Search Results (489)

Ischemic stroke ranks among the top global causes of disability and mortality, with a highly dynamic pathological process. Post-stroke neuroinflammation, mediated by microglia, demonstrates a dual role in both injury and repair. The CX3CR1/CX3CL1 signaling axis, highly expressed in microglia, acts as a key regulator. This review examines the spatiotemporal dynamics of the axis across the stroke process and its involvement in neural repair. Crucially, this signaling pathway demonstrates stage-dependent functional duality: its cellular sources, receptor expression profiles, and functional consequences undergo temporally orchestrated shifts, manifesting coexisting or interconverting protective and damaging properties. Ignoring this dynamism compromises the therapeutic efficacy of targeted interventions. Thus, we propose a triple precision strategy of “stroke phase—biomarker—targeted intervention”. It uses specific biomarkers for precise staging and designs interventions based on each phase’s signaling characteristics. Despite challenges like biomarker validation, mechanistic exploration, and cross-species differences, integrating cutting-edge technologies such as spatial metabolomics and AI-driven dynamic modeling promises to shift stroke therapy toward personalized spatiotemporal programming. Temporally targeting CX3CR1 signaling may offer a key basis for developing next-generation precision neural repair strategies for stroke. Full article

Branching is a critical agronomic trait in flowering Chinese cabbage (Brassica rapa subsp. chinensis), influencing plant architecture and yield. In this study, there was a highly significant difference between CX010 (single primary rosette branches) and BCT18 (multiple primary rosette branches). Phenotypic analysis revealed significant differences in primary rosette branch numbers, with BCT18 showing up to 15 branches and CX010 displaying only one main stem branch. Genetic analysis indicated that branching was controlled by quantitative trait loci (QTL) with a normal distribution of branch numbers. Using bulked segregant analysis coupled with sequencing (BSA-seq), we identified a candidate interval of approximately 2.96 Mb on chromosome A07 linked to branching. Fine mapping narrowed this to a 172 kb region containing 29 genes, with BraA07g032600.3C (BrTCP1) as the most likely candidate. cDNA cloning of the BrTCP1 gene revealed several variations in BCT18 compared to CX010, including a 6 bp insertion, 10 SNPs, and two single-nucleotide deletions. Expression analysis indicated that BrTCP1 was highly expressed in the rosette stems of CX010 compared to BCT18, consistent with its role as a branching suppressor. The heterologous mutants in Arabidopsis confirmed the conserved role of BrTCP1 in branch inhibition. These findings reveal that BrTCP1 might be a key regulator of branching in flowering Chinese cabbage, providing insights into the molecular mechanisms underlying this trait and offering a framework for genetic improvement in Brassica crops. Full article

Patients with ulcerative colitis exhibit an increased risk for supraventricular arrhythmia during the active disease phase of the disease and show signs of atrial electrophysiological remodeling in remission. The goal of this study was to determine the basis for colitis-induced changes in atrial excitability. In a mouse model (C57BL/6; 3 months) of dextran sulfate sodium (DSS)-induced active colitis (3.5% weight/volume, 7 days), electrocardiograms (ECG) revealed altered atrial electrophysiological properties with a prolonged P-wave duration and PR interval. ECG changes coincided with a decreased atrial conduction velocity in Langendorff perfused hearts. Action potentials (AP) recorded from isolated atrial myocytes displayed an attenuated maximal upstroke velocity and amplitude during active colitis, as well as a prolonged AP duration (APD). Voltage clamp analysis revealed a colitis-induced shift in the voltage-dependent activation of the Na-current (I_Na) to more depolarizing voltages. In addition, protein levels of Na_v1.5 protein and connexin isoform Cx43 were reduced. APD prolongation depended on a reduction in the transient outward K-current (I_to) mostly generated by K_v4.2 channels. The changes in ECG, atrial conductance, and APD were reversible upon remission. The change in conduction velocity predominantly depended on the reversibility of the reduced Cx43 and Na_v1.5 expression. Treatment of mice with inhibitors of Angiotensin-converting enzyme (ACE) or Angiotensin II (AngII) receptor type 1 (AT1R) prevented the colitis-induced atrial electrophysiological remodeling. Our data support a colitis-induced increase in AngII signaling that promotes atrial electrophysiological remodeling and puts colitis patients at an increased risk for atrial arrhythmia. Full article

Chronic hepatitis B virus (CHB) infection remains a leading cause of hepatic inflammation and damage. Several studies have suggested the significant role of CX3C chemokine receptor 1 (CX3CR1) in inflammatory damages. The polymorphisms V249I and T280M affect receptor expression and function. In the current study, we investigated the association of V249I and T280M variants of the CX3CR1 fractalkine receptor with susceptibility to CHB disease. In total, 280 patients with chronic hepatitis B and 260 controls from different cities of Tunisia recruited in the Pasteur Institute of Tunisia between January 2017 and December 2022 were genotyped for the V249I and T280M CX3CR1 gene. The allele and genotype frequencies of these variants did not show significant associations with susceptibility to CHB infection (p > 0.05). Analysis of allele and genotype frequencies showed that there was no differences in age and sex distribution between patients and the control group, but when CHB patients were stratified according to age, a clear significant difference was obtained for the T280M polymorphism (p < 10⁻³, OR = 88.91; p < 10⁻³, OR = 37.42, for genotype and allelic distribution, respectively) with the MM genotype being more frequent in patients aged ≥ 50 years. The most frequently combined genotypes in the Tunisian population were VVTT, VITT and VITM both in patients (48.9%, 22.5% and 22.1%, respectively) and in controls (52%, 23.8%, 13.5%, respectively) compared to the extremely rare IITT, IITM or IIMM genotypes. In conclusion, this study suggests a noteworthy genotype–age association, particularly involving the T280M variant Full article

The aging process involves a decline in certain cognitive abilities. Cognitive aging progresses more quickly with obesity and more slowly with exercise and fasting. All of these conditions have strong impacts on white adipose tissue, which suggests that this tissue may play a pivotal role in the progression of cognitive aging. Brain-derived neurotrophic factor (BDNF), a neurotrophin indispensable for maintaining brain functions, becomes insufficient with age. Obesity also decreases the BDNF level in the hippocampus. This deficiency not only results in cognitive impairment but increases susceptibility to obesity. Both exercise and fasting increase the BDNF level in the hippocampus. Our study demonstrates that the chemokine ligand CX3CL1 in white adipose tissue is involved in the regulation of the BDNF level in the hippocampus. Aging reduces CX3CL1 expression, interfering with the mechanisms. Other studies have suggested that obesity increases adipose CX3CL1 expression; however, CX3CL1 augmented under obese condition may not contribute to the promotion of the BDNF level in the hippocampus. This suggests that the malfunction of the adipose CX3CL1-mediated mechanism could be involved in the downregulation of the hippocampus BDNF level under obese conditions. Studies have also suggested that the adipose CX3CL1-mediated mechanism appears to be involved in the exercise-induced promotion of BDNF expression in the hippocampus. Its involvement in the fasting-induced BDNF promotion is still unknown. Therefore, aging, obesity, and exercise appear to affect white adipose tissue to regulate the hippocampus BDNF level. While further studies are required to elucidate the precise role of the adipose CX3CL1-mediated regulation of BDNF expression, studies on white adipose tissue may provide new therapeutic targets for preventing age-associated cognitive decline. Full article

(1) Objectives: Understanding the genetic basis of muscle development and meat quality traits in divergent pig breeds is crucial for advancing precision breeding strategies. (2) Methods: This study investigated transcriptome differences in the longissimus dorsi muscle between Chinese Congjiang Xiang (CX) and Landrace (LAN) pigs. RNA sequencing was performed on muscle tissues from ten individuals of each breed, generating 874.5 million raw reads with an average mapping rate of 89.3% to the pig reference genome. (3) Results: Transcriptional profiling revealed distinct expression patterns with 785 genes exclusively expressed in CX pigs and 457 genes unique to LAN pigs, while 7099 co-expressed genes were shared by both breeds. Differential expression analysis identified 2459 significantly different genes (|log2FC| ≥ 1, adjusted p-value < 0.05), with 1745 up-regulated and 714 down-regulated in CX pigs. Among the most significantly up-regulated genes in CX pigs were flavor-associated genes (ELOVL5/6, FASN, DGAT2, ALDH1A3, PPAR-γ) with log2FC values ranging from 1.21 to 3.88. GO and KEGG pathway analyses revealed that up-regulated genes in CX pigs were significantly enriched in immune response pathways (adjusted p-value < 0.01), while down-regulated genes were primarily associated with myosin complex formation and PPAR signaling pathway. PPI network analysis identified PPAR-γ as a central hub gene with 16 direct interactions to other flavor-related genes. (4) Conclusions: These findings demonstrate that the superior meat flavor characteristics of indigenous Chinese pigs are driven by enhanced expression of lipid metabolism genes and distinctive immune-related pathways, providing specific molecular targets for breeding programs aimed at improving meat quality while maintaining production efficiency in commercial breeds. Full article

γ-aminobutyric acid (GABA) is a four-carbon non-protein amino acid, with many regulatory effects in humans. It aids in regulating blood glucose levels and pressure and is widely recognized for its ability to promote cognitive balance through the alleviation of stress and improvements in sleep quality. The GABA content of longan pulp is higher than that of many other fruits and vegetables; however, much is still unknown about GABA’s biosynthesis in longan. In this study, we found that the GABA content of ‘Baoshi No. 1’ (BS1) pulp was significantly higher than that of ‘Chunxiang’ (CX) pulp. The GAD activity was higher in BS1 pulp than CX pulp, while there was no significant difference in the GABA-T activity. Additionally, five GAD genes were identified in longan, and an analysis of their transcriptional levels showed that only the expression level of DlGAD3 corresponded to the GABA content and GAD activity. DlGAD3 was localized in the cytoplasm, and its transient overexpression promoted an increase in the GABA content in Nicotiana benthamiana leaves. Overall, our results show that DlGAD3 is able to promote the accumulation of GABA and may play a major role in its biosynthesis in longan pulp. Full article

Bisphenol AF (BPAF) is widely utilized as an analog of bisphenol A (BPA) in the plastics industry. However, there is limited evidence on its neurodevelopmental toxicity. Existing studies suggest that BPAF has greater accumulation in vivo than other bisphenol analogs, and could pass through the placental barrier and the blood–brain barrier. In this study, we used the human neural progenitor cells line ReNcell CX, which was derived from 14-week human cortical brain tissue, as an in vitro model to investigate the neurodevelopmental toxicity effects of BPAF and BPA on ReNcell CX cells, and explored the possible mechanism by which BPAF induced neurodevelopmental toxicity on ReNcell CX cells. The results showed that BPAF reduced the proliferation of neural progenitor cells and changed the differentiation towards neurons after exposure for 24 h. Compared with BPA, ReNcell CX cells are more susceptible to BPAF exposure. In a 3D neurospheres model, BPAF affected the distance that neurons migrated outwards at the concentration of 2 μM. Furthermore, BPAF increased ROS levels in cells and reduced the expression of key proteins in the Nrf2/HO-1 pathway and its downstream molecules, such as SOD, GSH, and CAT. In conclusion, BPAF induces damage to critical nodes in neural progenitor cell development through the Nrf2/HO-1 pathway. Therefore, clarifying its neurodevelopmental toxicity and elaborating on the neurodevelopmental toxicity effects and mechanisms of bisphenol AF will help identify intervention targets for neurodevelopmental toxicity, and will have important public health significance for the safety assessment and risk prediction of bisphenol-related chemicals. Full article

The objective of this study was to elucidate the proteomic and transcriptomic alterations within the cartilage in Kashin–Beck disease (KBD) compared to a normal control. We conducted a comparison of the expression profiles of proteins, mRNAs, and lncRNAs via data-independent acquisition (DIA) proteomics and transcriptome sequencing in six KBD individuals and six normal individuals. To facilitate the functional annotation enrichment analysis of the differentially expressed (DE) proteins, DE mRNAs, and DE lncRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we conducted integration analysis of multi-omics datasets using mixOmics. We revealed a distinct proteomic signature, highlighting 53 DE proteins, with notable alterations in the pathways related to tryptophan metabolism and microbial metabolism. Additionally, we identified 160 DE mRNAs, with the functional enrichment analysis uncovering pathways related to RNA metabolism and protein splicing. Furthermore, our analysis of the lncRNAs demonstrated biological processes involved in protein metabolism and cellular nitrogen compound metabolic processes. The integrative analysis uncovered significant correlations, including the positive correlation between superoxide dismutase 1 (SOD1) and mitochondrial import receptor subunit TOM6 homolog (TOMM6), and the negative correlation between C-X9-C motif-containing 1 (CMC1) and succinate–CoA ligase [GDP-forming] subunit beta, mitochondrial (SUCLG2). Our results provide novel insights into the molecular mechanisms underlying KBD. Full article

Endothelial progenitor cells (EPC) are considered to support neovascularization and endothelial repair by being incorporated into newly formed or injured vessels and by improving vascularization in a paracrine manner by secreting proangiogenic factors. Here, we studied the role of gap junctional communication between EPC and endothelial cells in long-term co-cultures in vitro. The cultivation of endothelial cells together with mouse embryonic EPC (E 7.5) induced the spontaneous formation of angiogenic networks after 3–6 days consisting of both cell types, but not in the respective monocultures, whereas their respective cultivation on a basement matrix induced the formation of tube-like structures, as expected. The angiogenic network formation could not be mimicked by the incubation of endothelial cells with supernatants of EPC only. We therefore hypothesized that direct interaction and cell-cell communication is required to induce the angiogenic network formation in co-cultures with endothelial cells. Expression analysis demonstrated expression of the gap junctional protein connexin 43 (Cx43) in EPC. Moreover, dye injection studies as well as FACS analysis identified gap junctional communication between endothelial cells and EPC. The inhibition of gap junctions by pharmacological blockers significantly reduced the angiogenic network formation, confirming that gap junctional communication between both cell types is required for this process. Full article

Salt stress can trigger endoplasmic reticulum (ER) stress and affect potato yield. The endomembrane system is tightly regulated in response to salt stress for maintaining cellular homeostasis. However, little is known about the genes involved in the ER-mediated cytoprotective pathways in potato plants. Previously characterized genes involved in the ER stress signaling pathway in Arabidopsis were used as prototypes. We identified 29 genes involved in ER stress response in the potato genome. Transcriptome data analysis showed that the expression levels of related genes were significantly different in different tissues. Most genes can response to β-aminobutyric acid, benzothiadiazole, salt, and mannitol. qRT-PCR assay revealed that they could respond to NaCl and tunicamycin, which was consistent with the fact that the promoter region of related genes contained ER-stress- and abiotic-stress-related cis-elements. Furthermore, we found that StbZIP60 has a splicing form, StbZIP60s, under salt and ER stress, which can be spliced at the CxGxxG site in the C terminus to create a frame shift through the excision of 23 base pairs. StbZIP60 is localized in the cytoplasm and nucleus, whereas most of the StbZIP60s translocated to the nucleus. This study provides a basis for further analyses of the functions of salt-stress- and ER-stress-related genes in potato plants. Full article

Phthorimaea absoluta, an important pest of tomato crops, has reportedly developed high levels of resistance to the insecticide chlorantraniliprole, which has a unique mode of action and high efficacy. This study evaluated the sustained multigenerational effects of chlorantraniliprole on P. absoluta, focusing on resistance development, growth, development, reproductive capacity, population parameters, and nutritional indicators. After continuous selection with sublethal chlorantraniliprole for eight generations (CX-Sub₈), bioassays showed that CX-Sub₈ had 225.37-fold higher resistance than the susceptible strain. The age-stage, two-sex life table analysis revealed that the preadult development time and mean generation time were significantly prolonged, while population reproduction and pupal weight were reduced. Moreover, the relative fitness of CX-Sub₈ was 0.62, and changes in the life table parameters correlated with an increase in the serial number of selection cycles. The second-instar larvae of CX-Sub₈ presented lower triglyceride, glycerol, trehalose, free fatty acid, and protein contents than the unselected strain (CX-S₈). Transcriptome analysis identified 2517 differentially expressed genes, with most being enriched in nutrient metabolism-related pathways, such as amino acid biosynthesis and fatty acid degradation metabolism. These results indicate that multigenerational sublethal chlorantraniliprole treatment disrupts the nutritional metabolism, and inhibits the growth, development, and reproduction of P. absoluta. Full article

Background: The current animal models of multiple sclerosis (MS) predominantly emphasize white matter inflammation, reflecting early-stage disease. However, progressive MS (PMS) is characterized by cortical pathology, including subpial demyelination, chronic meningeal inflammation, and microglial activation, which are underrepresented in the existing models. While alternative mouse models replicate the relapsing–remitting phenotype and gray matter pathology, pathology is frequently dispersed throughout the brain, complicating the analysis of the specific lesion sites. Methods: To address this gap, we developed a novel model that integrates laser-induced focal demyelination with cytokine-driven meningeal inflammation to replicate the key aspects of PMS cortical pathology. Results: Using two-photon laser irradiation, we induced controlled subpial cortical lesions in CX3CR1-GFP mice, leading to microglial activation, astrocytosis, and focal demyelination. The addition of IFNγ-expressing adenovirus to promote meningeal inflammation which resulted in prolonged glial responses, increased immune cell infiltration, and exacerbated demyelination, mimicking the PMS-associated pathology. Conclusions: This model provides a powerful tool to investigate the mechanisms underlying the cortical lesion development and immune-mediated neurodegeneration in PMS. By capturing the critical aspects of cortical pathology, it enables the evaluation of therapeutic strategies targeting neuroinflammation and demyelination, ultimately aiding in the development of new treatments of progression in PMS patients. Full article

Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study’s end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. Overall, the combination of polyphenols in these extracts may offer a promising pharmacological strategy to prevent chronic reflexive and non-reflexive pain responses by modifying central sensitization markers, not only at the contusion site but also in key supraspinal regions implicated in neuropathic pain. Overall, these data highlight the potential of polyphenolic extracts for spinal cord injury-induced chronic neuropathic pain. Full article

Schistosoma japonicum eggs in the host liver form granuloma and liver fibrosis and then lead to portal hypertension and cirrhosis, seriously threatening human health. Natural killer (NK) cells can kill activated hepatic stellate cells (HSCs) against hepatic fibrosis. We used single-cell sequencing to screen hepatic NK cell subsets against schistosomiasis liver fibrosis. Hepatic NK cells were isolated from uninfected mice and mice infected for four and six weeks. The NK cells underwent single-cell sequencing. The markers’ expression in the NK subsets was detected through Reverse Transcription–Quantitative PCR (RT-qPCR). The proportion and granzyme B (Gzmb) expression of the total NK and Thy1⁺NK were detected. NK cells overexpressing Thy1 (Thy1-OE) were constructed, and functions were detected. The results revealed that the hepatic NK cells could be divided into mature, immature, regulatory-like, and memory-like NK cells and re-clustered into ten subsets. C3 (Cx3cr1⁺NK) and C4 (Thy1⁺NK) increased at week four post-infection, and other subsets decreased continuously. The successfully constructed Thy1-OE NK cells had significantly higher effector molecules and induced greater HSC apoptosis than the control NK cells. It revealed a pattern of hepatic NK cells in a mouse model of schistosomiasis. The Thy1⁺NK cells could be used as target cells against hepatic fibrosis. Full article