Progression Of Pathology Research Articles

Circulating chemokine levels and receptor polymorphisms have potential as biomarkers for fibrosis stages in patients with chronic hepatitis C infection.

Chemokines and their receptors, which regulate lymphoid organ development and immune cell trafficking, are integral to the mechanisms underlying viral control, hepatic inflammation, and liver damage in chronic hepatitis C (CHC) infection. This study explores the potential relationship between serum chemokine levels/polymorphisms and hepatitis C infection in affected individuals, with a particular focus on their utility as biomarkers across different stages of fibrosis. Serum levels of the chemokines CXCL11, CXCL12, and CXCL16 were measured in patients with mild/moderate and advanced fibrosis due to CHC, as well as in healthy controls, using the ELISA method. The CXCL12 rs1801157 and CXCL16 rs2277680 polymorphisms were analyzed in blood samples from patients and healthy controls through RT-qPCR. Serum levels of CXCL11, CXCL12, and CXCL16 were significantly elevated in patients with advanced fibrosis compared to healthy controls. Furthermore, CXCL11 levels were markedly higher in patients with advanced fibrosis than in those with mild/moderate fibrosis. The frequency of the CXCL12 rs1801157 AA genotype was significantly higher in the advanced fibrosis group compared to the healthy control group. Similarly, the CXCL16 rs2277680 GA genotype was significantly more prevalent in the advanced fibrosis group than in the mild/moderate fibrosis group. The current study highlights that, in addition to the potential association between chemokine levels/polymorphisms and an increased risk of disease complications and pathological progression in CHC infection, serum CXCL11 levels and the CXCL16 rs2277680 allel polymorphism may be important factors in determining the fibrosis stage of hepatitis C infection.

MtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction.

Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death.

Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain.

Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.

Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability

Traumatic brain injury is a leading cause of chronic neurologic disability and a risk factor for development of neurodegenerative disease. However, little is known regarding the pathophysiology of human traumatic brain injury, especially in the window after acute injury and the later life development of progressive neurodegenerative disease. Given the proposed mechanisms of toxic protein production and neuroinflammation as possible initiators or contributors to progressive pathology, we examined phosphorylated tau accumulation, microgliosis and astrogliosis using immunostaining in the orbitofrontal cortex, a region often vulnerable across traumatic brain injury exposures, in an age and sex-matched cohort of community traumatic brain injury including both mild and severe cases in midlife. We found that microglial response is most prominent after chronic traumatic brain injury, and interactions with neurons in the form of satellite microglia are increased, even after mild traumatic brain injury. Taking our investigation into a mouse model, we identified that these satellite microglia suppress neuronal excitability in control conditions but lose this ability with chronic traumatic brain injury. At the same time, network hyperexcitability is present in both mouse and human orbitofrontal cortex. Our findings support a role for loss of homeostatic control by satellite microglia in the maladaptive circuit changes that occur after traumatic brain injury.

Identification, Clinical Values, and Prospective Pathway Signaling of Lipid Metabolism Genes in Epilepsy and AED Treatment.

The dysregulation of lipid metabolism has been associated with the etiology and progression of the neurological pathology. However, the roles of lipid metabolism and the molecular mechanism in epilepsy and the use of antiepileptic drugs (AEDs) are relatively understudied. Gene expression profiles of GSE143272 from blood samples were included for differential analysis, and the lipid metabolism-related differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The STRING database and Cytoscape software were used to establish and visualize protein-protein interaction (PPI) networks. RT-PCR and western blotting were used to verify the expression levels of lipid metabolism-related DEGs in serum and cerebrospinal fluid (CSF). Eleven lipid metabolism-related DEGs were identified including CXCL8, PTGS2, FOSB, G0S2, HLA-C, CLEC12A, ARG1, ELANE, RSAD2, CTSG, and DEFA1. And among them, five lipid metabolism-related Hub DEGs including CXCL8, PTGS2, ELANE, CTSG, and ARG1 were finally verified in serum samples of epilepsy patients. Moreover, CXCL8 was selected and validated in the epilepsy without AEDs and epilepsy with AEDs. G0S2 was significantly decreased in serum and CSF in epilepsy with AEDs compared to epilepsy without AEDs. Collectively, these findings suggest that lipid metabolism is closely related to epilepsy. This revelation opens up opportunities to further investigate the associated molecular mechanisms and possible therapeutic targets for epilepsy.

Anterior-temporal network hyperconnectivity is key to Alzheimer's disease: from ageing to dementia.

Curing Alzheimer's disease remains hampered by an incomplete understanding of its pathophysiology and progression. Exploring dysfunction in medial temporal lobe networks, particularly the anterior-temporal (AT) and posterior-medial (PM) systems, may provide key insights, as these networks exhibit functional connectivity alterations along the entire Alzheimer's continuum, potentially influencing disease propagation. However, the specific changes in each network and their clinical relevance across stages are not yet fully understood. This requires considering commonly used biomarkers, clinical progression, individual variability, and age confounds. Here, we leveraged monocentric longitudinal data from 261 participants spanning the adult lifespan and the Alzheimer's continuum. The sample included cognitively unimpaired adults aged 19 to 85 years (n = 209; eight out of 64 older adults over 60 were Aβ-positive) and Aβ-positive patients fulfilling diagnostic criteria for mild cognitive impairment (MCI, n = 26; 18 progressed to Alzheimer-dementia within seven years) or Alzheimer's type dementia (n = 26). Participants underwent structural and resting-state functional (f) MRI, florbetapir and FDG-PET, and global cognitive assessments, with up to three visits over a maximum period of 47 months. Network connectivity was assessed using seed-based analyses with the perirhinal and parahippocampal cortices as seeds, within data-driven masks reflecting the AT and PM networks. Generalized additive and linear mixed models were run to assess age-specific effects and Alzheimer's-related alterations. In this context, we explored various markers of pathological and clinical severity, including cerebral amyloid uptake, glucose metabolism, hippocampal volume, global cognition, diagnostic staging, and time to dementia onset. Our findings revealed distinct patterns of connectivity linked to normal aging or Alzheimer's disease. Advancing age throughout adulthood was associated with lower PM connectivity and more subtle changes in AT connectivity, while Alzheimer's disease was characterised by AT hyperconnectivity without global changes in PM connectivity. Specifically, AT connectivity was higher in MCI and Alzheimer-dementia patients compared to older controls and was positively associated with amyloid burden, glucose hypometabolism, hippocampal atrophy, and global cognitive deficits in older adults, ranging from unimpaired to demented. Additionally, higher AT connectivity correlated with faster progression to Alzheimer-dementia in MCI patients. This comprehensive approach allowed to reveal that excessive connectivity within the AT network is intrinsically linked to the pathological and clinical progression of Alzheimer's disease. These insights may guide future research to better understand cascading events leading to the disease and hold promise for developing prognostic tools and therapeutic interventions targeting these specific network alterations.

Mannose Promotes β-Amyloid Pathology by Regulating BACE1 Glycosylation in Alzheimer's Disease.

Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV)or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits.

Clinical effects of phospholipase D2 in attenuating acute pancreatitis.

The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2 (PLD2) exerted a regulatory effect on neutrophil migration, thereby alleviating the progression of acute pancreatitis. To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration, thereby alleviating the progression of acute pancreatitis. The study involved 90 patients diagnosed with acute pancreatitis, admitted to our hospital between March 2020 and November 2022. A retrospective analysis was conducted, categorizing patients based on Ranson score severity into mild (n = 25), moderate (n = 30), and severe (n = 35) groups. Relevant data was collected for each group. Western blot analysis assessed PLD2 protein expression in patient serum. Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration. Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay. Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration. Overall data analysis did not find significant differences between patient groups (P > 0.05). The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups (P < 0.05). The expression level of PLD2 in the moderate group was also lower than that in the mild group (P < 0.05). The severity of acute pancreatitis is negatively correlated with PLD2 expression (r = -0.75, P = 0.002). The mRNA levels of C-X-C chemokine receptor type 1, C-X-C chemokine receptor type 2, C-C chemokine receptor type 2, and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups (P < 0.05), and the expression levels in the moderate group are also higher than those in the mild group (P < 0.05). The levels of C-reactive protein, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the severe group were higher than those in the moderate and mild groups (P < 0.05), and the levels in the moderate group were also higher than those in the mild group (P < 0.05). The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups (P < 0.05), and the moderate group was also higher than the mild group (P < 0.05). In addition, the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group (P < 0.05), and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group (P < 0.05). The number of migrating neutrophils in the severe group + PLD2 inhibitor group was significantly higher than that in the severe group (P < 0.05), indicating that PLD2 inhibitors significantly stimulated neutrophil migration. PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis. Its protein expression varied among patients based on the severity of the disease, and a negative correlation existed between PLD2 expression and disease severity. Additionally, PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.

Tissue fibrosis in cardiorenal syndrome: crosstalk between heart and kidneys.

Cardiorenal syndrome (CRS) is represented as an intricate dysfunctional interplay between the heart and kidneys, marked by cardiorenal inflammation and fibrosis. Unlike other organs, the repair process in cardiorenal injury involves a regenerative phase characterized by proliferation and polyploidization, followed by a subsequent pathogenic phase of fibrosis. In CRS, acute or chronic cardiorenal injury leads to hyperactive inflammation and fibrotic remodeling, associated with injury-mediated immune cell (Macrophages, Monocytes, and T-cells) infiltration and myofibroblast activation. An inflammatory to fibrotic transition corresponds with macrophage transition (M1-M2) associated with increased TGF-β response. Chronic inflammation disrupts hemodynamic pathways, leading to imbalanced oxidative stress and the production of cytokines and growth factors that promote fibrotic stimulation, contributing to pathological cardiorenal remodeling. The inflammatory response paves the pre-fibrotic cardiorenal niche and drives subsequent fibrotic remodeling by activated myofibroblasts. A fibrotic cardiorenal response in CRS is characterized by increased and degradation-resistant deposition of extracellular proteins especially fibrillar Collagen -I, -III, -V, and non-fibrillar Collagen-IV by active myofibroblasts. Recent advances in basic research animal models of CRS have advanced the knowledge of cardiorenal fibrosis. However, a significant need for clinical applications, trials, and evaluation is still needed. Circulating biomarkers like procollagen peptides and TGF-β have clinically been associated with cardiorenal fibrosis diagnosis in CRS. Treatments targeting the fibrotic pathways have also shown efficacy in amelioration of cardiorenal fibrosis in preclinical models. Recent combination therapies targeting multiple fibrotic pathways have been shown to offer promising results. Understanding the heterogenic pathological progression and fibrogenesis could identify novel therapeutic approaches for clinical CRS diagnosis and treatment.

3-Hydroxyanthranic acid inhibits growth of oral squamous carcinoma cells through growth arrest and DNA damage inducible alpha.

The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism. The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay. 3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both in vitro and in vivo. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells in vivo and in vitro. 3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.

The Emerging Role of Mitochondria Oxygen Redox in Pathological Progression of Neurodegenerative Disorders.

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington disease, pose serious threats to human health, leading to substantial economic burdens on society and families. Despite extensive research, the underlying mechanisms driving these diseases remain incompletely understood, impeding effective diagnosis and treatment. In recent years, growing evidence has highlighted the crucial role of oxidative stress in the pathogenesis of various neurodegenerative diseases. However, there is still a lack of comprehensive reviews that systematically summarize the impact of mitochondrial oxidative stress on neurodegenerative diseases. This review aims to address this gap by summarizing the molecular mechanisms by which mitochondrial oxidative stress promotes the initiation and progression of neurodegenerative disorders. Furthermore, it discusses the potential of antioxidant-based therapeutic strategies for the treatment of these diseases. By shedding light on the role of mitochondrial oxidative stress in neurodegenerative diseases, this review not only serves as a valuable reference for further research on the disease mechanisms, but also offers novel perspectives for the treatment of these disorders.

Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although genes causing familial cases have been identified, those of sporadic ALS, which occupies the majority of patients, are still elusive. In this study, we adopted machine learning to build binary classifiers based on the New York Genome Center (NYGC) ALS Consortium’s RNA-seq data of the postmortem spinal cord of ALS and non-neurological disease control. The accuracy of the classifiers was greater than 83% and 77% for the training set and the unseen test set, respectively. The classifiers contained 114 genes. Among them, 41 genes have been reported in previous ALS studies, and others are novel in this field. These genes are involved in mitochondrial respiration, lipid metabolism, endosomal trafficking, and iron metabolism, which may promote the progression of ALS pathology.

Protection of Alzheimer’s disease progression by a human-origin probiotics cocktail

Microbiome abnormalities (dysbiosis) significantly contribute to the progression of Alzheimer’s disease (AD). However, the therapeutic efficacy of microbiome modulators in protecting against these ailments remains poorly studied. Herein, we tested a cocktail of unique probiotics, including 5 Lactobacillus and 5 Enterococcus strains isolated from infant gut with proven microbiome modulating capabilities. We aimed to determine the probiotics cocktail’s efficacy in ameliorating AD pathology in a humanized AD mouse model of APP/PS1 strains. Remarkably, feeding mice with 1 × 1011 CFU per day in drinking water for 16 weeks significantly reduced cognitive decline (measured by the Morris Water Maze test) and AD pathology markers, such as Aβ aggregation, microglia activation, neuroinflammation, and preserved blood-brain barrier (BBB) tight junctions. The beneficial effects were linked to a reduced inflammatory microbiome, leading to decreased gut permeability and inflammation in both systemic circulation and the brain. Although both male and female mice showed overall improvements in cognition and biological markers, females did not exhibit improvements in specific markers related to inflammation and barrier permeability, suggesting that the underlying mechanisms may differ depending on sex. In conclusion, our results suggest that this unique probiotics cocktail could serve as a prophylactic agent to reduce the progression of cognitive decline and AD pathology. This is achieved by beneficially modulating the microbiome, improving intestinal tight junction proteins, reducing permeability in both gut and BBB, and decreasing inflammation in the gut, blood circulation, and brain, ultimately mitigating AD pathology and cognitive decline.

Micronucleus counts correlating with male infertility: a clinical analysis of chromosomal abnormalities and reproductive parameters.

Investigating the correlation between micronucleus formation and male infertility has the potential to improve clinical diagnosis and deepen our understanding of pathological progression. Our study enrolled 2252 male patients whose semen was analyzed from March 2023 to July 2023. Their clinical data, including semen parameters and age, were also collected. Genetic analysis was used to determine whether the sex chromosome involved in male infertility was abnormal (including the increase, deletion, and translocation of the X and Y chromosomes), and subsequent semen analysis was conducted for clinical grouping purposes. The participants were categorized into five groups: normozoospermia, asthenozoospermia, oligozoospermia, oligoasthenozoospermia, and azoospermia. Patients were randomly selected for further study; 41 patients with normozoospermia were included in the control group and 117 patients with non-normozoospermia were included in the study group according to the proportions of all enrolled patients. Cytokinesis-block micronucleus (CBMN) screening was conducted through peripheral blood. Statistical analysis was used to determine the differences in micronuclei (MNi) among the groups and the relationships between MNi and clinical data. There was a significant increase in MNi in infertile men, including those with azoospermia, compared with normozoospermic patients, but there was no significant difference between the genetic and nongenetic groups in azoospermic men. The presence of MNi was associated with sperm concentration, progressive sperm motility, immotile spermatozoa, malformed spermatozoa, total sperm count, and total sperm motility. This study underscores the potential utility of MNi as a diagnostic tool and highlights the need for further research to elucidate the underlying mechanisms of male infertility.

Intranasal amyloid model of Alzheimer's disease - potential opportunities and challenges.

Amyloid beta 1-42 (Aβ1-42) peptide is one of the most studied disease-related amyloidogenic peptides implicated in the pathophysiology of Alzheimer's disease (AD). Despite significant scientific breakthroughs in the recent past, the existing non-transgenic animal models do not demonstrate accurate pathology of AD progression. This review has presented a concise mechanistic understanding of the intranasal amyloid-based animal model of AD, along with its advantages, challenges, and major limitations. Furthermore, discussions on how to combat these challenges to pave the road toward developing novel therapeutics for AD, have also been included. Preclinical exploration of repeated intranasal amyloid-beta exposure would certainly aid the translational development of a robust animal model of AD. This will also provide a better understanding of disease progression and pathology in the intranasal animal model.

Peficitinib suppresses diffuse-type tenosynovial giant cell tumor by targeting TYK2 and JAK/STAT signaling.

Diffuse-type tenosynovial giant cell tumor (dTGCT) is a destructive but rare benign proliferative synovial neoplasm. Although surgery is currently the main treatment modality for dTGCT, the recurrence risk is up to 50%. Therefore, there is a great need for effective drugs against dTGCT with minor side effects. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays a central role in rheumatoid arthritis (RA), a disease with similar characteristics as dTGCT, but its function in dTGCT remains unknown. dTGCT fibroblast-like synoviocytes (FLS) and macrophages were isolated from 10 synovial tissue samples from dTGCT patients for the screening and validation of the five clinically approved JAK inhibitors to treat RA against dTGCT. Cell viability, cell death, inflammation and the activity of the JAK family members of cultured dTGCT FLS (both 2-D and 3-D) and macrophages were investigated for the efficacy of the JAK inhibitors. Here, we found that similar to RA, JAK/STAT signaling was markedly activated in the dTGCT synovium. Of the 5 JAK inhibitors, peficitinib was shown to have the most potency in addressing some of the pathological responses of dTGCT FLS and macrophages. The potency of peficitinib was much higher than pexidartinib, which is the only FDA-approved drug for dTGCT. Mechanistically, peficitinib inhibited tyrosine kinase 2 (TYK2), a JAK family member necessary for the pathological progression of dTGCT FLS and macrophages. In summary, we not only revealed JAK/STAT (especially TYK2) signaling as the major mechanism underlying dTGCT, but also identified peficitinib as a promising drug against dTGCT.

Clinical-grade human dental pulp stem cells improve adult hippocampal neural regeneration and cognitive deficits in Alzheimer's disease.

Background: Disrupted hippocampal functions and progressive neuronal loss represent significant challenges in the treatment of Alzheimer's disease (AD). How to achieve the improvement of pathological progression and effective neural regeneration to ameliorate the intracerebral dysfunctional environment and cognitive impairment is the goal of the current AD therapy. Methods: We examined the therapeutic potential of clinical-grade human derived dental pulp stem cells (hDPSCs) in cognitive function and neuropathology in AD. Specifically, we investigated the effect of neural crest-specific derived hDPSCs on endogenous neural regeneration and long-term efficacy following a single transplantation in the triple-transgenic mouse model (3xTg-AD). Results: Our research demonstrated that a single administration of clinical-grade hDPSCs yielded dramatic short-term therapeutic benefits (5 weeks) and sustained partial efficacy (6 months) with respect to improving cognitive impairment and delaying typical pathological progression in 3xTg-AD mice. Intriguingly, exogenous hDPSCs were robustly self-differentiated into newborn functional neurons in the hippocampus of 3xTg-AD mice. The foremost evidence is provided that hDPSCs promote endogenic neural regeneration by enhancing the activation of the Wnt/β-catenin pathway, which may contribute to stabilizing the hippocampal neural network to reverse memory deficits. Conclusion: These findings highlight the multifunctional potential of hDPSCs in AD treatment, which enhances cognition through alleviating neuropathology and providing neural regenerative driving force. Understanding these multiplicity effects is critical to advancing the clinical translation of stem cell-based therapies for AD.

A Transformer-Based Pipeline for German Clinical Document De-Identification.

Commercially available large language models such as Chat Generative Pre-Trained Transformer (ChatGPT) cannot be applied to real patient data for data protection reasons. At the same time, de-identification of clinical unstructured data is a tedious and time-consuming task when done manually. Since transformer models can efficiently process and analyze large amounts of text data, our study aims to explore the impact of a large training dataset on the performance of this task. We utilized a substantial dataset of 10,240 German hospital documents from 1,130 patients, created as part of the investigating hospital's routine documentation, as training data. Our approach involved fine-tuning and training an ensemble of two transformer-based language models simultaneously to identify sensitive data within our documents. Annotation Guidelines with specific annotation categories and types were created for annotator training. Performance evaluation on a test dataset of 100 manually annotated documents revealed that our fine-tuned German ELECTRA (gELECTRA) model achieved an F1 macro average score of 0.95, surpassing human annotators who scored 0.93. We trained and evaluated transformer models to detect sensitive information in German real-world pathology reports and progress notes. By defining an annotation scheme tailored to the documents of the investigating hospital and creating annotation guidelines for staff training, a further experimental study was conducted to compare the models with humans. These results showed that the best-performing model achieved better overall results than two experienced annotators who manually labeled 100 clinical documents.

Exploring molecular mechanism of Panlongqi Tablet (PLQT) against RA: Integrated network pharmacology, molecular docking and experiment validation

Background and purposePanlongqi Tablet (PLQT), a proprietary Chinese medicine composed of 29 herbs, has been included in the Chinese Medical Insurance List and has shown promising therapeutic effects on patients with rheumatoid arthritis (RA) in clinical practice. However, the molecular mechanisms of PLQT against RA have not been fully elucidated. This study aimed to further decipher the active ingredients and molecular mechanism of PLQT anti-RA. MethodsA Complete Freund’s adjuvant (CFA)-induced rat model was established to evaluate the pharmacodynamic effects of PLQT against RA, the assessment included arthritis index, paw thickness, ankle diameter, morphological and histopathological analysis. Network analysis was used to elucidate the active ingredients and underlying mechanisms of PLQT in the treatment of RA, molecular docking was conducted to assess the binding of active ingredients to key targets. In vitro and in vivo experimental verification were employed to reveal the mechanism of PLQT against RA. ResultsExperimentally, PLQT improved CFA-induced arthritis without evident side effects. Network analysis revealed that the active ingredients in PLQT were mainly flavonoids, biscoumarin derivatives, alklaloid and lignans. Integrated with molecular docking studies, the molecular mechanisms of PLQT against RA were enriched in inflammatory response, immune regulation, angiogenesis, osteoclast differentiation and autophagy. In vitro experiments confirmed that PLQT exerted anti-inflammatory and immune regulatory effects by targeting the inflammatory response of M1 macrophages and the biological functions of T lymphocytes. In addition, In vivo experiments verified that PLQT could further inhibit synovial angiogenesis to prevent RA. ConclusionThis study integrated network pharmacology analysis, molecular docking and experimental validation to elucidate the active components of PLQT and its mechanisms in intervening the pathological progression of RA, providing a more comprehensive theoretical basis for the clinical application of PLQT in the treatment of RA.

Single-nucleus transcriptome profiling provides insights into the pathophysiology of adhesive arachnoiditis.

Adhesive arachnoiditis (AA) is a rare form of chronic degenerative pathology associated with persistent inflammation in the arachnoid matter of the spinal cord. Despite the existing knowledge, the detailed pathological mechanisms underlying AA are not fully understood. This study aimed to elucidate through comprehensive single nuclei RNA sequencing (snRNA-seq) to delineate the transcriptomic landscape of AA. From six arachnoid membrane samples, a total of 52,886 cells met the quality control standards for analysis. The main cell populations identified with specific gene markers were as follows: fibroblasts, glial cells, microglial cells, endothelial cells, mural cells, plasma cells, and T cells. Downstream analysis of fibroblasts, glial cells, and microglial cells was performed. Notably, fibroblast subsets 1 and 3 demonstrated a strong association with AA. Among them, subcluster 3 demonstrated elevated expression of genes COL1A1, COL3A1, and FN1, indicative of enhanced Wnt/β-catenin and extracellular matrix (ECM) synthesis pathways. Subcluster 3 was predicted to progressively transform into subcluster 1. In subcluster 1, there was a significant upregulation of genes such as BMP and ALPL, signaling enhanced activation of calcification-related pathways. This was highly relevant to end-stage arachnoid ossification formation. After being activated, microglial cells transformed into inflammatory disease-associated microglial cells and continued to express high levels of chemokines CCL2, CCL4, IL-1β, and other inflammatory factors NAMPT, INPP5D and NLRP3. This might be the main reason why AA recurrence is frequently observed in patients. These insights enhance our understanding of the pathological progression of AA and may contribute to the identification of novel therapeutic targets.