Molecular Pathological Mechanisms Research Articles

Uncovering potential molecular markers and pathological mechanisms of Parkinson's disease and myocardial infarction based on bioinformatics analysis

Background The direct association between Parkinson's disease (PD) and Myocardial infarction (MI) has been the subject of relatively limited research. Objective The purpose of this study was to identify the genes most associated with PD and MI to explore their common pathogenesis. Methods The gene expression profiles of PD and MI were downloaded from GEO database. Differential expression analysis was performed to identify the common differential expression genes (DEGs) of PD and MI, followed by functional annotation. Subsequently, protein-protein interaction network were constructed, and hub DEGs were identified based on CytoHubba plugin and LASSO regression analysis. To explore the potential molecular mechanism of hub DEGs, GSEA analysis, immune correlation analysis, drug prediction and molecular docking were performed, and transcription factors (TF) and lncRNA-miRNA-mRNA (ceRNA) regulatory networks were constructed. Results A total of 48 DEGs with the same expression trend were identified in the MI vs. normal control (NC) and PD vs. NC groups. Functional annotation results showed that the common DEGs were significantly enriched in immune and inflammation-related pathways. RPS4Y1 and UTY were the most relevant hub DEGs for PD and MI, and may be involved in the HALLMARK_MYC_TARGETS_V1 and HALLMARK_PROTEIN_SECRETION pathways. TP63 was a common TF of RPS4Y1 and UTY. The PVT1/KCNQ1OT1-hsa-miR-31-5p-RPS4Y1 and KCNQ1OT1-hsa-let-7a-5p/hsa-miR-19b-3p-UTY axes may play an important role in regulating PD and MI. CYCLOHEXIMIDE and ATALAREN may be potential drugs for the treatment of PD and MI comorbidity. In addition, PD and MI exhibit different patterns of immune cell infiltration and immune function status, which may be related to the specific pathological processes of the disease. Conclusions This study revealed for the first time that RPS4Y1 and UTY may be common biomarkers of PD and MI and may be potential therapeutic targets. This study provides new perspective on the common molecular mechanisms between PD and MI.

Brucella osteoarthritis: recent progress and future directions

Brucellosis is a common zoonosis, and Brucella osteoarthritis is the most common chronic complication of brucellosis. Development of brucellosis osteoarthritis involves multiple organs, tissues, and cells. Brucella grows and multiplies in intrinsic cells of the skeleton, including osteoblasts, osteocyte and osteoclasts, which results in sustained release of bacteria that leads to exacerbation of the immune response. Concurrently, activation of the immune system caused by invasion with Brucella may affect the dynamic balance of the skeleton. A variety of in vitro and in vivo models have been employed to study Brucella osteoarthritis, such as using bone marrow-derived macrophages to establish cell models and mice to develop animal models of Brucella osteoarthritis. However, limited studies on the molecular pathological mechanisms of Brucella osteoarthritis have been performed and inadequate animal models have been developed due to the challenging parameters of Brucella research. This paper reviews recent advances in the clinical features, molecular pathological mechanisms, and animal models of Brucella osteoarticular infections. This review underscores the complexity of the pathogenesis of Brucella osteoarticular infections and highlights inflammation as a contributing factor to bone loss caused by Brucella. Additionally, the significant proliferation of Brucella in skeletal resident cells also is an important factor leading to bone loss. A deeper understanding of the molecular pathological mechanism of Brucella osteoarthrosis and their animal models could provide robust support for the prevention and treatment of Brucella osteoarticular disease.

An atlas of neuropathic pain-associated molecular pathological characteristics in the mouse spinal cord

Peripheral nerve injury (PNI)-induced neuropathic pain (NP) is a severe disease with high prevalence in clinics. Gene reprogramming and tissue remodeling in the dorsal root ganglia (DRG) and spinal cord (SC) drive the development and maintenance of neuropathic pain (NP). However, our understanding of the NP-associated spatial molecular processing landscape of SC and the non-synaptic interactions between DRG neurons and SC cells remains limited. We here integrate spatial transcriptomics (ST) with single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-sequencing (bulk RNA-seq) to characterize regional pathological heterogeneity of the SC under NP conditions. First, the SC of NP mice manifests unique spatial atlases of genes, cell populations, cell-cell cross-talks, signaling pathways, and transcriptional regulatory networks compared to sham mice. We further report that injured DRG sensory neurons and the corresponding ventral horn of the SC show similar expression patterns after PNI. In addition, for the first time, we systematically exhibit “cross-talk omics” between the DRG neurons and SC dorsal horn neurons and glial cells, indicating an altered communication profile under NP conditions. Together, our findings decode the spatial and cellular heterogeneity of molecular pathological mechanisms underlying NP, providing a foundation for designing therapeutic targets for this disorder.

Hypomyelinating Leukodystrophy 14 (HLD14)-Related UFC1 p.Arg23Gln Decreases Cell Morphogenesis: A Phenotype Reversable with Hesperetin.

In the central nervous system (CNS), proper interaction between neuronal and glial cells is crucial for the development of mature nervous tissue. Hypomyelinating leukodystrophies (HLDs) are a group of genetic CNS disorders characterized by hypomyelination and/or demyelination. In these conditions, genetic mutations disrupt the biological functions of oligodendroglial cells, which are responsible for wrapping neuronal axons with myelin sheaths. Among these, an amino acid mutation of the ubiquitin-fold modifier conjugating enzyme 1 (UFC1) is associated with HLD14-related disease, characterized by hypomyelination and delayed myelination in the brain. UFC1 is a critical component of the UFMylation system, functioning similarly to E2-conjugating enzymes in the ubiquitin-dependent protein degradation system. We describe how a missense mutation in UFC1 (p.Arg23Gln) leads to the aggregation of UFC1 primarily in lysosomes in FBD-102b cells, which are undergoing oligodendroglial cell differentiation. Cells with mutated UFC1 exhibit reduced Akt kinase phosphorylation and reduced expression of differentiation and myelination marker proteins. Consistently, these cells exhibit impaired morphological differentiation with a reduced ability to extend widespread membranes. Interestingly, hesperetin, a citrus flavonoid with known neuroprotective properties, was found to restore differentiation abilities in cells with the UFC1 mutation. These findings indicate that the HLD14-related mutation in UFC1 causes its lysosomal aggregation, impairing its morphological differentiation. Furthermore, the study highlights potential therapeutic insights into the pathological molecular and cellular mechanisms underlying HLD14 and suggests hesperetin as a promising candidate for treatment.

Increased GABBR2 Expression on Cell Membranes Causes Increased Ca2 + Inward Flow, Associated with Cognitive Impairment in Early Alzheimer's Disease.

Alzheimer's disease (AD) and mild cognitive impairment (MCI) are a serious global public health problem. The aim of this study was to analyze the key molecular pathological mechanisms that occur in early AD progression as well as MCI. Expression profiling data from brain homogenates of 8 normal volunteers, and 6 patients with prodromal AD who had developed MCI were analyzed, and the data were obtained from GSE12685. Further, overexpression of GABBR2 was achieved in human neuroblastoma cell lines SH-SY5Y and BE(2)-M17 using expression plasmid transfection. GABBR2 was significantly overexpressed in brain tissues of patients with prodromal AD who had developed MCI, as compared to normal brains. Moreover, GABBR2 overexpressing cells showed a significant increase in intracellular Ca2+ concentration, a large amount of reactive oxygen species production, a large opening of the mitochondrial permeability transition pore and a significant increase in apoptosis compared with control cells. GABBR2 overexpression was significantly involved in early AD progression and MCI by causing cellular events such as intracellular Ca2+ imbalance, oxidative stress, and mitochondrial dysfunction.

Neuroinflammatory history results in overlapping transcriptional signatures with heroin exposure in the nucleus accumbens and alters responsiveness to heroin in male rats

Recent progress in psychiatric research has highlighted neuroinflammation in the pathophysiology of opioid use disorder (OUD), suggesting that heightened immune responses in the brain may exacerbate opioid-related mechanisms. However, the molecular mechanisms resulting from neuroinflammation that impact opioid-induced behaviors and transcriptional pathways remain poorly understood. In this study, we have begun to address this critical knowledge gap by exploring the intersection between neuroinflammation and exposure to the opioid heroin, utilizing lipopolysaccharide (LPS)-induced neuroinflammation, to investigate transcriptional changes in the nucleus accumbens (NAc), an essential region in the mesolimbic dopamine system that mediates opioid reward. By integrating RNA sequencing with bioinformatic and statistical analyses, we observed significant transcriptional overlaps between neuroinflammation and experimenter-administered heroin exposure in the NAc. Furthermore, we identified a subset of NAc genes synergistically regulated by LPS and heroin, suggesting that LPS history may exacerbate some heroin-induced molecular neuroadaptations. We extended our findings to examine the impact of neuroinflammatory history on responsiveness to heroin in a locomotor sensitization assay and observed LPS-induced exacerbation of heroin sensitization, indicating that neuroinflammation may increase sensitivity to opioids’ behavioral effects. Lastly, we performed comparative analysis of the NAc transcriptional profiles of LPS-heroin rats with those obtained from voluntary heroin intake in a rat model of heroin self-administration (SA) and published human OUD datasets. We observed significant convergence of the three datasets and identified transcriptional patterns in the preclinical models that recapitulated human OUD neuropathology, highlighting the utility of preclinical models to further investigate molecular mechanisms of OUD pathology. Overall, our study elucidates transcriptional interconnections between neuroinflammation and heroin exposure, and also provides evidence of the behavioral ramifications of such interactions. By bridging the gap between neuroinflammation and heroin exposure at the transcriptional level, our work provides valuable insights for future research aimed at mitigating the influence of inflammatory pathways in OUD.

Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs.

This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis. The triple-transgenic (PNPLA3I148M-GIPRdn-hIAPP) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs. The TG2 pigs presented mild metaflammation and insulin resistance (IR) which is similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury. ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.

Describing and Mapping the Research Trend of Scientific Publications on Arrhythmogenic Right Ventricular Cardiomyopathy Across Four Decades: A Bibliometric Analysis.

To perform a bibliometric analysis of publications of arrhythmogenic right ventricular cardiomyopathy (ARVC) from 1981 to 2023 to summarize the current publications and explore frontiers on this topic. We integrated the scientific publications on ARVC in the Web of Science (WOS) Core Collection database from January 1981 to September 2023, using the retrieval strategy of medical subject headings combined with keywords. We focused on articles and reviews that were published in English. Relevant information such as the journal and publisher, the title, authors, organizations, abstract, keywords, published date, and number of citations, were collected. Bibliometric analysis was performed and visualized by the R software and Microsoft Excel. The results revealed a total of 4792 records related to ARVC from the WOS database, and 2992 original articles or reviews which were selected for bibliometric analysis. There were 79 countries and regions, 3724 research institutions, and 12 157 scholars who have published in this topic. The number of scientific publications of ARVC increased year-by-year, with an annual growth rate of 12.12%. We also investigated the top 10 contributing countries, organizations with affiliations, most influential researchers, highest-cited articles, and highest-frequency keywords. In addition, the most active areas of research on ARVC included that of fatal complications, molecular pathological mechanisms, diagnosis, therapy, and prognosis respectively according to the keywords trend analysis. Our study reports the publication landscape of ARVC during the past four decades based on bibliometric analysis. This study provides a deeper understanding of the published literature on ARVC.

Neural Circuitries between the Brain and Peripheral Solid Tumors.

The recent discovery of the pivotal role of the central nervous system in controlling tumor initiation and progression has opened a new field of research. Increasing evidence suggests a bidirectional interaction between the brain and tumors. The brain influences the biological behavior of tumor cells through complex neural networks involving the peripheral nervous system, the endocrine system, and the immune system, whereas tumors can establish local autonomic and sensory neural networks to transmit signals into the central nervous system, thereby affecting brain activity. This review aims to summarize the latest research in brain-tumor cross-talk, exploring neural circuitries between the brain and various peripheral solid tumors, analyzing the roles in tumor development and the related molecular mediators and pathologic mechanisms, and highlighting the critical impact on the understanding of cancer biology. Enhanced understanding of reciprocal communication between the brain and tumors will establish a solid theoretical basis for further research and could open avenues for repurposing psychiatric interventions in cancer treatment.

Evaluating renal injury characteristics in different rat models of hyperuricemia and elucidating pathological molecular mechanisms via serum metabolomics.

Hyperuricemia has emerged as a significant global health concern, closely associated with various metabolic disorders. The adverse effects frequently observed with current pharmacological treatments for hyperuricemia highlight the urgent need for reliable animal models to elucidate the disease's pathophysiological mechanisms, thereby facilitating the development of safer and more effective therapies. In this study, we established three rat models of hyperuricemia using potassium oxonate, either alone or in combination with fructose and adenine. Each model exhibited distinct pathological changes, with the combination of potassium oxonate, fructose, and adenine causing significantly more severe damage to liver and kidney functions than potassium oxonate alone. Serum metabolomics analyses revealed profound dysregulation in the metabolic pathways of purine, pyrimidines, and glutathione, underscoring the pivotal role of oxidative stress in the progression of hyperuricemia. We identified key biomarkers such as orotidine, ureidosuccinic acid, uracil, and pseudouridine, which are associated with uric acid-induced damage to hepatic and renal systems. MetOrigin tracing analysis further revealed that differential metabolites related to hyperuricemia are primarily involved in host-microbiome co-metabolic pathways, particularly in purine metabolism, with bacterial phyla such as Pseudomonadota, Actinomycetota, and Ascomycota being closely linked to the critical metabolic processes of uric acid production. These findings not only enhance our understanding of the pathogenic mechanisms underlying hyperuricemia but also provide a robust experimental model foundation for the development of innovative treatment strategies.

Epidermal proteomics demonstrates Elafin as a psoriasis-specific biomarker and highlights increased anti-inflammatory activity around psoriatic plaques.

Eczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different. Further molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data. In this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins. Our findings confirmed the psoriasis-associated cytokine IL-36γ as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36γ and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment. Overall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease.

Northern Pulmonary Hypertension: A Forgotten Kind of Pulmonary Circulation Pathology.

Northern pulmonary hypertension (NPH) is a medical condition that is still enigmatic in non-Russian-speaking countries. The extant previous literature is mostly available in the Russian language and, therefore, not accessible to the rest of the world. The recent increased interest in climate changes and environmental effects on pulmonary circulation prompted us to summarize the knowledge from the past about the effects of cold on pulmonary vasculature. In this review, we, for the first time, describe, in detail, the pathological attributes of human NPH, a medical disorder that occurs in people living in extremely cold regions, in the English language. Briefly, NPH is characterized by the hyper-muscularization of the pulmonary arteries and de novo muscularization of the arterioles with the ultimate development of right ventricular hypertrophy. However, the profound molecular mechanisms of the NPH pathology are to be revealed in future comprehensive studies.

Propofol Protects the Blood-Brain Barrier After Traumatic Brain Injury by Stabilizing the Extracellular Matrix via Prrx1: From Neuroglioma to Neurotrauma.

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

Calcium saccharate/DUSP6 suppresses renal cell carcinoma glycolytic metabolism and boosts sunitinib efficacy via the ERK-AKT pathway

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.

Abstract 6609: NRF2/ACSS2 axis regulates alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells

Abstract Esophageal diseases such as gastroesophageal reflux disease (GERD) and esophageal cancer have a strong association with alcohol drinking. However, the molecular mechanisms of alcohol-induced esophageal pathology remain unclear. In our previous study, we identified acyl-CoA synthetase short-chain family member 2 (ACSS2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) in the esophageal epithelial cells in vitro and in vivo. Ethanol exposure enhanced de novo lipogenesis in NRF2high cells and generated a more energetic and invasive phenotype. In this study, we aimed to investigate the role of the NRF2/ACSS2 axis in regulating alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells. We first demonstrated that ethanol exposure activated NRF2 signaling and upregulated the expression of NRF2 and ACSS2 in human esophageal squamous epithelial cells. 13C-ethanol/13C-acetate metabolic flux assay showed a dramatic NRF2-dependent increase of labeling of the TCA cycle intermediates and de novo lipogenesis in NRF2high cells in comparison with NRF2null or NRF2low cells. Long-term ethanol exposure caused metabolic reprogramming, in particular induced de novo lipogenesis, in the mouse esophagus according to metabolomics profiling of 833 metabolites. PET/CT and autoradiography showed increased 11C-acetate uptake in the NRF2high esophagus of a conditional tissue-specific mouse (Sox2CreER;LSL-Nrf2E79Q) due to upregulation of transporters and metabolic enzymes. In summary, Our data demonstrated the functional role of the NRF2-ACSS2 axis in alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells both in vitro and in vivo, suggesting NRF2/ACSS2 inhibition as a novel mechanism-based prevention for alcohol-associated esophageal pathology. Citation Format: Zhaohui Xiong, Boopathi Subramaniyan, Chorlada Paiboonrungruang, Yahui Li, Wentao He, Hong Yuan, Guofang Zhang, Xiaoxin Chen. NRF2/ACSS2 axis regulates alcohol-induced metabolic reprogramming in esophageal squamous epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6609.

Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson’s Disease Pathology

Parkinson’s disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities.

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

The DNA repair enzyme, aprataxin, plays a role in innate immune signaling.

Ataxia with oculomotor apraxia type 1 (AOA1) is a progressive neurodegenerative disorder characterized by a gradual loss of coordination of hand movements, speech, and eye movements. AOA1 is caused by an inactivation mutation in the APTX gene. APTX resolves abortive DNA ligation intermediates. APTX deficiency may lead to the accumulation of 5'-AMP termini, especially in the mitochondrial genome. The consequences of APTX deficiency includes impaired mitochondrial function, increased DNA single-strand breaks, elevated reactive oxygen species production, and altered mitochondrial morphology. All of these processes can cause misplacement of nuclear and mitochondrial DNA, which can activate innate immune sensors to elicit an inflammatory response. This study explores the impact of APTX knockout in microglial cells, the immune cells of the brain. RNA-seq analysis revealed significant differences in the transcriptomes of wild-type and APTX knockout cells, especially in response to viral infections and innate immune pathways. Specifically, genes and proteins involved in the cGAS-STING and RIG-I/MAVS pathways were downregulated in APTX knockout cells, which suggests an impaired immune response to cytosolic DNA and RNA. The clinical relevance of these findings was supported by analyzing publicly available RNA-seq data from AOA1 patient cell lines. Comparisons between APTX-deficient patient cells and healthy control cells also revealed altered immune responses and dysregulated DNA- and RNA-sensing pathways in the patient cells. Overall, this study highlights the critical role of APTX in regulating innate immunity, particularly in DNA- and RNA-sensing pathways. Our findings contribute to a better understanding of the underlying molecular mechanisms of AOA1 pathology and highlights potential therapeutic targets for this disease.

NPC1L1 Plays a Novel Role in Nonalcoholic Fatty Liver Disease.

Niemann-Pick C1-Like 1 (NPC1L1) is a key protein in the transport of cholesterol, which exists in the brush marginal membrane of the intestinal epithelial cells and the timid duct membrane of the liver. It affects cholesterol absorption and plasma low-density lipoprotein levels. Cholesterol is both an important component of the cell membrane and a precursor of bile acid and steroid hormone synthesis. Abnormal cholesterol metabolism is closely related to nonalcoholic steatohepatitis (NASH). NASH can progress to fibrosis and cirrhosis, with serious consequences. NPC1L1 is involved in the regulation of cholesterol and lipid metabolism and plays an important role in maintaining the balance of cholesterol metabolism in the body. It also plays an important role in some metabolic diseases such as nonalcoholic fatty liver disease, obesity, and hypercholesterolemia. Therefore, it is necessary to elucidate the molecular pathological mechanism of NPC1L1 in the regulation of cholesterol metabolism and the occurrence and development of NASH, which can provide a target for the development of novel drugs for the treatment of NASH and other diseases. More importantly, it helps to accelerate the development of drugs that regulate lipid metabolism at multiple levels and reduce liver steatosis, which is extremely important for the prevention and treatment of NASH and related severe metabolic diseases.

Altered expression of inflammation-associated molecules in striatum: an implication for sensitivity to heavy ion radiations.

Heavy ion radiation is one of the major hazards astronauts face during space expeditions, adversely affecting the central nervous system. Radiation causes severe damage to sensitive brain regions, especially the striatum, resulting in cognitive impairment and other physiological issues in astronauts. However, the intensity of brain damage and associated underlying molecular pathological mechanisms mediated by heavy ion radiation are still unknown. The present study is aimed to identify the damaging effect of heavy ion radiation on the striatum and associated underlying pathological mechanisms. Two parallel cohorts of rats were exposed to radiation in multiple doses and times. Cohort I was exposed to 15 Gy of 12C6+ ions radiation, whereas cohort II was exposed to 3.4 Gy and 8 Gy with 56Fe26+ ions irradiation. Physiological and behavioural tests were performed, followed by 18F-FDG-PET scans, transcriptomics analysis of the striatum, and in-vitro studies to verify the interconnection between immune cells and neurons. Both cohorts revealed more persistent striatum dysfunction than other brain regions under heavy ion radiation at multiple doses and time, exposed by physiological, behavioural, and 18F-FDG-PET scans. Transcriptomic analysis revealed that striatum dysfunction is linked with an abnormal immune system. In vitro studies demonstrated that radiation mediated diversified effects on different immune cells and sustained monocyte viability but inhibited its differentiation and migration, leading to chronic neuroinflammation in the striatum and might affect other associated brain regions. Our findings suggest that striatum dysfunction under heavy ion radiation activates abnormal immune systems, leading to chronic neuroinflammation and neuronal injury.