Dysfunction Of Pathways Research Articles

NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients.

The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers -Cerebrospinal fluid (CSF) analysis negative for Alzheimer's Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.

The analgesic effect of acupuncture in neuropathic pain: regulatory mechanisms of DNA methylation in the brain

Abstract Recent research has demonstrated that chronic pain, resulting from peripheral nerve injury, leads to various symptoms, including not only allodynia and hyperalgesia but also anxiety, depression, and cognitive impairment. These symptoms are believed to arise due to alterations in gene expression and neural function, mediated by epigenetic changes in chromatin structure. Emerging evidence suggests that acupuncture can modulate DNA methylation within the central nervous system, contributing to pain relief and the mitigation of comorbidities. Specifically, acupuncture has been shown to adjust the DNA methylation of genes related to mitochondrial dysfunction, oxidative phosphorylation, and inflammation pathways within cortical regions, such as the prefrontal cortex, anterior cingulate cortex, and primary somatosensory cortex. In addition, it influences the DNA methylation of genes associated with neurogenesis in hippocampal neurons. This evidence indicates that acupuncture, a treatment with fewer side effects compared with conventional medications, could offer an effective strategy for pain management.

Decreased Water Diffusivity Along the Perivascular Space in Older Adults With Poor Sleep Quality.

This study included 52 Japanese older adults with Pittsburgh Sleep Quality Index (PSQI) scores > 5 and 52 healthy controls (HCs) with PSQI score ≤ 5. Diffusion-weighted imaging (DWI) and 3D T1-weighted imaging were acquired using 3T magnetic resonance imaging. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated using preprocessed DWI. The choroid plexus volume (CPV) was calculated using FreeSurfer 6.0. The mean ALPS index and CPV were compared between the older adults with poor sleep quality (PSQ) and HCs using a general linear model, adjusted for covariates including age, sex, years of education, total intracranial volume, systolic blood pressure, hemoglobin A1c, and white matter lesion volume. We also conducted a partial correlation analysis between the mean ALPS index and CPV, Montreal Cognitive Assessment (MoCA), and PSQI scores, adjusting for all the mentioned covariates. The PSQ group had a significantly lower mean ALPS index than HCs. The mean ALPS index in the PSQ group was negatively correlated with CPV and positively correlated with the MoCA score. Therefore, older adults with PSQ may experience dysfunction in the excretory pathway of the perivascular space around the medullary veins. This impairment may be associated with an increase in CPV and cognitive dysfunction.

MiR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia.

Chronic limb-threatening ischaemia (CLTI), the most severe manifestation of peripheral arterial disease (PAD), is associated with a poor prognosis and high amputation rates. Despite novel therapeutic approaches being investigated, no significant clinical benefits have been observed yet. Understanding the molecular pathways of skeletal muscle dysfunction in CLTI is crucial for designing successful treatments. This study aimed to identify miRNAs dysregulated in muscle biopsies from PAD cohorts. Using MIcroRNA ENrichment TURned NETwork (MIENTURNET) on a publicly accessible RNA-sequencing dataset of PAD cohorts, we identified a list of miRNAs that were over-represented among the upregulated differentially expressed genes (DEGs) in CLTI. Next, we validated the altered expression of these miRNAs and their targets in mice with hindlimb ischaemia (HLI). Our results showed a significant downregulation of miR-1, miR-133a, and miR-29b levels in the ischaemic limbs versus the contralateral non-ischaemic limb. A miRNA target protein-protein interaction network identified extracellular matrix components, including collagen-1a1, -3a1, and -4a1, fibronectin-1, fibrin-1, matrix metalloproteinase-2 and -14, and Sparc, which were upregulated in the ischaemic muscle of mice. This is the first study to identify miR-1, miR-133a, and miR-29b as potential contributors to fibrosis and vascular pathology in CLTI muscle, which supports their potential as novel therapeutic agents for this condition.

Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons

Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.

Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids

Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

Research progress on the association of insulin resistance with type 2 diabetes mellitus and Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway. This pathway is activated when insulin binds to the insulin receptor on nerve cells, and it helps regulate the metabolism of glucose and lipids. Dysfunction in the insulin signaling pathway can lead to a decrease in brain insulin levels and insulin sensitivity, thereby inducing disruptions in insulin signal transduction and leading to disorders in brain energy metabolism. Moreover, these dysfunctions also contribute to the accumulation of β-amyloid (Aβ) deposition and the hyperphosphorylation of Tau protein, both of which are characteristic features of AD. Therefore, this article focuses on insulin resistance to reveal the complex mechanism between brain insulin resistance and AD occurrence in T2DM. On this basis, this article further summarizes the biological effects and mechanisms of antidiabetic drugs on the two diseases, aiming to provide new ideas for the discovery of drugs for the treatment of T2DM combined with AD.

LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis

ObjectivesAllergic rhinitis (AR) is a complex disorder with variable pathogenesis. Increasing evidence suggests that the LRRC8A is involved in maintaining cellular stability, regulating immune cell activation and function, and playing significant roles in inflammation. However, the involvement of LRRC8A in AR inflammation and its underlying mechanisms remain unclear.MethodsLRRC8A expression in AR patients, confirmed by qRT-PCR and Western blotting, was analyzed to investigate its relationship with the clinical characteristics of AR patients. In vitro, IL-13 stimulated HNEpCs to establish a Th2 inflammation model, with subsequent LRRC8A knockout or overexpression. NOX1/NOX4 inhibitor (GKT137831) and chloride channel inhibitor (DCPIB) were utilized to investigate AR development mechanisms during LRRC8A overexpression. An OVA-induced AR model with nasal mucosa LRRC8A knockdown confirmed LRRC8A's regulatory role in AR inflammation.ResultsLRRC8A mRNA and protein levels were significantly elevated in AR patients, positively correlating with NADPH oxidase subunits and Th2 inflammatory markers. In vitro, IL-13 stimulation of HNEpCs resulted in upregulation of LRRC8A and increased expression of NOX1, NOX4, and p22phox, along with mitochondrial dysfunction and NF-κB pathway activation. The knockout of LRRC8A reversed these effects. In nasal mucosal epithelial cells, DCPIB and GKT137831 completely blocked mitochondrial dysfunction caused by the overexpression of LRRC8A, which led to up-regulation of NOX1, NOX4, and p22phox. In vivo, knocking down LRRC8A reduced eosinophil infiltration, downregulated the expression of NOX1, NOX4, p22phox IL-4, IL-5, and IL-13, and decreased NF-κB pathway activation.ConclusionLRRC8A drives the upregulation of NOX1, NOX4, and p22phox, leading to ROS overproduction and mitochondrial dysfunction. It also activates NF-κB, ultimately leading to nasal mucosal epithelial inflammation. LRRC8A may be a potential target for the treatment of AR.

TMIC-19. EXCESSIVE LIPID PRODUCTION SHAPES GLIOMA TUMOR MICROENVIRONMENT

Abstract Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature has lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

Stem Cell Membrane-Camouflaged Biomimetic Nanoparticles Inhibiting Leptin Pathway for Intervertebral Disc Degeneration Therapy.

Leptin, a kind of adipokine, with its receptor in which the long isoform plays a crucial role in signal transduction, has been identified in intervertebral disc (IVD) tissues, especially showing an increased expression in degenerated discs. Initially identified as a metabolic sensor, leptin has recently been found able to regulate inflammation into imbalance, which favors catabolic degradative processes, thus contributing to progressive intervertebral disc degeneration (IDD). Therefore, efficiently inhibiting the leptin pathway may provide a new strategy to treat IDD. In this study, we introduced an innovative drug delivery system (DDS) that employs stem cell membranes (SCM) to encapsulate (Zeolitic imidazolate frameworks-8) ZIF-8 nanoparticles. These nanoparticles are used to transport a plasmid containing shRNA targeting the leptin receptor (LEPR), with the aim of facilitating repair in IDD. The regenerative performances of this DDS in IDD were verified through a combination of the in vitro western blot and immunofluorescence with the in vivo radiologic examination and histological staining. The DDS demonstrated excellent cell adhesion properties and gene transfection efficiency in vitro, along with impressive treatment outcomes in vivo. Both in vitro and in vivo studies revealed that the DDS effectively reduced leptin receptor expression and alleviated the inflammatory environment, thereby promoting regeneration in degenerated IVDs. We propose that the DDS represents a promising novel approach for treating IDD and may also be beneficial for other degenerative diseases linked to leptin pathway dysfunction.

Unveiling tomorrow: Carbonic anhydrase activators and inhibitors pioneering new frontiers in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H2O2 generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

Expression of soluble guanylate cyclase (sGC) and its ability to form a functional heterodimer are crucial for reviving the NO-sGC signaling in PAH

In order to determine the underpinnings of a dysfunctional NO-sGC signal pathway which occurs in pulmonary arterial hypertension (PAH), we investigated pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients. We found low expression of sGC, a poor sGCα1β1 heterodimer and this correlated with low expression of its facilitator chaperon, hsp90. Treating PASMCs overnight (16 h) with low micromolar doses of a slow release NO donor DETANONOate, reinstated the sGCα1β1 heterodimer and restored its NO-heme dependent activity. Transwell co-culture of HEK cells stably expressing eNOS with PAH PASMCs also restored the sGC heterodimer and its heme-dependent activity with sGC stimulator, BAY 41–2272. To determine whether the dysfunctionality in the NO-sGC pathway stems from a dysfunctional eNOS producing negligible NO, we did transwell co-cultures of pulmonary arterial endothelial cells (PAECs) with PASMCs. Our results indicated that PAECs from both control and PAH samples when activated for eNOS restored both sGC heterodimer and its heme-dependent sGC activity in the corresponding PASMCs, suggesting that PAECs from PAH can also generate NO. In line with these results expression of eNOS, its support chaperon hsp90, its specific kinase Akt, p-Akt or post-translational modifications (PTMs) like OGlcNAc or phospho-tyrosine were unchanged in PAH relative to controls. Additionally there was uniform expression of Hbα/β and Mb in PASMCs or PAECs in PAH or controls and these globins can effectively scavenge the eNOS generated NO, as there was evidence of strong eNOS-Hb/Mb interactions. Our studies suggest that factors such as globin NO scavenging along with vascular remodeling in PAH can cause hampered vasodilation which in the face of poor NO levels as occurs in PAH are additional impediments for effective vasodilation. However importantly our studies suggests that future therapies can use low doses of NO along with sGC stimulators as a potential drug for PAH subjects.

Data-independent acquisition proteomic analysis of the brain microvasculature in Alzheimer’s disease identifies major pathways of dysfunction and upregulation of cytoprotective responses

Brain microvascular dysfunction is an important feature of Alzheimer’s disease (AD). To better understand the brain microvascular molecular signatures of AD, we processed and analyzed isolated human brain microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC–MS/MS) to generate a quantitative dataset at the peptide and protein level. Brain microvessels were isolated from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects with clinical and neuropathologic concordance for Alzheimer’s disease, and 21 age-matched controls. In our analysis, we identified 168 proteins whose abundance was significantly increased, and no proteins that were significantly decreased in AD. The most highly increased proteins included amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), and fatty acid binding protein 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis identified the enrichment of increased proteins involved in cellular detoxification and antioxidative responses. A systematic evaluation of protein functions using the UniProt database identified groupings into common functional themes including the regulation of cellular proliferation, cellular differentiation and survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation and heme breakdown, protein degradation, cytoskeleton, subcellular trafficking, cell motility, and cell signaling. This suggests that AD brain microvessels exist in a stressed state of increased energy demand, and mount a compensatory response to ongoing oxidative and cellular damage that is associated with AD. We also used public RNAseq databases to identify cell-type enriched genes that were detected at the protein level and found no changes in abundance of these proteins between control and AD groups, indicating that changes in cellular composition of the isolated microvessels were minimal between AD and no-AD groups. Using public data, we additionally found that under half of the proteins that were significantly increased in AD microvessels had concordant changes in brain microvascular mRNA, implying substantial discordance between gene and protein levels. Together, our results offer novel insights into the molecular underpinnings of brain microvascular dysfunction in AD.

Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today?

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.

Elucidating the neuropathological and molecular heterogeneity of amyloid-beta and tau in Alzheimer's disease through machine learning and transcriptomic integration.

Discerning functional brain network variations related to neuropathological aggregates in Alzheimer's disease (AD), including amyloid-beta (Abeta) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimer's continuum cases (Abeta positive (A+), n = 129) and normal elderly (Abeta negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual Abeta and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the Aβ-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimer's continuum pathological biomarkers.

Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.

Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction

The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants. Thus, to further advance this field of research, in the current study we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs, and have further validated some of these findings in a mouse model of ocular hypertension. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs. Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs.

1-Deoxynojirimycin Derivative Containing Tegafur Induced HCT-116 Cell Apoptosis through Mitochondrial Dysfunction and Oxidative Stress Pathway

1-Deoxynojirimycin Derivative Containing Tegafur Induced HCT-116 Cell Apoptosis through Mitochondrial Dysfunction and Oxidative Stress Pathway

Butyl benzyl phthalate induces neurotoxicity in Eisenia fetida: Mechanisms revealed by biochemical and metabolomic analyses

Phthalates, particularly butyl benzyl phthalate (BBP), are ubiquitous environmental contaminants with potential neurotoxic effects. However, their impact on soil organisms, especially earthworms (Eisenia fetida), remains poorly understood. The current study investigated the neurotoxic effects of BBP on Eisenia fetida in artificial and red soils using an integrated approach combining biochemical assays, metabolomics, and molecular docking. Earthworms were exposed to 0, 1, and 10 mg kg−1 BBP for 14 and 28 days. Biochemical assays revealed significant increases in oxidative stress markers and disruptions in neurotransmission-related enzyme activities. Metabolomic analysis of the cerebral ganglia identified alterations in energy metabolism, lipid metabolism, and neuroactive ligand-receptor interaction signaling pathways. Molecular docking studies corroborated these findings, showing strong interactions between BBP and essential neuronal proteins, particularly the sodium pump. The integration of these data suggests that BBP-induced neurotoxicity in Eisenia fetida is primarily mediated by calcium signaling pathway dysfunction and calcium homeostasis imbalance. Notably, neurotoxic effects were more pronounced in red soil than in artificial soil, highlighting the importance of considering soil type in ecotoxicological assessments. The current study provides novel insights into the mechanisms of BBP-induced neurotoxicity in soil invertebrates and underscores the potential ecological risks associated with phthalate contamination in agricultural environments.

A case of Russell body gastritis associated with psychiatric disorder

Abstract Introduction/Objective Russell body gastritis is a benign and rare entity characterized by infiltration of lamina propria with plasma cells stuffed with spherical eosinophilic cytoplasmic inclusions known as Russell bodies which represent immunoglobulins. Russell bodies accumulate due to dysfunction in secretion pathway of plasma cells. Plasma cells with Russell bodies are also termed Mott cells. Although exact etiology is unknown, but it can be seen in association with other conditions like mucosa associated lymphoid tissue (MALT) lymphoma, multiple myeloma and plasmacytoma. This condition most commonly affects the antrum and may present as erythema or sometimes nodular lesion. Definitive diagnosis is based on histology. Methods/Case Report A middle-aged male with past medical history significant for polysubstance use disorder, bipolar disorder, and osteoarthritis was evaluated for bleeding per rectum and dyspepsia in the setting of chronic nonsteroidal anti-inflammatory drugs (NSAID) and ethanol use. Physical examination was remarkable for an external hemorrhoid and complete blood count showed anemia. Upper GI endoscopy and colonoscopy was performed. Patchy erythema was seen in antrum and duodenal bulb, and colonoscopy was unremarkable. Microscopic examination showed numerous plasma cells with Russell bodies (Mott cells) in the lamina propria and mild chronic inflammation in gastric mucosa. H. Pylori was negative by immunohistochemistry (IHC). Plasma cells were polyclonal and positive for CD138, and negative for cytokeratin which excluded plasmacytoma and signet-ring adenocarcinoma, respectively. Patient was placed on proton pump inhibitor therapy and discharged. Results (if a Case Study enter NA) Russell body gastritis can be seen in patients with and without H. Pylori infection. Cytokeratin, kappa and lambda immunohistochemistry stains, and gene rearrangement studies may be needed to exclude frequent lesions that may enter in the differential diagnosis. Long term effects and clinical significance of russell bodies accumulation is yet to be determined. Conclusion Russell body gastritis is a rare morphologic variant of chronic gastritis that may enter in the differential diagnosis with other more serious lesions. A careful morphologic examination and occasionally IHC stains / molecular studies are needed to make the correct diagnosis.