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Cell Death & Disease Jun 2024Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq,...
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.
Topics: Cholangiocarcinoma; Humans; ErbB Receptors; Lipid Metabolism; Bile Duct Neoplasms; Cell Line, Tumor; Animals; Cisplatin; Signal Transduction; Cell Proliferation; Single-Cell Analysis; Myelin and Lymphocyte-Associated Proteolipid Proteins; Mice; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Apoptosis; Male
PubMed: 38866777
DOI: 10.1038/s41419-024-06775-7 -
Reviews in the Neurosciences Jun 2024Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other... (Review)
Review
Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and and studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.
PubMed: 38865989
DOI: 10.1515/revneuro-2024-0027 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to...
OBJECTIVE
To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ.
METHODS
Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups.
RESULTS
The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm . (2 831.01±1 212.72) cm, < 0.001] and increased central area duration [(88.43±22.06) s . (56.85±18.58) s, =0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm . (7 949.39±1 140.55) cm, < 0.001] and increased central area duration [(54.78±11.66) s . (88.43±22.06) s, =0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls ( < 0.001 for both), with the treatment group displaying significant improvement ( < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm . (2.79±0.94) mm, < 0.001 for diffusion area; (2.48±0.38) mm . (0.05±0.12) mm, < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm . (13.93±3.35) mm, < 0.001 for diffusion area; (0.50±0.30) mm . (2.48±0.38) mm, < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) μm . (13 354.92±4 054.05) μm, < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) μm . (3 663.88±733.77) μm, < 0.001].
CONCLUSION
UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.
Topics: Animals; Mice; Triterpenes; Schizophrenia; Mice, Inbred C57BL; Female; Disease Models, Animal; Demyelinating Diseases; Extracellular Fluid; Ursolic Acid; Dizocilpine Maleate; Aquaporin 4
PubMed: 38864135
DOI: 10.19723/j.issn.1671-167X.2024.03.016 -
Communications Biology Jun 2024Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse...
Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related.
Topics: Klotho Proteins; MicroRNAs; Animals; Aging; Alzheimer Disease; Brain; Mice; Glucuronidase; Humans; Longevity; Mice, Knockout; RNA, Transfer; Male; Neurons; Mice, Inbred C57BL
PubMed: 38862813
DOI: 10.1038/s42003-024-06407-y -
Translational Psychiatry Jun 2024There is growing evidence of a shared pathogenesis between Alzheimer's disease and depression. Therefore, we aimed to further investigate their shared disease...
There is growing evidence of a shared pathogenesis between Alzheimer's disease and depression. Therefore, we aimed to further investigate their shared disease mechanisms. We made use of publicly available brain-specific eQTL data and gene co-expression networks of previously reported genetic loci associated with these highly comorbid disorders. No direct genetic overlap was observed between Alzheimer's disease and depression in our dataset, but we did detect six shared brain-specific eQTL genes: SRA1, MICA, PCDHA7, PCDHA8, PCDHA10 and PCDHA13. Several pathways were identified as shared between Alzheimer's disease and depression by conducting clustering pathway analysis on hippocampal co-expressed genes; synaptic signaling and organization, myelination, development, and the immune system. This study highlights trans-synaptic signaling and synaptoimmunology in the hippocampus as main shared pathomechanisms of Alzheimer's disease and depression.
Topics: Alzheimer Disease; Humans; Genetic Predisposition to Disease; Hippocampus; Comorbidity; Quantitative Trait Loci; Gene Regulatory Networks; Depression; Depressive Disorder
PubMed: 38862462
DOI: 10.1038/s41398-024-02968-y -
Cureus May 2024Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune disorder characterized by recurrent episodes of demyelination affecting the...
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune disorder characterized by recurrent episodes of demyelination affecting the central nervous system. The following case report showcases a thorough analysis of a 21-year-old female patient presenting with MOGAD, outlining her clinical presentation, diagnostic workup, treatment protocol, and long-term management outcomes. Through a multidisciplinary approach, we aim to augment the understanding of this complex neurological entity and steer optimal therapeutic interventions.
PubMed: 38854354
DOI: 10.7759/cureus.59840 -
Cureus May 2024Longitudinally extensive myelitis with 15 or more vertebrae in length is extremely rare, with limited evidence regarding clinical features and therapeutic response. We...
Longitudinally extensive myelitis with 15 or more vertebrae in length is extremely rare, with limited evidence regarding clinical features and therapeutic response. We report a case of a 29-year-old male patient with extremely longitudinally extensive myelitis ultimately diagnosed as myelin oligodendrocyte glycoprotein-associated disease (MOGAD). The patient presented with an acute onset of meningismus, limb weakness, sensory disturbance below the C5 level, ataxia, and urinary retention. T2-weighted imaging on MRI showed an extremely longitudinally extensive spinal cord lesion ranging from C2 to the medullary conus, together with a left pontine lesion. Positive anti-myelin oligodendrocyte glycoprotein antibodies were serologically detected, which led to the diagnosis of MOGAD. Intravenous methylprednisolone followed by 1 mg/kg oral prednisolone with taper resulted in complete symptomatic and radiological resolution. The striking complete resolution despite the symptomatic and radiological severity observed in this case has been described in a few previously reported MOGAD cases. Extremely longitudinally extensive myelitis with excellent therapeutic response may be a characteristic presentation of MOGAD.
PubMed: 38854217
DOI: 10.7759/cureus.59938 -
Cureus May 2024Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system disease presenting as optic neuritis, myelitis, and brainstem syndromes. It may be...
Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system disease presenting as optic neuritis, myelitis, and brainstem syndromes. It may be aquaporin-4 seropositive, anti-myelin oligodendrocyte glycoprotein (MOG) antibody seropositive, or double seronegative. Double-seronegative NMOSD can pose a diagnostic and therapeutic challenge. Treatment typically aims to decrease the incidence of relapse, for which high-dose intravenous methylprednisolone is the first-line agent. Non-steroid treatments include azathioprine, mycophenolate mofetil, and rituximab. This case describes a 45-year-old female presenting with left arm numbness and weakness for three months. She had been previously diagnosed with optic neuritis in 2013 but was lost to follow-up. Progression of weakness warranted admission to the neurology department. Diagnostic work and imaging were suggestive of neuromyelitis optica. Tests for aquaporin-4, anti-MOG, immunoglobulin G, and immunoglobulin M in the cerebrospinal fluid were all negative. Initial treatment comprised methylprednisolone; however, due to the progression of symptoms, she was given two cycles of rituximab. Rituximab targets the CD20 antigen in B cells and is thought to reduce the risk of relapse and the severity of NMOSD. The patient's Barthel index score, expanded disability status scale score, and motor examination improved after two cycles of rituximab.
PubMed: 38854188
DOI: 10.7759/cureus.60004 -
BioRxiv : the Preprint Server For... May 2024The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously...
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
PubMed: 38854101
DOI: 10.1101/2024.05.27.594821 -
Research Square May 2024White matter loss is a well-documented phenomenon in Alzheimer's disease (AD) patients that has been recognized for decades. However, the underlying reasons for the...
BACKGROUND
White matter loss is a well-documented phenomenon in Alzheimer's disease (AD) patients that has been recognized for decades. However, the underlying reasons for the failure of oligodendrocyte progenitor cells (OPCs) to repair myelin deficits in these patients remain elusive. A single nucleotide polymorphism (SNP) in Clusterin has been identified as a risk factor for late-onset Alzheimer's disease and linked to a decrease in white matter integrity in healthy adults, but its specific role in oligodendrocyte function and myelin maintenance in Alzheimer's disease pathology remains unclear.
METHODS
To investigate the impact of Clusterin on OPCs in the context of Alzheimer's disease, we employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer's disease.
RESULTS
Our findings demonstrate that Clusterin, a risk factor for late-onset AD, is produced by OPCs and inhibits their differentiation into oligodendrocytes. Specifically, we observed upregulation of Clusterin in OPCs in the 5xFAD mouse model of AD. We also found that the phagocytosis of debris, including amyloid beta (Aβ), myelin, and apoptotic cells leads to the upregulation of Clusterin in OPCs. In vivo experiments confirmed that Aβ oligomers stimulate Clusterin upregulation and that OPCs are capable of phagocytosing Aβ. Furthermore, we discovered that Clusterin significantly inhibits OPC differentiation and hinders the production of myelin proteins. Finally, we demonstrate that Clusterin inhibits OPC differentiation by reducing the production of IL-9 by OPCs.
CONCLUSION
Our data suggest that Clusterin may play a key role in the impaired myelin repair observed in AD and could serve as a promising therapeutic target for addressing AD-associated cognitive decline.
PubMed: 38853911
DOI: 10.21203/rs.3.rs-4415143/v1