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Abstract Background Inflammation is a critical protective response in the body, essential for combating infections and healing injuries. However, chronic inflammation can be harmful and significantly contribute to the development and progression of chronic diseases, with macrophage-mediated responses being central to these processes. This study presents “SBR-Pel,” a new therapeutic blend of Shinbaro tab (SBR), a traditional herbal formula, and pelubiprofen (Pel), a non-steroidal anti-inflammatory drug, and investigated their combined anti-inflammatory effects to create a treatment that both improves efficacy and reduces side effects. Methods To this end, we performed both in vitro and in vivo analyses, utilizing a mouse model of inflammation. Viability and cytotoxicity assays, immunohistochemistry, enzyme-linked immunosorbent assays, real-time polymerase chain reaction assays, nociception assays, writhing tests, and blood biochemical analyses were performed. Results In vitro, SBR-Pel synergistically reduced the production of nitric oxide and reactive oxygen species and the expression of pro-inflammatory cytokines. SBR-Pel also significantly attenuated paw edema in vivo in a Complete Freund’s adjuvant-induced inflammation model in adult mice. Furthermore, immunohistochemical analyses showed that treatment with SBR-Pel reduced both the infiltration of CD68+ macrophages and the expression of pro-inflammatory cytokines in inflamed tissues. Additionally, compared with individual treatment alone, SBR-Pel enhanced the expression of anti-inflammatory cytokines CD206, TGF-β, and IL-10, indicating a synergistic effect. Our research demonstrates that SBR-Pel effectively diminishes inflammatory pain by reducing macrophage infiltration and pro-inflammatory cytokine secretion. Additionally, while 1.5 mg/kg of Pel alone increases levels of liver and kidney toxicity markers, such as aspartate aminotransferase, alanine aminotransferase, and creatinine, combining it with SBR at a reduced dosage of 0.5 mg/kg maintains these markers at normal levels. Conclusions This combined effect highlights SBR-Pel’s potential as an effective treatment for inflammatory diseases driven by heightened macrophage activity, while also minimizing side effects by reducing the Pel dosage.

Abstract Background Spinocerebellar ataxia type 3 (SCA3) is a hereditary disease caused by abnormally expanded CAG repeats in the ATXN3 gene. The study aimed to identify potential biomarkers for assessing therapeutic efficacy by investigating the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in patients with SCA3. Methods In this prospective, cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between expanded CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) scores were investigated using partial correlation and mediation analyses. Sample sizes of potential biomarkers were calculated. Results Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. Expanded CAG repeat size was associated with right cerebellar lobule IV volume (r = − 0.423, P

Animal models are valuable tools for studying the underlying mechanisms of and potential treatments for intervertebral disc diseases. In this review, we discuss the advantages and limitations of animal models of disc diseases, focusing on lumbar spinal stenosis, disc herniation, and degeneration, as well as future research directions. The advantages of animal models are that they enable controlled experiments, long-term monitoring to study the natural history of the disease, and the testing of potential treatments. However, they also have limitations, including species differences, ethical concerns, a lack of standardized protocols, and short lifespans. Therefore, ongoing research focuses on improving animal model standardization and incorporating advanced imaging and noninvasive techniques, genetic models, and biomechanical analyses to overcome these limitations. These future directions hold potential for improving our understanding of the underlying mechanisms of disc diseases and for developing new treatments. Overall, although animal models can provide valuable insights into pathophysiology and potential treatments for disc diseases, their limitations should be carefully considered when interpreting findings from animal studies.

Abstract Background Ambrosia artemisiifolia is a highly invasive herb with deleterious effects on public health and agricultural systems. Flowering time in this species has been reported to vary along a latitudinal gradient, which may contribute to local adaptation and invasion success in China. However, the molecular basis for the flowering time differentiation remains unclear. Results A common garden experiment confirmed a latitudinal gradient in flowering time among seven Chinese populations. Differentially expressed genes (DEGs) across sampling times and flowering time groups were identified through transcriptome sequencing and analyses of DGE and WGCNA, and were partially annotated to circadian rhythm, light response and hormone response through GO enrichment. By annotating to Flowering Interactive Database (FLOR-ID) and protein-protein interaction (PPI) databases, 53 candidate genes for flowering time differentiation were identified, with 23 of these genes linked to the photoperiod pathway. Additionally, 43 of 53 candidate genes exhibited expression correlated with latitude. Six genes, including FKF1, FT, FUL, MAF2, WNK4 and WNK5, were inferred to promote flowering, while 5 genes, FBH3, FLK, NCL(1), POL2A, and ZHD4, likely repress flowering, based on their expression patterns in relation to latitude and sampling times. Notably, NCL(1), FBH3, MAF2, and FLK may function differently in A. artemisiifolia compared to Arabidopsis thaliana. Conclusions This study identified key candidate genes related to the differentiation of flowering time in Chinese ragweed populations, providing valuable insights into molecular mechanisms of phenological adaptation and invasive success of ragweed.

Zearalenone (ZEA), a mycotoxin, poses a significant global hazard to human and animal health. Natural products (NPs) have shown promise for mitigating the adverse effects of ZEA owing to their diverse functional activities. However, the current challenge lies in the absence of an efficient strategy for systematic screening and identification of NPs that can effectively protect against ZEA-induced toxicity. This study describes a phenotype-based screening strategy for screening NP libraries and discovering more effective compounds to mitigate or counteract the adverse consequences of ZEA exposure in animals. Using this strategy, we initially identified 96 NPs and evaluated the potency and efficacy of two effective candidate compounds, fraxetin, and hydroxytyrosol, based on embryonic phenotype and locomotor activity using a scoring system and the TCMacro method. Furthermore, we performed transcriptome and protein−protein interaction (PPI) network analyses to extract two mRNA signatures to query the Connectivity Map (CMap) database and predict NPs. The predicted NPs showed the potential to reverse the gene expression profiles associated with ZEA toxicity. Consequently, we further screened these compounds using our model, which indicated that hispidin, daphnetin, and riboflavin exhibit promising in vivo efficacy in zebrafish. Notably, throughout the process, fraxetin consistently stood out as the most promising NP. Biological pathway analysis and functional verification revealed that fraxetin completely reversed the toxic effects of ZEA at very low doses. This was achieved by repairing damaged cell apoptosis, modifying the cell cycle pathway, and preventing senescence induction, indicating good application potential. Overall, we demonstrated that this integration strategy can be successfully applied to effectively discover potential antidotes.

Abstract Objective Expand genetic screening for atypical Type I sialidosis (ST‐1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population. Methods We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation. Results A total of 31 patients from 23 unrelated families were genetically diagnosed with ST‐1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST‐1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic–clonic seizures. Mobility and independence varied greatly across the cohort. Cherry‐red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians. Interpretation ST‐1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry‐red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

Abstract FARS2‐associated hereditary spastic paraplegia, later onset spastic paraplegia type 77, is a rarely neurodegenerative disease. Here, we reported two affected siblings in an autosomal recessive spastic paraplegia family with a pseudo‐homozygous missense variant and Alu‐mediated exon 5 deletion in FARS2. Both patients gradually developed altered gaits and weakness in both lower limbs. In our literature review, spastic paraplegia type 77 shows high heterogeneity in clinical manifestations. Our study broadens the scope of pathogenic mechanisms of SPG77 resulting from compound heterozygous mutations in FARS2 and provides strong evidence that deletion in FARS2 due to recombination event mediated by Alu element.

Abstract Objective Human T‐cell leukemia virus type 1‐associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20+ B lymphocytes in circulation. Methods Single‐cell RNA sequencing (scRNA‐seq) data was analyzed to identify HTLV‐1‐associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B‐cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819). Results ScRNA‐seq results suggest a significant effect of HTLV‐1‐associated B cells on T cells. Additionally, HTLV‐1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV‐1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67‐positive cells in CD4+ T cells fell. Interpretation This study provided evidence that depleting B‐lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity.

Ochratoxin A (OTA) is one of the most common pollutants in aquatic feed. As a first line of defense, intestinal barriers could be utilized against OTA in order to prevent disorders. Natural product supplementation is one of the most popular strategies to alleviate toxicity induced by mycotoxins, but there is a lack of knowledge about how it functions in the teleost intestine. In this study, 720 juvenile grass carp of about 11 g were selected and four treatment groups (control group, OTA group, curcumin [Cur] group, and OTA + Cur group) were set up to conduct a 60-day growth test. After the test, the growth performance and intestinal health related indexes of grass carp were investigated. The addition of dietary Cur could have the following main results: (1) inhibit absorption and promote efflux transporters mRNA expression, reducing the residuals of OTA, (2) decrease oxidative stress by reducing oxidative damage and enhancing the expression of antioxidant enzymes, (3) promote mitochondrial fusion proteins to inhibit the expression of mitotic proteins and mitochondrial autophagy proteins and enhance mitochondrial function, (4) reduce necroptosis-related gene expression through inhibiting the tumor necrotic factor receptor-interacting protein kinase/mixed lineage kinase domain-like pathway, (5) reduce the expression of pro-inflammatory factors by inhibiting the Toll-like receptor 4/nuclear factor-κB signaling pathway to alleviate the intestinal inflammatory response. In summary, the results suggested that Cur could alleviate OTA-induced intestinal damage by enhancing antioxidant capacity and mitochondrial function as well as reducing necroptosis and inflammation in the grass carp intestine. This study provided a theoretical basis and production implications for dietary Cur that could improve growth performance and alleviate the intestinal damage induced by OTA in fish.

This research evaluated the effects of copper (Cu) on intestinal antioxidant capacity and apical junctional complex (AJC) in juvenile grass carp. A total of 1080 healthy juvenile grass carp (11.16 ± 0.01 g) were fed six diets including different dosages of Cu, namely 0, 2, 4, 6, 8 mg/kg (Cu citrate [CuCit] as Cu source) and 3 mg/kg (CuSO4·5H2O as Cu source). The trial lasted for 9 weeks. The findings revealed that dietary optimal Cu supplementation (2.2 to 4.1 mg/kg) promoted intestinal growth, including intestinal length, intestinal length index, intestinal weight, and intestinal somatic index (P 0.05). On the other hand, optimal Cu increased intestinal tight junction (TJ) proteins (except for claudin 15b) and adherens junction (AJ) proteins (E-cadherin, α-catenin, β-catenin, nectin and afadin) mRNA levels (P

Abstract Bladder cancer (BLCA) is a prevalent cancer with high case‐fatality rates and a substantial economic burden worldwide. Understanding its molecular underpinnings to guide clinical management is crucial. Ferroptosis, a recently described non‐apoptotic form of cell death, is initiated by the lethal accumulation of iron‐dependent lipid peroxidation products. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in BLCA remain unclear. Re‐analysis of single‐cell RNA data reveals a decrease in high‐ferroptosis cancer cells as BLCA advances. USP52/PAN2 is identified as a key regulator of ferroptosis in BLCA through an unbiased siRNA screen targeting 96 deubiquitylases (DUBs). Functionally, USP52 depletion impedes glutathione (GSH) synthesis by promoting xCT protein degradation, increasing lipid peroxidation and ferroptosis susceptibility, thus suppressing BLCA progression. Mechanistically, USP52 interacts with xCT and enzymatically cleaves the K48‐conjugated ubiquitin chains at K4 and K12, enhancing its protein stability. Clinical BLCA samples demonstrate a positive correlation between USP52 and xCT expression, with high USP52 levels associated with aggressive disease progression and poor prognosis. In vivo, USP52 depletion combined with ferroptosis triggers imidazole ketone Erastin (IKE) synergistically restrains BLCA progression by inducing ferroptosis. These findings elucidate the role of the USP52‐xCT axis in BLCA and highlight the therapeutic potential of targeting USP52 and ferroptosis inducers in BLCA.

Resveratrol (RES), a type of stilbenoid, is known for its significant role in enhancing meat quality by virtue of activating SIRT1. Against this backdrop, this study explored the impact of resveratrol on various parameters influencing flesh quality in adult grass carp. Over a span of 9 weeks, adult grass carp were fed diets with five different levels of RES (0, 40, 80, 160 and 320 mg/kg). Our findings demonstrated that resveratrol supplementation had no adverse effects on the growth performance of adult grass carp. Notably, adding the right amount of resveratrol to the diets caused the protein and amino acid levels, pH24 h, and shear force of grass carp muscle to rise. Additionally, it led to a reduction in cooking loss and lactic acid content. Moreover, Addition of appropriate levels of resveratrol to the feed promoted myofiber hyperplasia in adult grass carp, which may be achieved by stimulating adult myoblast proliferation and differentiation. Subsequent studies have found that appropriate levels of resveratrol inhibit endoplasmic reticulum stress (ERS), which promotes muscle fiber development. Additionally, resveratrol was found to lead to an increase in unsaturated fatty acid (UFA) content in grass carp muscle. This alteration in fatty acid composition could be attributed to changes in fatty acid transport, synthesis, and catabolism. According to muscle protein carbonyl level, muscle protein content and frequency of muscle fibers smaller than 20 μm, the optimum resveratrol supplementations of grass carp were 178.33, 198.33 and 226.67 mg/kg.

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD.

Abstract Background Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. Results By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. Conclusions Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal–fetal interface formation.

Background/Objectives: Lumbar spinal stenosis (LSS) is a degenerative condition characterized by the narrowing of the spinal canal, resulting in chronic pain and impaired mobility. However, the molecular mechanisms underlying LSS remain unclear. In this study, we performed RNA sequencing (RNA-seq) to investigate differential gene expression in a rat LSS model and identify the key genes and pathways involved in its pathogenesis. Methods: We used bioinformatics analysis to identify significant alterations in gene expression between the LSS-induced and sham groups. Results: Pearson’s correlation analysis demonstrated strongly consistent intragroup expression (r > 0.9), with distinct gene expression between the LSS and sham groups. A total of 113 differentially expressed genes (DEGs) were identified, including upregulated genes such as Slc47a1 and Prg4 and downregulated genes such as Higd1c and Mln. Functional enrichment analysis revealed that these DEGs included those involved in key biological processes, including synaptic plasticity, extracellular matrix organization, and hormonal regulation. Gene ontology analysis highlighted critical molecular functions such as mRNA binding and integrin binding, as well as cellular components such as contractile fibers and the extracellular matrix, which were significantly affected by LSS. Conclusions: Our findings provide novel insights into the molecular mechanisms underlying LSS and offer potential avenues for the development of targeted therapies aimed at mitigating disease progression and improving patient outcomes.