars and technological advances promoting more sedentary behaviour. There is increasing evidence to suggest that obesity predisposes individuals to developing cognitive impairment and dementia. However, the relationship between the brain and the peripheral metabolic state is complex, and many of the underlying mechanisms of cognitive impairment in obesity are yet to be fully elucidated. To better understand the links between obesity and dementia, further work is required to determine pathological changes occurring in the brain during obesity. In this mini-review, we discuss the role of two pathological features of obesity (the gut-brain axis and systemic inflammation) and their potential contribution to dementia.
      PubDate: 2023-12-01
       
  • Inflammasome Activation Mediates Apoptotic and Pyroptotic Death in
           Astrocytes Under Ischemic Conditions

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      Abstract: Abstract Inflammation is a hallmark mechanism of ischemic stroke-induced brain injury. Recent studies have shown that an intracellular multimeric protein complex known as an inflammasome is a key factor for inducing an inflammatory response, and apoptotic and pyroptotic cell death in ischemic stroke. Inflammasome assembly leads to the activation of pro-inflammatory caspases, and the maturation and secretion of pro-inflammatory cytokines IL-1β and IL-18. While the role of inflammasomes in ischemic stroke-induced neuronal death, and microglial activation and cell death have been established, little is known about the role of inflammasomes in astrocytes under ischemic conditions. In this study, we investigated the expression and activation of inflammasome components in protoplasmic and fibrous astrocytes under ischemic conditions. We found that both protoplasmic and fibrous astrocytes expressed a differential increase in inflammasome protein components, and that their activation promoted maturation of IL-1β and IL-18, and secretion of IL-1β, as well as initiating apoptotic and pyroptotic cell death. Pharmacological inhibition of caspase-1 decreased expression of cleaved caspase-1 and production of mature IL-1β, and protected against inflammasome-mediated apoptotic and pyroptotic cell death. Overall, this study provides novel insights into the role of inflammasome signaling in astrocytes under ischemic conditions.
      PubDate: 2023-12-01
       
  • Increased IL-6 Levels and the Upregulation of Iron Regulatory Biomarkers
           Contribute to the Progression of Japanese Encephalitis Virus Infection’s
           Pathogenesis

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      Abstract: Abstract Integrated analysis of iron regulatory biomarkers and inflammatory response could be an important strategy for Japanese encephalitis viral (JEV) infection disease management. In the present study, the inflammatory response was assessed by measuring serum Interleukin-6 (IL-6) levels using ELISA, and the transcription levels of iron homeostasis regulators were analyzed via RT-PCR. Furthermore, inter-individual variation in the transferrin gene was analyzed by PCR–RFLP and their association with clinical symptoms, susceptibility, severity, and outcomes was assessed through binary logistic regression and classification and regression tree (CART) analysis. Our findings revealed elevated levels of IL-6 in serum as well as increased expression of hepcidin (HAMP), transferrin (TF), and transferrin receptor-1 (TFR1) mRNA in JEV infection cases. Moreover, we found a genetic variation in TF (rs4481157) associated with clinical symptoms of meningoencephalitis. CART analysis indicates that individuals with the wild-type TF genotype are more susceptible to moderate JEV infection, while those with the homozygous type are in the high-risk group to develop a severe JEV condition. In summary, the study highlights that JEV infection induces alteration in both IL-6 levels and iron regulatory processes, which play pivotal roles in the development of JEV disease pathologies.
      PubDate: 2023-10-31
      DOI: 10.1007/s12017-023-08762-1
       
  • Author Correction: Potential of Quercetin to Protect Cadmium Induced
           Cognitive Deficits in Rats by Modulating NMDA‑R Mediated Downstream
           Signaling and PI3K/AKT—Nrf2/ARE Signaling Pathways in Hippocampus

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      PubDate: 2023-10-20
      DOI: 10.1007/s12017-023-08765-y
       
  • MicroRNAs as a Tool for Differential Diagnosis of Neuromuscular Disorders

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      Abstract: Abstract Neuromuscular disorders (NMD) are a class of progressive disorders that are characterized by wasting of the muscles. Some of the disorders like Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophies (LGMD), and mild spinal muscular atrophy (SMA) type III share several presenting clinical features, and hence, diagnosis is usually a challenging task. In this study, the diagnostic potential of some species of microRNAs (miRNAs) that are known to play roles in normal and pathological contexts of myocytes (myomiRs) were evaluated to assess their potential in differential diagnosis of NMDs. In this study, seventy-four patients with different neuromuscular disorders along with thirty age-matched healthy control subjects were enrolled. Peripheral blood samples were collected from enrolled subjects followed by miRNA extraction and reverse transcription followed by quantification of the circulating levels of the studied miRNAs (miR-499, miR-206, miR-208a, miR-223, miR-191, miR-103a-3p, miR-103a-5p), by real-time PCR and statistical analysis. The data indicated that miR-499 level showed high circulating levels in DMD patients as well as in patients with other related disorders such as BMD. However, the levels of miR-499 were much higher in DMD patients and it can be used to diagnose DMD. In addition, miR-206 can selectively differentiate between DMD and all other disorders. The results also revealed that miR-208a and miR-223 were significantly dysregulated in SMA patients, and miR-103a-3p could distinguish DMD from BMD. The expression levels of some miRNA species can be utilized in the process of differential diagnosis of NMDs and can serve as a diagnostic biomarker, and such findings will pave the way towards generating targeted therapies.
      PubDate: 2023-10-19
      DOI: 10.1007/s12017-023-08763-0
       
  • Diurnal Characteristics of the Orexin System Genes and Its Effects on
           Pathology at Early Stage in 3xTg-AD Mice

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      Abstract: Abstract Orexin and its receptors are closely related to the pathogenesis of Alzheimer’s disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD.
      PubDate: 2023-10-16
      DOI: 10.1007/s12017-023-08767-w
       
  • CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral
           Deficits in a Mouse Model of Sepsis-Associated Encephalopathy

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      Abstract: Abstract Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1β, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.
      PubDate: 2023-10-05
      DOI: 10.1007/s12017-023-08764-z
       
  • Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in
           Medulloblastoma Cells: Involvement of HDACs and EGFR

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      Abstract: Abstract Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 μM) and D283 (IC50 = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.
      PubDate: 2023-09-23
      DOI: 10.1007/s12017-023-08758-x
       
  • Author Correction: Inflammasome Activation Mediates Apoptotic and
           Pyroptotic Death in Astrocytes Under Ischemic Conditions

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      PubDate: 2023-09-21
      DOI: 10.1007/s12017-023-08760-3
       
  • Neuroprotective Effects of Sinomenine on Experimental Autoimmune
           Encephalomyelitis via Anti-Inflammatory and Nrf2-Dependent Anti-Oxidative
           Stress Activity

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      Abstract: Abstract Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Sinomenine (SIN), a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, has powerful anti-inflammatory and immunosuppressive therapeutic benefits. In our previous research, we found that SIN increased resistance to oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in PC12 neuronal cells. However, whether SIN can improve the symptoms and pathological features of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, via the Nrf2 signaling pathway remains unclear. EAE was immunized followed by SIN treatment. Then we evaluated the effects of SIN in EAE. Subsequently, primary microglia were cultured to explore the effect of SIN on microglia activation. Further, the levels of Nrf2 and its downstream molecules were detected to assess the molecular mechanisms of SIN. We demonstrated that SIN effectively ameliorated the severity of EAE, accompanied by a reduction in the demyelination, axonal damage and inhibition of inflammatory cell infiltration. Mechanistically, SIN decreased the inflammatory cytokines expression, and suppressed microglia and astrocytes activation in EAE mice. Furthermore, SIN suppressed lipopolysaccharide (LPS)-induced microglial activation and the production of pro-inflammatory factors in vitro. Moreover, SIN inhibited oxidative stress via the activation of the Nrf2 signaling pathway. Our work proves that SIN exerts its neuroprotective effects by the Nrf2-dependent anti-oxidative stress and diminishing neuroinflammation, suggesting that the “antioxiflammation” effect of SIN is expected to be an ideal treatment strategy for MS/EAE.
      PubDate: 2023-09-21
      DOI: 10.1007/s12017-023-08756-z
       
  • Fibroblast Growth Factor Receptor 2 (FGFR2), a New Gene Involved in the
           Genesis of Autism Spectrum Disorder

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      Abstract: Abstract Autism spectrum disorder (ASD) is a long-known complex neurodevelopmental disorder, and over the past decades, with the enhancement of the research genomic techniques, has been the object of intensive research activity, and many genes involved in the development and functioning of the central nervous system have been related to ASD genesis. Herein, we report a patient with severe ASD carrying a G > A de novo variant in the FGFR2 gene, determining a missense mutation. FGFR2 encodes for the ubiquitous fibroblast growth factor receptor (FGFR) type 2, a tyrosine kinase receptor implicated in several biological processes. The mutated version of this protein is known to be responsible for several variable overlapping syndromes. Even if there still is only sparse and anecdotal data, recent research highlighted a potential role of FGFR2 on neurodevelopment. Our findings provide new insights into the potential causative role of FGFR2 gene in complex neurodevelopmental disorders.
      PubDate: 2023-09-21
      DOI: 10.1007/s12017-023-08759-w
       
  • CircPTP4A2 Promotes Microglia Polarization in Cerebral Ischemic Stroke via
           miR-20b-5p/YTHDF1/TIMP2 Axis

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      Abstract: Abstract Activated microglia play dual roles in ischemic stroke (IS) according to its polarization states. Herein, we investigated the function of circPTP4A2 in regulating microglia polarization in IS. IS models were established by MACO/R and OGD/R treatment. TTC staining was employed to detect cerebral infarct size. Cell vitality was measured using CCK-8 assay. CD16 and CD206 levels were examined using flow cytometry. The interactions between circPTP4A2, miR-20b-5p, and YTHDF1 were analyzed by dual-luciferase reporter gene, RIP, or RNA pull-down assays. circPTP4A2 was upregulated in IS patients. circPTP4A2 knockdown alleviated MCAO/R-induced cerebral injury in mice. circPTP4A2 knockdown promoted microglia M2 polarization after OGD/R. circPTP4A2 promoted YTHDF1 expression by sponging miR-20b-5p. The promoting effect of circPTP4A2 knockdown on microglia M2 polarization was abrogated by miR-20b-5p inhibition. YTHDF1 activated the NF-κB pathway by increasing TIMP2 mRNA stability and expression. circPTP4A2 downregulation promoted microglia M2 polarization to inhibit IS development by regulating the miR-20b-5p/YTHDF1/TIMP2/NF-κB axis.
      PubDate: 2023-09-14
      DOI: 10.1007/s12017-023-08751-4
       
  • Optogenetic Inhibition of Glutamatergic Neurons in the Dysgranular
           Posterior Insular Cortex Modulates Trigeminal Neuropathic Pain in CCI-ION
           Rat

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      Abstract: Abstract In individuals with chronic neuropathic pain, the posterior insular cortex (PIC) has been found to exhibit increased glutamatergic activity, and the dysgranular portion of PIC (DPIC) has been investigated as a novel cortical target for pain modulation. However, the role of DPIC glutamatergic neurons (DPICg) in trigeminal neuropathic pain (TNP) remains unclear. Here, we examined the outcomes of DPICg inhibition in a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION). Animals were randomly divided into TNP, sham, and control groups. TNP animals underwent CCI-ION surgery. Either optogenetic or null viruses were delivered to the contralateral DPICg of TNP and sham animals. In vivo single-unit extracellular recordings from the ipsilateral spinal trigeminal nucleus caudalis (TNC) and contralateral ventral posteromedial (VPM) thalamus were obtained under both “ON” and “OFF” stimulation states. Behavioral responses during the stimulation-OFF and stimulation-ON phases were examined. Expression of c-Fos, pERK, and CREB immunopositive neurons were also observed. Optogenetic inhibition of contralateral DPICg decreased the neural firing rate in both TNC and VPM thalamus, the expression of sensory-responsive cell bodies, and transcriptional factors in the DPIC of TNP group. Improvements in hyperalgesia, allodynia, and anxiety-like responses in TNP animals were also observed during stimulation-ON condition. In fine, descending pain processing is influenced by neuroanatomical projections from the DPIC to the pain matrix areas, and DPICg could play a necessary role in this neural circuitry. Therefore, the antinociceptive effect of DPICg inhibition in this study may provide evidence for the therapeutic potential of DPICg in TNP.
      PubDate: 2023-09-12
      DOI: 10.1007/s12017-023-08752-3
       
  • The Role of Ubiquitin–Proteasome System and Mitophagy in the
           Pathogenesis of Parkinson's Disease

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      Abstract: Abstract Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin–proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.
      PubDate: 2023-09-12
      DOI: 10.1007/s12017-023-08755-0
       
  • Identification of a Novel ARSA Gene Mutation Through High-Throughput
           Molecular Diagnosis Method in Two Girls with Late Infantile Metachromatic
           Leukodystrophy

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      Abstract: Abstract Metachromatic leukodystrophy (MLD) is a rare leukoencephalopathy caused by pathogenic mutations in the ARSA gene. It manifests as severe motor symptoms, mental problems, and sometimes, seizures. We aimed to investigate the phenotypic manifestations and genetic causes of MLD in an Iranian family. We present the case of a 3-year-old girl who presented with hypotonia, muscular atrophy, and seizures. Neurological and neuromuscular examinations were performed to evaluate clinical characteristics. Whole exome sequencing (WES) was used to detect disease-causing variants. In silico analysis was performed to predict the pathogenicity of this variant. GROMACS software was utilized for molecular dynamic simulation (MDS). Neurological studies revealed marked slowing of motor conduction velocities and an increased motor unit action potential duration. Brain MRI scan revealed white matter abnormalities. By applying WES, we identified a novel homozygous missense variant (NM_000487.6, c.938G > C, p.R313P) in ARSA. Direct sequencing identified this homozygous variant in her asymptomatic younger sister, whereas both parents carried a heterozygous variant. This mutation has not been reported in genetic databases or in literature. In silico analysis predicted that any variation in this DNA position would cause disease, as it is highly conserved. The c.938G > C variant was classified as a pathogenic variant according to ACMG/AMP guidelines. MDS analysis indicated that c.938G > C had a significant impact on both the structure and stabilization of ARSA, ultimately resulting in impaired protein function. The identification of this variant expands the spectrum of ARSA gene mutations associated with MLD and highlights the importance of genetic testing for the diagnosis of MLD.
      PubDate: 2023-09-08
      DOI: 10.1007/s12017-023-08757-y
       
  • Dysregulated COMT Expression in Fragile X Syndrome

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      Abstract: Abstract Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.
      PubDate: 2023-09-08
      DOI: 10.1007/s12017-023-08754-1
       
 
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