Disease Pathways Research Articles

GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation

The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.

Tailored management strategies for IgA nephropathy based on clinical presentations.

The treatment landscape for IgA nephropathy (IgAN) is rapidly evolving with the introduction of novel therapies targeting diverse disease pathways. Some have already been approved in different countries, while others are under investigation in randomized controlled trials (RCTs) with encouraging results. However, almost all performed RCTs have included only patients with refractory non-nephrotic proteinuria and preserved renal function. Other clinical presentations (rapidly progressive forms, malignant hypertension, thrombotic microangiopathy, nephrotic syndrome) have received less attention and are systematically excluded from RCTs. On the other hand, certain aspects, such as the impact of hematuria or the management in special populations (e.g. pregnant patients or transplant recipients), remain underexplored. This review proposes therapeutic algorithms to guide treatment decisions in different clinical scenarios, while highlighting gaps in current research.

Zebrafish navigating the metabolic maze: insights into human disease - assets, challenges and future implications.

Zebrafish (Danio rerio) have become indispensable models for advancing our understanding of multiple metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome. This review provides a comprehensive analysis of zebrafish as a powerful tool for dissecting the genetic and molecular mechanisms of these diseases, focusing on key genes, like pparγ, lepr, ins, and srebp. Zebrafish offer distinct advantages, including genetic tractability, optical transparency in early development, and the conservation of key metabolic pathways with humans. Studies have successfully used zebrafish to uncover conserved metabolic mechanisms, identify novel disease pathways, and facilitate high-throughput screening of potential therapeutic compounds. The review also highlights the novelty of using zebrafish to model multifactorial metabolic disorders, addressing challenges such as interspecies differences in metabolism and the complexity of human metabolic disease etiology. Moving forward, future research will benefit from integrating advanced omics technologies to map disease-specific molecular signatures, applying personalized medicine approaches to optimize treatments, and utilizing computational models to predict therapeutic outcomes. By embracing these innovative strategies, zebrafish research has the potential to revolutionize the diagnosis, treatment, and prevention of metabolic disorders, offering new avenues for translational applications. Continued interdisciplinary collaboration and investment in zebrafish-based studies will be crucial to fully harnessing their potential for advancing therapeutic development.

Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques

Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high NR1H3 expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis.

Retraction: MicroRNA-34c inhibits osteogenic differentiation and valvular interstitial cell calcification via STC1-mediated JNK pathway in calcific aortic valve disease

Retraction: MicroRNA-34c inhibits osteogenic differentiation and valvular interstitial cell calcification via STC1-mediated JNK pathway in calcific aortic valve disease

Review of Alzheimer's disease and treatments

Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects older adults and is characterized by progressive memory loss and cognitive dysfunction. The disease is the most common type of dementia worldwide and imposes a significant burden on patients, families and society. More than 50 million people worldwide are affected by Alzheimer's disease, placing enormous financial strain on healthcare systems and families. The main molecular metabolic pathways of Alzheimer's disease include amyloid beta protein metabolic pathway and tau protein phosphorylation pathway. Abnormal accumulation of amyloid beta protein in the brain to form plaques, and excessive phosphorylation of tau protein to form neurofibrillary tangles, these pathological changes lead to nerve cell damage and death, resulting in the gradual loss of cognitive function. Current treatments can only slow the progression of the disease or alleviate symptoms and cannot completely cure AD. Finding effective treatment and intervention strategies can not only significantly improve the quality of life of Alzheimer's patients, but also reduce the burden of the disease on society and families. This article will review the background and epidemiology of Alzheimer's disease, discuss its main molecular metabolic pathways in detail, and review the current status of treatment, with a view to providing references for future research and treatment strategies.

Imperfect wound healing sets the stage for chronic diseases.

Although the age of the genome gave us much insight about how our organs fail with disease, it also suggested that diseases do not arise from mutations alone; rather, they develop as we age. In this Review, we examine how wound healing might act to ignite disease. Wound healing works well when we are younger, repairing damage from accidents, environmental assaults, and battles with pathogens. Yet, with age and accumulation of mutations and tissue damage, the repair process can devolve, leading to inflammation, fibrosis, and neoplastic signaling. We discuss healthy wound responses and how our bodies might misappropriate these pathways in disease. Although we focus predominantly on epithelial-based (lung and skin) diseases, similar pathways might operate in cardiac, muscle, and neuronal diseases.

Exploring sex-specific genetic architecture of coronary artery disease in Tehran: a cardiometabolic genetic study

ABSTRACT Background The development of coronary artery disease (CAD) is influenced by sex and genetic factors. Genome-wide association studies (GWAS) have linked genetic loci to CAD, mostly in European populations. The study aims to find sex-related genetic differences in the Iranian population. Research design and methods We conducted a sex-stratified GWAS with 4519 subjects (1832 males and 2687 females) in the discovery group and 922 subjects (495 males and 427 females) in the confirmation group of an Iranian cohort. We analyzed 9,141,124 variants using a genome-wide complex trait analysis (GCTA) tool. Results We detected distinct genetic variants associated with CAD in males: rs34952209 [OR = 1.79; p = 5.216E–8], rs1432687863 [OR = 1.95; p = 8.477E–8], and in females, rs7314741 [OR = 1.67; p = 7.142-8E] positively influenced CAD risk. The CAD-associated SNPs that were obtained have been confirmed using independent samples. Rs3495229 May impact histone mark and Pou2f2 motifs, while rs7314741 in the LEM Domain Containing 3 (LEMD3) promoter may affect a regulatory motif for the STAT transcription factor. According to Roadmap and ENCODE data, Rs1432687863 is a new variant affecting CAD in males, potentially through H3K9me3 in the heart. Conclusions Our findings highlight the role of sex-specific genetic differences in CAD development, providing novel insights into disease pathways which is not appropriate using a sex-combined strategy.

The Therapeutic Potential of Targeting the Pd-L1/Pd-1 Immune Checkpoint Pathway in Alzheimer's Disease

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Emerging evidence suggests that the PD-L1/PD-1 immune checkpoint pathway plays a critical role in modulating neuroinflammation, microglial function, and amyloid-β clearance in AD. This review summarizes the current understanding of the PD-L1/PD-1 pathway in AD and discusses its potential as a therapeutic target. Preclinical studies and clinical trials have demonstrated that targeting the PD-L1/PD-1 axis can enhance microglial phagocytosis, promote amyloid-β clearance, and reduce neuroinflammation. We examine the potential benefits and challenges of using existing immunotherapy drugs, such as anti-PD-L1 and anti-PD-1 antibodies, in the context of AD. Additionally, we explore the development of novel, more specific agents targeting the PDL1/ PD-1 pathway, as well as potential synergistic approaches with other immunomodulatory or amyloid-β-targeting treatments. This review provides a comprehensive and up-to-date analysis of the PD-L1/PD-1 immune checkpoint pathway's role in Alzheimer's disease, highlighting its promising therapeutic potential for improving patient outcomes. Further research is warranted to optimize treatment strategies and evaluate the long-term safety and efficacy of targeting this axis in clinical settings.

The POINTER Imaging baseline cohort: Associations between multimodal neuroimaging biomarkers, cardiovascular health, and cognition.

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta-amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ-, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. In this heterogenous, at-risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non-AD (Alzheimer's disease) pathway to brain injury and cognitive decline. ·The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle ·POINTER Imaging collected multimodal neuroimaging data in this unique, at-risk cohort ·Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression ·Associations between amyloid and tau, and tau and cognition, were relatively weak ·CVD risk and tau pathology were independently related to memory.

Computational dissection through network pharmacology and structure-based analysis unravels mechanistic actions of bioactive compounds in a hepatoprotective herb, Picrorhiza kurroa for the treatment of NAFLD and NASH

Non-Alcoholic fatty liver disease has become a silent pandemic worldwide with no authorized medicine available. Picrorhiza kurroa is a traditional hepatoprotective herb wherein extracts provide therapeutic efficacy but not the individual compounds. Hence, the aim of the study is exploration of active molecules in P. kurroa extracts and identification of mechanistic actions to pinpoint potential leads towards drug development. We employed network pharmacology to identify the significance of combinatorial effect of compounds on multiple targets. The NAFLD/NASH associated genes encoding protein targets overlapped with the predicted protein targets of P. kurroa compounds. Then, overlapping targets were considered further to capture the interactive targets from Protein-Protein-Interaction network of NAFLD and NASH. The networks were generated to capture the role of proteins in different signaling pathways, diseases, and effective compounds as therapeutics. Furthermore, structural, and biophysical analysis was performed for significant complexes. We observed that the compounds like astragalin, Picroside-I, Vernicoside, Rutin, Quercetin, Kaempferol, Gallic acid, Ellagic acid in P. kurroa acted synergistically by enhancing the bioavailability of active compounds and affecting various morbidities of NAFLD through involvement in different signaling and disease pathways such as oxidative phosphorylation, FoxO signaling, inflammation, several cancerous and diabetic pathways. The network pharmacology revealed the interactive behavior of proteins involved in NAFLD treated by P. kurroa compounds. Furthermore, molecular docking and molecular dynamic simulation study showed potential candidates in therapeutics. Overall, the study suggested multi-target drug discovery for treating complex diseases by providing leads in herbal extracts as potential therapeutic botanicals.

DNA and RNA Methylation in Periodontal and Peri-implant Diseases.

Periodontal and peri-implant diseases are primarily biofilm-induced pathologies in susceptible hosts affecting the periodontium and dental implants. Differences in disease susceptibility, severity, and patterns of progression have been attributed to immune regulatory mechanisms such as epigenetics. DNA methylation is an essential epigenetic mechanism governing gene expression that plays pivotal roles in genomic imprinting, chromosomal stability, apoptosis, and aging. Clinical studies have explored DNA methylation inhibitors for cancer treatment and predictive methylation profiles for disease progression. In periodontal health, DNA methylation has emerged as critical, evidenced by clinical studies unraveling its complex interplay with inflammatory genes and its regulatory role in periodontitis contributing to disease severity. Human studies have shown that methylation enzymes associated with gene reactivation (e.g., ten-eleven translocation-2) are elevated in periodontitis compared with gingivitis. Dysregulation of these genes can lead to the production of inflammatory cytokines and an altered initial response to bacteria via the toll-like receptor signaling pathway in periodontal diseases. In addition, in peri-implant diseases, this dysregulation can result in altered DNA methylation levels and enzymatic activity influenced by the properties of the titanium surface. Beyond traditional perspectives, recent evidence highlights the involvement of RNA methylation (e.g., N6-methyladenosine [m6A], N6,2'-0-dimethyladenosine [m6Am]) in periodontitis and peri-implantitis lesions, playing vital roles in the innate immune response, production of inflammatory cytokines, and activation of dendritic cells. Both DNA and RNA methylation can influence the gene expression, virulence, and bacterial behavior of well-known periodontal pathogens such as Porphyromonas gingivalis. Alterations in bacterial methylation patterns result in changes in the metabolism, drug resistance, and gene expression related to survival in the host, thereby promoting tissue degradation and chronic inflammatory responses. In summary, the present state-of-the-art review navigates the evolving landscape of DNA and RNA methylation in periodontal and peri-implant diseases, integrating recent developments and mechanisms to reshape the understanding of epigenetic dynamics in oral health.

Proteomics in Acute Heart Transplant Rejection, On Behalf of the GRAfT Investigators.

Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets. Within the prospective, multicenter Genomic Research Alliance for Transplantation study, 181 proteins were evaluated from blood drawn at the time of endomyocardial biopsy; protein fold change, logistic regression, and pathway analyses were conducted, with protein discovery adjusted for a 5% false discovery rate. Among 104 adult heart transplant patients (31% female sex, 53% Black race, median age 52 y), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR). Differential expression was found in 2 proteins during ACR (inflammatory proteins CXCL10 and CD5) and 73 proteins during AMR. The most abundant AMR proteins were the heart failure biomarkers N-terminal pro-B-type natriuretic peptide and suppression of tumorigenicity 2. In univariate logistic regression, odds of identifying ACR on endomyocardial biopsy increased with doubling of CXCL10 (odds ratio [OR] 2.2 [95% confidence interval (CI), 1.3-3.6]) and CD5 (OR 4.7 [95% CI, 1.7-12.9]) concentrations, and odds of AMR increased with doubling of N-terminal pro-B-type natriuretic peptide (OR 13.0 [95% CI, 2.7-62.7) and suppression of tumorigenicity 2 (OR 4.8 [95% CI, 2.1-10.7]) concentrations. After multivariable analysis with clinical covariates, these proteins showed similar odds of ACR or AMR on biopsy. Pathway analysis identified T cell-receptor signaling and cell differentiation as key pathways in ACR and cardiovascular disease and cell turnover in AMR. Proteomic analysis reveals unique biomarkers and biological pathway expression in ACR and AMR. Cardiac injury-associated biomarkers were more pronounced in AMR, whereas inflammatory biomarkers were more pronounced in ACR. Proteomic analysis may provide insights into rejection pathophysiology, detection, and therapy.

Investigation of Ginseng-Ophiopogon Injection on Enhancing Physical Function by Pharmacogenomics and Metabolomics Evaluation.

Ginseng-ophiopogon injection (GOI) is a clinically commonly used drug for Qi deficiency syndrome characterized by decreased physical function in China. This study aimed to clarify common pharmacological mechanisms of GOI in enhancing physical function. We performed an integrative strategy of weight-loaded swimming tests in cold water (5.5°C), hepatic glycogen and superoxide dismutase (SOD) detections, GC-TOF/MS-based metabolomics, multivariate statistical techniques, network pharmacology of known targets and constituents, and KEGG pathway analysis of GOI. Compared with the control group, GOI showed significant increases in the weightloaded swimming time, hepatic levels of glycogen and SOD. Additionally, 34 significantly differential serum metabolites referred to glycolysis, gluconeogenesis and arginine biosynthesis were affected by GOI. The target collection revealed 98 metabolic targets and 50 experimentreported drug targets of ingredients in GOI involved in enhancing physical function. Further, the PPI network analysis revealed that 8 ingredients of GOI, such as ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, and notoginsenoside R1, were well-associated with 48 hub targets, which had good ability in enhancing physical function. Meanwhile, nine hub proteins, such as SOD, mechanistic target of Rapamycin (mTOR), and nitric oxide synthases, were confirmed to be affected by GOI. Finally, 98 enriched KEGG pathways (P<0.01 and FDR<0.001) of GOI were obtained from 48 hub targets of the PPI network. Among them, pathways in cancer, Chagas disease, lipid and atherosclerosis, and PI3K-Akt signaling pathway ranked top four. This study provided an integrative and efficient approach to understand the molecular mechanism of GOI in enhancing physical function.

Role of miRNA regulation in IGFBP-2 overexpression and neuronal ferroptosis: Insights into the Nrf2/SLC7A11/GPX4 pathway in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease with pathological features including amyloid plaque deposits and neurofibrillary tangles. In this study, the expressions of miRNA, IGFBP-2 and neuronal ferritin were detected by qPCR, Western blot and immunohistochemistry. The regulatory effects of miRNA on IGFBP-2 and neuronal ferritin were further verified by intervention experiments with miRNA mimics and inhibitors. Double luciferase reporter gene assay and RNA immunoprecipitation were used to investigate the interaction between miRNA and target genes. Finally, the effect of miRNA on Nrf2/SLC7A11/GPX4 pathway was evaluated by antioxidant enzyme activity and oxidative stress marker detection. The overexpression of IGFBP-2 was found to be significantly increased with the deposition of neuronal ferritin. Expression levels of specific mirnas were significantly down-regulated in AD models and negatively correlated with IGFBP-2 and neuronal ferritin expression. Intervention experiments with miRNA mimics and inhibitors have confirmed that these mirnas can regulate the expression of IGFBP-2 and neuronal ferritin. Further studies revealed that these mirnas affect antioxidant enzyme activity and oxidative stress levels by targeting key genes in the Nrf2/SLC7A11/GPX4 pathway, thereby regulating the deposition of neuronal ferritin.

Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.

Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.

041 Deciphering the contribution of JAK-STAT signaling pathway in inflammatory skin diseases

041 Deciphering the contribution of JAK-STAT signaling pathway in inflammatory skin diseases

Global perspectives and hotspots of VEGF signaling pathway in Liver disease from 2008 to 2023: A bibliometric analysis and visualization

Global perspectives and hotspots of VEGF signaling pathway in Liver disease from 2008 to 2023: A bibliometric analysis and visualization

Unveiling the therapeutic potential of quercetin and its metabolite (Q3OG) for targeting inflammatory pathways in Crohn's disease: A network pharmacology and molecular dynamics approach

Unveiling the therapeutic potential of quercetin and its metabolite (Q3OG) for targeting inflammatory pathways in Crohn's disease: A network pharmacology and molecular dynamics approach

Oral agents for lowering lipoprotein(a).

To review the development of oral agents to lower Lp(a) levels as an approach to reducing cardiovascular risk, with a focus on recent advances in the field. Extensive evidence implicates Lp(a) in the causal pathway of atherosclerotic cardiovascular disease and calcific aortic stenosis. There are currently no therapies approved for lowering of Lp(a). The majority of recent therapeutic advances have focused on development of injectable agents that target RNA and inhibit synthesis of apo(a). Muvalaplin is the first, orally administered, small molecule inhibitor of Lp(a), which acts by disrupting binding of apo(a) and apoB, in clinical development. Nonhuman primate and early human studies have demonstrated the ability of muvalaplin to produce dose-dependent lowering of Lp(a). Ongoing clinical trials will evaluate the impact of muvalaplin in high cardiovascular risk and will ultimately need to determine whether this strategy lowers the rate of cardiovascular events. Muvalaplin is the first oral agent, developed to lower Lp(a) levels. The ability of muvalaplin to reduce cardiovascular risk remains to be investigated, in order to determine whether it will be a useful agent for the prevention of cardiovascular disease.