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Background Baicalin, which is isolated from Radix Scutellariae , possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms. Methods A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression. Results The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia. Conclusion Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples ( n  = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL–ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n  = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment ( n  = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management. Analysis of tumor samples from patients with nasopharyngeal carcinoma shows that gemcitabine plus cisplatin chemotherapy activates a unique population of innate-like B cells, which enhance the cytotoxic CD8 + T cell response and are associated with better clinical outcomes.

Background The genomes within organelles are crucial for physiological functions such as respiration and photosynthesis and may also contribute to environmental adaptation. However, the limited availability of genetic resources, particularly mitochondrial genomes, poses significant challenges for in-depth investigations. Results Here, we explored various assembly methodologies and successfully reconstructed the complex organelle genomes of two Rhododendron species: Rhododendron nivale subsp. boreale and Rhododendron vialii . The mitogenomes of these species exhibit various conformations, as evidenced by long-reads mapping. Notably, only the mitogenome of R. vialii can be depicted as a singular circular molecule. The plastomes of both species conform to the typical quadripartite structure but exhibit elongated inverted repeat (IR) regions. Compared to the high similarity between plastomes, the mitogenomes display more obvious differences in structure, repeat sequences, and codon usage. Based on the analysis of 58 organelle genomes from angiosperms inhabiting various altitudes, we inferred the genetic adaptations associated with high-altitude environments. Phylogenetic analysis revealed partial inconsistencies between plastome- and mitogenome-derived phylogenies. Additionally, evolutionary lineage was determined to exert a greater influence on codon usage than altitude. Importantly, genes such as atp4 , atp9 , mttB , and clpP exhibited signs of positive selection in several high-altitude species, suggesting a potential link to alpine adaptation. Conclusions We tested the effectiveness of different organelle assembly methods for dealing with complex genomes, while also providing and validating high-quality organelle genomes of two Rhododendron species. Additionally, we hypothesized potential strategies for high-altitude adaptation of organelles. These findings offer a reference for the assembly of complex organelle genomes, while also providing new insights and valuable resources for understanding their adaptive evolution patterns.

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.

Glutathione S‐transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self‐renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin‐dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2‐related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization‐dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient‐derived organoids from an ALK‐translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long‐term control of LUAD through targeting CSCs. This study unveils the role of  calcium/calmodulin‐‐depdendent protein kinase 2 isoform A (CaMK2A)/nuclear factor erythroid 2‐related factor (NRF2)/glutathione S‐transferase pi (GSTP1) axis under hypoxia in lung cancer stem cell maintenance. GSTP1 inhibitor Ezastiostat exhibits the potential as a combined treatment with tyrosine kinase inhibitor (TKI) to reverse TKI resistance, illustrating GSTP1 as promising therapeutic target for lung adenocarcinoma.

Lung cancer is a malignant tumor with high rates of mortality and shows significant hereditary predisposition. Previous genome-wide association studies suggest that rs748404, located at promoter of TGM5 (transglutaminase 5), is associated with lung carcinoma. By analysis of 1000 genomes project data for three representative populations in the world, another five SNPs are identified to be in strong linkage disequilibrium with rs748404, thus suggesting that they may also be associated with lung carcinoma risk. However, it is ambiguous about the actually causal SNP(s) and the mechanism for the association. Dual-luciferase assay indicates that the functional SNPs are not rs748404, rs12911132 or rs35535629 but another three SNPs (rs66651343, rs12909095 and rs17779494) in lung cell. By chromosome conformation capture, it is disclosed that the enhancer encompassing the two SNPs, rs66651343 and rs12909095, can interact with the promoter of CCNDBP1 (cyclin D1 binding protein 1). RNA-seq data analysis indicates that CCNDBP1 expression is dependent on the genotype of these two SNPs. Chromatin immunoprecipitation assay suggests that the fragments spanning rs66651343 and rs12909095 can bind with the transcription factors, cut like homeobox 1 and SRY-box transcription factor 9, respectively. Our results establish the connection between genetic variations at this locus and lung cancer susceptibility.

Background Spermatogenic dysfunction is an important cause of azoospermia. Numerous studies have focused on germ-cell-related genes that lead to spermatogenic impairment. However, based on the immune-privileged characteristics of the testis, the relationship of immune genes, immune cells or immune microenvironment with spermatogenic dysfunction has rarely been reported. Results Using integrated methods including single-cell RNA-seq, microarray data, clinical data analyses and histological/pathological staining, we found that testicular mast cell infiltration levels were significantly negatively related to spermatogenic function. We next identified a functional testicular immune biomarker, CCL2, and externally validated that testicular CCL2 was significantly upregulated in spermatogenic dysfunctional testes and was negatively correlated with Johnsen scores (JS) and testicular volumes. We also demonstrated that CCL2 levels showed a significant positive correlation with testicular mast cell infiltration levels. Moreover, we showed myoid cells and Leydig cells were two of the important sources of testicular CCL2 in spermatogenic dysfunction. Mechanistically, we drew a potential “myoid/Leydig cells-CCL2-ACKR1-endothelial cells-SELE-CD44-mast cells” network of somatic cell–cell communications in the testicular microenvironment, which might play roles in spermatogenic dysfunction. Conclusions The present study revealed CCL2-relevant changes in the testicular immune microenvironment in spermatogenic dysfunction, providing new evidence for the role of immunological factors in azoospermia.

Radiotherapy resistance remains a major clinical challenge, largely driven by tumors’ ability to dynamically adapt through complex molecular networks. Critically, the ubiquitin system has emerged as a critical regulator of this resistance. This review examines how the ubiquitin system orchestrates radiotherapy resistance through spatiotemporal control of DNA repair fidelity, metabolic reprogramming, and immune evasion. We explore how the ubiquitin code, defined by its chain topology diversity (such as K48-linked proteolysis versus K63-mediated signaling) and crosstalk with phosphorylation, SUMOylation, and acetylation, generates diverse resistance mechanisms. These mechanisms, however, also present vulnerabilities exploitable for radio-sensitization. Notably, monoubiquitylation of both histone and non-histone protein collaboratively modulates chromatin dynamics and DNA damage responses to maintain genome integrity during radiation. Furthermore, ubiquitination critically regulates caner metabolism, reprogramming processes such as ferroptosis susceptibility, hypoxia adaptation, and nutrient flux, thereby creating targetable vulnerabilities for radio-sensitization. While targeting key E3 ligases and deubiquitinases (DUBs) shows preclinical promise, clinical translation faces obstacles including functional redundancy, unintended on-target toxicity, and adaptive tumor responses. Distinct from other post-translational modifications (PTMs), the ubiquitin system offers unique clinical advantages: its dynamic reversibility, chain topology diversity, and recent breakthroughs in targeted degradation (e.g., PROTACs) enable precise disruption of radioresistance networks. By integrating these mechanistic insights with biomarker-guided therapeutic strategies, ubiquitin-targeting agents are emerging as fundamental components of next-generation radiotherapy protocols.

Background The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the “enteric nervous system–vagus nerve–brain” axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. Methods Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. Results The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. Conclusions These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.

The activities and gene expression of antioxidative enzymes and the ROS content were analyzed in two typical storage-tolerant cultivars (Xushu 32 and Shangshu 19) and another two storage-sensitive cultivars (Yanshu 25 and Sushu 16) to explore the association between the storage capacity of sweetpotato ( Ipomoea batatas (L.) Lam) and ROS scavenging capability. The storage roots of the storage-tolerant cultivars maintained higher activities and expression levels of antioxidative enzymes, including ascorbate peroxidase (APX), peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD); lower activity and expression of lipoxygenase (LOX); and lower accumulation of ROS metabolites compared with the storage-sensitive cultivars. The antioxidative capability and ROS parameters of leaves were positively correlated with those of storage roots. Our results provide valuable insight for evaluating the storability of sweetpotato cultivars by analyzing the capabilities of the antioxidative system and the contents of ROS metabolites.