Pathological Mechanisms Research Articles

Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice.

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.

Lipid-based nanoparticles for drug delivery in Parkinson’s disease

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder that predominantly affects dopaminergic neurons in the substantia nigra and ventral tegmental area, resulting in symptoms such as tremors, muscle rigidity, bradykinesia, and potential cognitive and affective disturbances. The effective delivery of pharmacological agents to the central nervous system is hindered by various factors, including the restrictive properties of the blood‒brain barrier and blood‒spinal cord barrier, as well as the physicochemical characteristics of the drugs. Traditional drug delivery methods may not provide the therapeutic concentrations necessary for functional restoration in PD patients. However, lipid-based nanoparticles (NPs) offer new possibilities for enhancing the bioavailability of established treatment regimens and developing innovative therapies that can modify the course of the disease. This review provides a concise overview of recent advances in lipid-based NP strategies aimed at mitigating specific pathological mechanisms relevant to PD progression. This study also explores the potential applications of nanotechnological innovations in the development of advanced treatment modalities for individuals with PD.

Critical Considerations in Calling Disease-Causing EDAR Mutations in Nonsyndromic Oligodontia

Background/Objectives: Oligodontia, the absence of six or more teeth excluding third molars, is a rare genetic condition, unlike hypodontia (missing one or more teeth), which is a relatively common human disease. Methods: To identify the genetic etiology of nonsyndromic oligodontia (NSO) families, we performed mutational analysis and investigated the functional effects of identified EDAR mutations. Whole-exome sequencing was conducted on recruited families with NSO. Bioinformatic analysis identified mutations in oligodontia-causing candidate genes, which were confirmed by Sanger sequencing and segregation within families. The impact of EDAR mutations on the EDA signaling pathway was assessed using luciferase activity analysis. Results: EDAR mutations were identified in three NSO families. A homozygous missense EDAR mutation (NM_022336.4: c.319A>G p.(Met107Val)) was found in the singleton proband of family 1. The proband of family 2 carried compound heterozygous EDAR mutations: a maternal missense mutation (c.319A>G p.(Met107Val)) and a paternal missense variant (c.1270G>A p.(Val424Met)). The proband of family 3 had heterozygous EDAR mutations: a maternal missense mutation (c.389T>A p.(Ile130Asn)) and paternal intronic variants in cis (c.[357-4G>A;440+50C>T]). Luciferase assays confirmed reduced transcriptional activity for all identified missense mutations, while splicing assays revealed altered splicing patterns. Conclusions: In conclusion, recessive EDAR mutations, including novel ones, were identified in NSO families, and their pathological mechanism was explored through transcriptional activity measurements.

Protective Effects of Antcin H Isolated from Antrodia cinnamomea Against Neuroinflammation in Huntington's Disease via NLRP3 Inflammasome Inhibition.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumulation of the mutant HTT (mHTT) protein in neurons and glial cells. Key pathological mechanisms in HD include excitotoxicity, energy dysfunction, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. The NLRP3 inflammasome is a multimeric protein complex element of NLRP3, ASC, and caspase-1, which regulates interleukin (IL)-1β and IL-18 secretion. The NLRP3 inflammasome plays an important role in inflammatory reactions and is involved in the pathogenesis of several neurodegenerative diseases. We have previously demonstrated high NLRP3 inflammasome expression levels in the striatum of R6/2 mice (a transgenic HD mouse model). Systematic administration of an NLRP3 inhibitor (MCC950) to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, suggesting protective effects against HD. Antrodia cinnamomea is an indigenous medicinal fungus in Taiwan, which shows diverse medicinal and pharmacological activities, but its effects in HD are not well understood. Herein, we report that systematic administration of Antcin-H isolated from A. cinnamomea to R6/2 mice suppressed the NLRP3 inflammasome, IL-1β production, and reduced neuronal toxicity. Most importantly, oral administration of Antcin-H reduced disease progression by increasing neuronal survival, reducing neuroinflammation during an extended lifespan, and improving motor dysfunction in R6/2 mice. Taken together, our data suggest that Antcin-H has therapeutic potential for treating HD.

Platelet-Derived Growth Factor Subunit A Strengthens the Neurovascular Unit and Inhibits Retinal Vascular Regression Under Hyperoxic Conditions

Retinopathy of prematurity (ROP) is primarily caused by the exposure of preterm infants with underdeveloped blood vessels to high oxygen concentrations. This damages the astrocytes that promote normal vascular development, leading to avascularity, pathological neovascularization, and retinal detachment, and even blindness as the disease progresses. In this study, the aim was to investigate the differences in the characteristics of astrocytes and blood vessels between wild-type (WT) and genetically modified mice overexpressing platelet-derived growth factor subunit A (PDGF-A) in the retina immediately after high oxygen exposure, a protocol in the oxygen-induced retinopathy (OIR) model of ROP. Our results showed that PDGF-A mice exhibited an increased population of astrocytes and higher vascular density than WT mice and that PDGF-A strengthened the resistance to hyperoxic conditions. In the OIR model, PDGF-A mice had reduced avascular zone areas following hyperoxia exposure. Furthermore, immunostaining for NG2 and CD31 showed that pericytes tended to regress earlier than endothelial cells, particularly at the vessel edges in both WT and transgenic mice, indicating relatively higher susceptibility to hyperoxia-induced damage. These findings suggest that PDGF-A plays a crucial role in stabilizing retinal vessels and may serve as a novel therapeutic target for ROP, highlighting the potential significance of PDGF-A in the pathological mechanisms of retinal diseases.

Integration and Differentiation of Transplanted Human iPSC-Derived Retinal Ganglion Cell Precursors in Murine Retinas

Optic neuropathy such as glaucoma, stemming from retinal ganglion cell (RGC) degeneration, is a leading cause of visual impairment. Given the substantial loss of RGCs preceding clinical detection of visual impairment, cell replacement therapy emerges as a compelling treatment strategy. Human-induced pluripotent stem cells (hiPSCs) serve as invaluable tools for exploring the developmental processes and pathological mechanisms associated with human RGCs. Utilizing a 3D stepwise differentiation protocol for retinal organoids, we successfully differentiated RGC precursors from hiPSCs harboring a BRN3B-GFP RGC reporter, verified by GFP expression. Intravitreal transplantation of enriched RGC precursors into healthy or N-methyl-D-aspartate (NMDA)-injured mice demonstrated their survival, migration, and integration into the proper retinal layer, the ganglion cell layer, after 3 weeks. Notably, these transplanted cells differentiated into marker-positive RGCs and extended neurites. Moreover, enhanced cell survival was observed with immunosuppressive and anti-inflammatory treatments of the host prior to transplantation. These data underscore the potential of transplanted RGC precursors as a promising therapeutic avenue for treating degenerative retinal diseases resulting from RGC dysfunction.

Experimental study on the effect of Mongolian medicine warming acupuncture on proBDNF-tPA-BDNF balance in depression rats based on thermal imaging monitoring

Depression is a kind of mental illness affecting the whole world. Its pathological mechanism is complex, involving neurobiological and psychosocial factors.The depression model rats were randomly divided into control group, warm acupuncture group and drug treatment group. In order to evaluate the local thermal effect of warm acupuncture and moxibustion, real-time temperature changes of rat forebrain were monitored by thermal imaging technology. After the experiment, immunohistochemistry and Western blot were used to detect the expression levels of tPA and BDNF in the forebrain of each group of rats, and the relationship between tPA and BDNF was analyzed. The results of thermal imaging monitoring showed that local forebrain temperature in warm acupuncture group was significantly increased compared with control group (p < 0.05). The ratio of tPA to BDNF was significantly improved in the warm acupuncture and moxibustion group, suggesting that warm acupuncture and moxibustion can effectively regulate the balance of TPA-BDNF. The experimental results based on thermal imaging monitoring suggest that warm acupuncture can improve the balance of TPA-BDNF in the forebrain of depressed rats by promoting the expression of BDNF and tPA in the forebrain, which may provide a new method and mechanism basis for the treatment of depression.

Rheumatoid arthritis and PLA2R-associated mebranous nephropathy. Cause or coincidence?

The coexistence of rheumatoid arthritis (RA) and PLA2R-associated membranous nephropathy (MN) is uncommon. It is difficult to demonstrate whether the mechanisms of renal pathology are triggered by RA, but it has been observed that the pro-inflammatory molecules present in RA increase the expression of PLA2R. Rituximab could be effective in both conditions. RA affects 0.5% of adults in our country. It is an inflammatory disease that predominantly affects the joints causing destruction of the articular cartilage. Approximately 50% of patients present extra-articular manifestations. Renal involvement is relatively frequent and clinically significant because it worsens the course and mortality of the primary disease. The histological renal damage observed in these patients includes a wide variety of entities and histological patterns with both glomerular and tubulointerstitial involvement, with secondary MN being one of the most frequent. Coexistence with primary MN is rare. We present the case of a 46-year-old male recently diagnosed with RA who was referred to the nephrology department for renal function deterioration and subnephrotic proteinuria. The autoimmune study showed positive anti-PLA2R. Due to the unusual association between both entities, it was decided to perform a renal biopsy which showed abundant spikes. The immunofluorescence study showed contiguous parietal IgG positivity (3+). Immunohistochemistry showed positive granular IgG4, confirming the diagnosis of PLA2R-associated MN. MN is one of the most common causes of nephrotic syndrome in adults. The determination of anti-PLA2R has been a great advance in the rapid differential diagnosis of MN. In recent years, new target antigens associated with certain underlying pathologies have been discovered. However, PLA2R is not associated with any disease or exposure and therefore remains the antigen responsible for 80% of primary NMs. Anti-PLA2R antibodies can be produced by loss of central or peripheral tolerance. Whether these mechanisms are triggered by RA itself is difficult to prove. The cytokine TNF-like weak inducer of apoptosis (TWEAK) has been associated with RA. This proinflammatory molecule increases the expression of PLA2R in podocytes, sensitizing them to the damaging action of anti-PLA2Rs, which could justify a causal relationship between the two pathologies. The anti-PLA2R positivity in a patient with membranous nephropathy should not be sufficient to refrain from searching for a secondary cause, as a kidney biopsy is mandatory when another underlying disease coexists. Treatment should be tailored to the individual risk profile for progression. Rituximab could be an optimal option for both entities.

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.

Automated Fiber Quantification Analysis Identifies Tract-specific Microstructural Alterations in Brain in Intermittent exotropia

BackgroundGrowing evidence of neuroimaging has indicated brain microstructural abnormalities in comitant strabismus. Nonetheless, few studies have investigated neuropathological alterations in patients with intermittent exotropia (IXT). This study aimed at examining the characteristics of brain microstructure along major fiber tracts in IXT patients using an automated fiber quantification analysis. MethodsA total of 25 patients with IXT as well as 25 healthy participants matched for age and gender finished the diffusion tensor imaging scanning and the ophthalmic examination. Automated fiber quantification analysis of 20 major fiber tracts was carried out for IXT patients and healthy subjects, respectively. Diffusion metrics of 100 equidistant nodes resampled along each tract were measured for every subject and compared between two groups. Effect size analysis was performed to identify the most affected fiber tracts in IXT. ResultsWidely declined mean diffusivity was noted in IXT along major tracts containing bilateral thalamic radiations, bilateral corticospinal fasciculi, bilateral cingulum cingulate, left inferior fronto-occipital fasciculus, right arcuate fasciculus and superior longitudinal fasciculus. Local reduction in fractional anisotropy was observed in IXT along left cingulum hippocampus, right inferior longitudinal fasciculus and right uncinate fasciculus, in contrast to the regionally increased fractional anisotropy along bilateral thalamic radiation, left corticospinal tract and left arcuate fasciculus. Among the tracts with significantly changed diffusion metrics in IXT, right inferior longitudinal fasciculus was the most affected one in fractional anisotropy while left thalamic radiation was the most influenced one in mean diffusivity. ConclusionsAbnormalities in microstructural properties along visual-related fiber tracts are likely to contribute to difficulties in visual information processing in IXT patients, which could serve as the neural basis of underlying pathological mechanism of IXT.

MSCs-derived ECM functionalized hydrogel regulates macrophage reprogramming for osteoarthritis treatment by improving mitochondrial function and energy metabolism

Osteoarthritis (OA) is a degenerative disease that affects the entire joint, with synovial inflammation being a major pathological feature. Macrophages, as the most abundant immune cells in the synovium, have an M1/M2 imbalance that is closely related to the occurrence and development of OA. Mesenchymal stem cells (MSCs) have been shown to effectively suppress inflammation in the treatment of OA, but they still pose issues such as immune rejection and tumorigenicity. The extracellular matrix (ECM), as a major mediator of MSCs' immunoregulatory effects, offers a cell-free therapy to circumvent these risks. In this study, we developed an ECM-functionalized hydrogel by combining MSC-derived ECM with gelatin methacryloyl (GelMA). To enhance the immunomodulatory potential of MSCs, we pre-stimulated MSCs with the inflammatory factor interleukin-6 (IL-6) present in OA. In vitro results showed that the ECM-functionalized hydrogel promoted M2 macrophage polarization and inhibited the expression of various inflammatory genes, strongly indicating the hydrogel's powerful immunoregulatory capabilities. In an in vivo rat OA model, the ECM-functionalized hydrogel significantly reduced synovial inflammation and cartilage matrix degradation, alleviating the progression of OA. Furthermore, we utilized proteomics and transcriptomics analysis to reveal that the hydrogel accomplished macrophage metabolic reprogramming by regulating mitochondrial function and energy metabolism, thereby reducing inflammation. These findings suggest that the ECM-functionalized hydrogel is a promising biomaterial-based strategy for treating OA by targeting key pathological mechanisms.

Abnormal placental development induced by repeated cesarean sections: Investigating an animal model of placenta accreta spectrum disorders.

Placenta accreta spectrum (PAS) is a serious condition associated with severe postpartum hemorrhage, leading to emergency hysterectomy. Research has predominantly focused on clinical diagnosis and the prevention of adverse maternal outcomes, but the underlying pathological mechanisms remain poorly understood, partly due to the limitations of animal models. In this study, we conducted up to three cesarean sections (CS) on full-term pregnant mice, since a history of multiple CS is an independent risk factor for PAS. We evaluated pregnancy outcomes, placental development, morphology, trophoblast invasion, and angiogenesis at the maternal-fetal interface to assess the impact of repeated CS. Following repeated CS, the model mice displayed adverse pregnancy outcomes, including placental dysplasia, incomplete remodeling of spiral arteries, deep trophoblast invasion at the maternal-fetal interface, and reduced placental perfusion. Additionally, the mice exhibited abnormal fetal development, imbalances in angiogenic and anti-angiogenic both within the placenta and in peripheral blood. The pathological phenotypes of placenta and adverse pregnancy outcomes observed in mice with a history of three CSs closely resemble the clinical features of PAS. This model offers a valuable tool for studying the pathogenesis of PAS and could serve as a foundation for the development of early prevention strategies.

Antagonising Yin Yang 1 ameliorates the symptoms of lupus nephritis via modulating T lymphocyte signaling

Lupus nephritis (LN) is a chronic complication of systemic lupus erythematosus (SLE). At present, no drugs are capable of delaying the progression of LN without a risk of serious side effects. There is thus a pressing need for further studies of LN pathogenesis to identify novel therapeutic targets and aid in the development of new approaches to treating this debilitating disease. In this study, a multi-omics approach was used to characterize the pathogenesis of LN and to identify disease-related targets, ultimately leading to the identification and validation of Yin Yang 1 (YY1) as a promising therapeutic target in LN. A rapid approach to efficiently screening for candidate YY1 ligands was implemented using drug databases that established rebamipide as a YY1 antagonist suitable for use in the management of LN. Specifically, the YY1 antagonist activity of rebamipide was found to regulate lymphocyte activity, reduce autoantibody production, limit immune complex deposition, and suppress macrophage activation while improving symptoms in a murine model of LN. Results supportive of a similar pathologic mechanism of action were also obtained when analyzing renal tissue sections from LN patients, underscoring the potential clinical significance of YY1 and its antagonist rebamipide, suggesting that rebamipide may have positive effects on lymphocytes and may improve symptoms in treated patients. This study provides a robust foundation for further research focused on the pathogenesis and treatment of LN.

Identification of the Roles of Coagulation-related Signature and its Key Factor RABIF in Hepatoma Cell Malignancy.

Hepatoma is a high morbidity and mortality cancer, and coagulation is a potential oncogenic mechanism for hepatoma development. In this study, we aimed to reveal the role of coagulation in hepatoma. We applied the LASSO to construct a coagulation-related risk score (CRS) and a clinical nomogram with independent validation. The heterogeneity of various aspects, including functional enrichment, SNV, CN, immunocyte infiltration, immune pathways, immune checkpoint, and genomic instability indexes, was evaluated. Besides, the prognostic value of the CRS genes was tested. We selected the critical risky gene related to coagulation from the LASSO coefficients, for which we applied transwell and clone formation assays to confirm its roles in hepatoma cell migration and clone formation ability, respectively. The CRS and the nomogram predicted patients' survival with good accuracy in both two datasets. The high-CRS group was associated with higher cell cycle, DNA repair, TP53 mutation rates, amplification, and lower deletion rates at chromosome 1. For immunocyte infiltration, we noticed increased Treg infiltration and globally upregulated immune checkpoints and genomic instability indexes. Additionally, every single CRS gene affected the patient's survival. Finally, we observed that RABIF was the riskiest gene in the CRS. Its knockdown suppressed hepatoma cell migration and clone formation capability, which could be rescued by RABIF overexpression. We built a robust CRS with great potential as a prognosis and immunotherapeutic indicator. Importantly, we identified RABIF as an oncogene, promoting hepatoma cell migration and clone formation, revealing underlying pathological mechanisms, and providing novel therapeutic targets for hepatoma treatment.

N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity

Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca2+ quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca2+ influx. Quanta of Ca2+ via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca2+ quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca2+ quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function.

Enhancing Renal Autophagy via Yangshen Paidu Decoction: AMPK/mTOR Pathway Modulation in Chronic Renal Failure Management

Objective: Chronic Renal Failure (CRF) refers to the gradual decline in renal function caused by various chronic kidney diseases, eventually leading to end-stage renal failure. Yangshen Paidu Decoction (YPD) is a Traditional Chinese medicine (TCM) formula utilized in CRF treatment. This work has analyzed the effects of YPD on CRF and the specific mechanism. Methods: Network pharmacology was performed to screen effective components and targets of YPD, from which key targets and signaling pathways contributing the most to the treatment effects on CRF were determined. Subsequently, we validated the therapeutic role of YPD and the underlying pathological mechanisms using the 5/6-nephrectomy rat model. Results: Network pharmacology analysis showed the mTOR pathway to be a pivotal mechanism underlying the effectiveness of YPD in CRF treatment. YPD significantly suppressed urine protein levels, blood urea nitrogen, and serum creatinine in 5/6 nephrectomized rats. Furthermore, YPD remarkably improved renal pathological injuries. Western blot analysis revealed that YPD enhanced autophagy and upregulated the expression of nephrin, podocin, beclin1, p-AMPK/AMPK, and p- ULK1/ULK1, and attenuated the ratios of p-mTOR/mTOR to its downstream protein phosphorylated eIF4E-binding protein (p-4EBP1). However, these effects were notably reversed by the AMPK inhibitor compound C. Conclusion: Our findings have demonstrated YPD to suppress the mTOR pathway and stimulate autophagy by modulating AMPK pathways, thereby mitigating podocyte injury and enhancing renal function. Our study has confirmed autophagy and the AMPK/mTOR pathway as potential targets for YPD in CRF treatment.

ACO-Guided Genetic Analysis: Exploring the Role of Genes in Alzheimer's Disease

Alzheimer's disease (AD), a neurodegenerative disorder significantly impairing cognitive function and quality of life, necessitates an in-depth study of its pathogenic mechanisms. Despite extensive research, the disease's pathological mechanisms harbor numerous unknown elements. Analyzing DNA microarray data is crucial for elucidating gene co-expression relationships during AD's pathological processes. This study aimed at exploring the applicability of the ant colony optimization (ACO) algorithm in identifying linearly co-expressed genes in AD. This study utilized gene expression profile data of AD patients collected from the Gene Expression Omnibus (GEO) database, employing the ACO algorithm to explore the co-expression relationships among AD pathogenic genes in different stages. Through the analysis of co-expression relationships, we identified four related genes (SDHA, NDUFA10, SDHC, and GPI). By using the co-expressed genes as features, we applied the support vector machine (SVM) algorithm for AD classification. The results of these experiments revealed that each model achieved average AUC values of 0.90, 0.91, 0.86, and 0.92, respectively. Our research findings reveal that the ACO algorithm provides a new perspective for in-depth exploration of the pathogenic mechanisms of AD.

The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review

The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review

Exogenous α-Synuclein Induces Oxidative Damage to Dopaminergic Neurons Through p-NMDAR2B/Nur77.

Alpha-synuclein (α-syn) is a major pathological marker of Parkinson's disease (PD), and its abnormal expression and aggregation lead to dopaminergic neuron degeneration, in which oxidative stress plays an important role. However, the exact molecular mechanism by which α-syn causes PD remains unclear. In this study, exogenous α-syn, also known as α-syn preformed fibrils (α-syn PFFs), was used to construct in vivo and in vitro models of PD. Behavioral, Western blotting, biochemical, immunofluorescence, flow cytometry, electron microscopy, etc. were used to investigate the pathological mechanism of PD induced by α-syn. We found that 6months after striatum injection of α-syn PFFs, mice exhibited motor deficits. Meanwhile, the protein expression of pS129-α-syn (p-α-syn) and α-syn oligomer significantly increased, while the expression of TH significantly decreased, and the oxidative stress in the substantia nigra was aggravated. In addition, we found an increase in the protein expression of NMDAR2B and p-Tyr1472-NMDAR2B (p-NMDAR2B) and a decrease in the protein expression of Nur77. However, in α-syn PFFs-induced SH-SY5Y cells, we found that inhibiting p-NMDAR2B increased the protein expression of Nur77, while overexpression of Nur77 did not affect the expression of p-NMDAR2B. Inhibition of p-NMDAR2B and overexpression of Nur77 reversed α-syn PFF-induced oxidative stress, thus reducing mitochondrial damage and cytotoxicity. Therefore, we speculate that α-syn PFF-induced oxidative stress in dopaminergic neurons may be mediated by p-NMDAR2B/Nur77. Our study provides novel insights into the pathology mechanism underlying α-syn-induced PD.

Exploring molecular mechanisms of postoperative delirium through multi-omics strategies in plasma exosomes

Currently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.