Naturally derived Erythrinin C targets γ-secretase signaling to suppress triple-negative breast cancer progression and reverse paclitaxel resistance.

Actin-regulated plasticity as a key determinant of the bidirectional switch between chemoresistance and resensitization in triple-positive breast cancer.

A bioactive hydrogel harnessing the regenerative potential of notochordal cells serves as instructive cell carrier for nucleus pulposus repair.

Immune dysfunction contributes to comorbid depression in patients with multiple sclerosis.

Impact of gut microbiome, plasma metabolites, peripheral immune cells, and circulating inflammatory protein on chronic spontaneous urticaria: Bidirectional 2-sample Mendelian randomization study and mediation analysis.

Saikosaponin D alleviates chronic prostatitis/chronic pelvic pain syndrome by regulating the NF-κB pathway via lncRNA5682.

Cerebral ischemic stroke is caused by impaired blood flow to the brain parenchyma due to acute vessel occlusion. Although current therapies focusing on rapid restoration of blood flow achieve high rates of recanalization, outcomes remain unfavorable in a significant proportion of patients. Part of this discrepancy is due to intravascular inflammation driven by thrombo-inflammatory mechanisms that add to cerebral tissue loss. Despite being an inevitable consequence of vessel occlusion, altered shear stress remains largely overlooked as a contributor to endothelial dysfunction in stroke. To directly assess the impact of disturbed flow on the endothelial phenotype, human brain endothelial cells were cultured under controlled flow conditions using an ibidi pump system and exposed to flow alternating in both magnitude and direction. Subsequently, the expression of key endothelial proteins, including Claudin-5, PECAM-1, CD62e and endoglin, was analyzed. We show here that the sequence of shear-stress modulation, recapitulating the hemodynamic conditions of large-vessel occlusion and subsequent reperfusion in stroke, is sufficient to cause an inflammatory phenotype in human brain endothelial cells. In addition, we demonstrate that platelet activation induces the mechanosensors Piezo1 and syndecan-1, sensitizing brain endothelial cells to shear-stress alterations characteristic of ischemic stroke. Targeting shear-stress-mediated inflammatory activation of the brain endothelium may therefore offer a complementary strategy in stroke therapy, particularly in large-vessel occlusion with abrupt flow changes.

Chronic kidney disease progression involves phenotypic changes in tubular epithelial cells, and recent studies have highlighted the relationship between such pro-fibrotic phenotypes and cell cycle arrest in injured tubular epithelial cells undergoing repair. We investigated these processes using a mouse unilateral ischemia-reperfusion injury model with γGT.Fucci2aR mice, which express fluorescent cell cycle markers, and in vitro experiments with human kidney-2 cells and public single-cell RNA sequencing data. In the unilateral ischemia-reperfusion injury model, mVenus-positive cells (S/G2/M phases) in the γGT.Fucci2aR mice peaked on Day 3 post-injury, then rapidly declined. In kidneys with progressive tubular atrophy and interstitial fibrosis between 7-12 days post-injury, S/G2/M phase cells were limited. These findings were corroborated by analysis using public single-cell RNA sequencing data from the same mouse models, which confirmed dynamic cell cycle changes in the acute phase post-injury but no significant G2/M phase cells in the chronic phase. In vitro experiments with human kidney-2 cells demonstrated that cellular communication network factor 2 and transforming growth factor-β expression increased significantly as proliferating cells reached confluence and cell cycle progression slowed. Pro-fibrotic phenotypes in tubular epithelial cells were not exclusively acquired by G2/M-arrested cells, as reported in previous studies, but can also be acquired by cells in the quiescent G0/G1 phase during normal cell cycling. To develop novel therapeutics for chronic kidney disease, regulating pro-fibrotic gene expression in injured tubular epithelial cells, independent of specific cell cycle phases, appears to be crucial.

Multidimensional transcriptomic analysis and in vitro experiments dissect the landscape of 2',2',4',4'-Tetrabromodiphenyl ether in bladder cancer progression.

In fission yeast, inositol-1-pyrophosphates drive the synthesis of vacuolar inorganic polyphosphate (polyP), which serves as a phosphate reservoir during nutrient scarcity. Acute phosphate starvation of wild-type fission yeast cells triggers rapid depletion in tandem of inositol-1-pyrophosphates and polyP, and a gradual transition to G0 quiescence. Here, we report that HASX yeast cells, which lack the three pyrophosphatase enzymes that catabolize inositol pyrophosphates, mount an aberrant response to phosphate starvation associated with sustained elevation of inositol-1-pyrophosphates. This entails immediate cessation of growth; precocious onset of the phosphate starvation transcriptional program; persistently high vacuolar polyP levels; and rapid loss of polysomes, accumulation of 80S monosomes, and inefficient translation of starvation-induced pho1 mRNA. Two key findings are that: (i) the deviant phosphate starvation phenotype in HASX cells is effaced by deletion of vacuolar polyP polymerase Vtc4; and (ii) overdrive of Vtc4-catalyzed polyP synthesis by excess inositol-1-pyrophosphates rapidly exhausts the GTP pool in phosphate-starved HASX cells. GTP depletion, together with precocious repression of genes encoding translation factor GTPases, is the likely cause of the polysome decay. Our results provide new insights into how inositol pyrophosphate signaling and polyP dynamics influence the translation machinery, phosphate homeostasis, and the transcriptional response to nutrient stress.

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

Behcet's disease (BD) involves multiple immune cells, but the mechanism by which interferon α-2a (IFNα-2a) exerts therapeutic effects on BD through immune cell modulation remains unclear. This study aimed to investigate the role of CD4 + IFN-I-related T cells in BD with active uveitis during IFNα-2a therapy. A single-cell atlas of peripheral blood mononuclear cells (PBMCs) was constructed from BD patients with active uveitis, post-4-month IFNα-2a therapy BD patients, active BD patients, and healthy controls (HCs) by integrating in-house and public scRNA-seq data. Bulk mRNA sequencing of CD4 + T cells from active BD patients and HCs was performed for validation. Cell-cell interaction, in vitro coculture, and inhibitor experiments were used to explore the underlying mechanisms. CD4 + IFN-I-related T cells (characterized by high interferon-related gene expression) were significantly decreased in active BD patients but restored after IFNα-2a therapy. The LLT1-CD161 interaction intensity between CD4 + IFN-I-related T cells and NK cells was reduced in active BD and recovered post-therapy. CD4 + IFN-I-related T cells inhibited NK cell activation and IFN-γ secretion via the CD161 receptor. IFNα-2a therapy reverses the decreased frequency of CD4 + IFN-I-related T cells in active BD, which in turn inhibits the inflammatory phenotype of NK cells through LLT1-CD161 interaction, providing new insights into the therapeutic mechanism of IFNα-2a in BD.

MDK promotes the mast cell activation and pancreatic fibrosis in mice with chronic pancreatitis via MDK-NCL signaling pathway.

Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is a low-infectious-dose foodborne pathogen that uses norepinephrine gradients in the gut to locate sites for colonization and activate expression of virulence factors. Here, we identified features of transfer RNA (tRNA) reprogramming and codon-biased translation that play a role in this infectious process. Multivariate statistical analysis of genome-wide codon usage patterns revealed five gene clusters with unique codon biases, with one cluster containing all Locus of Enterocyte Effacement virulence genes that are all strongly biased for A/U-ending codons. EHEC cultures were then exposed to a norepinephrine gradient to induce type III secretion, as well as chemotaxis and flagellar motility, followed by a multi-omic interrogation of changes in tRNA modifications, tRNA abundance, and the proteome. We observed altered levels of multiple tRNA wobble modifications involved in G/C- versus A/U-ending codon recognition and a corresponding shift in the proteome toward genes enriched in A/U-ending codons. Our studies suggest EHEC can alter its tRNA pool in response to cues from the host, fine-tuning translational efficiency of its virulence program.IMPORTANCERegulation of microbial physiology and virulence during environmental changes has typically been ascribed to transcriptional mechanisms. Using convergent multi-omic technologies, we have discovered mechanisms of translational regulation of gene expression that regulate cell phenotype. Here, we applied these technologies to define mechanisms of translational regulation in the Escherichia coli O157:H7 response to norepinephrine exposure known to induce virulence.

Prostate cancer (PCa) is a leading cause of cancer mortality in men. Lamin B2 (LMNB2) has been implicated in various cancers, but its functional role and molecular mechanisms in PCa progression remain poorly characterized. We analyzed LMNB2 expression and clinical associations using transcriptomic data from TCGA, GEO and PCaDB. Functional enrichment analysis identified related pathways. LMNB2 was knocked down in PCa cell lines (LNCaP and PC-3) and its effects on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed. The Wnt/β-catenin pathway was investigated using agonist SKL2001. Subcutaneous xenograft models in nude mice were established for in vivo validation. The experimental findings demonstrate that reduced expression of LMNB2 substantially impairs cellular proliferation, tumor formation ability, and the epithelial-to-mesenchymal transition phenotype in prostate carcinoma cells by interfering with Wnt/β-catenin pathway activation. Furthermore, LMNB2 knockdown effectively suppressed tumor growth in mouse xenograft models. Notably, immunohistochemical evaluation of tumor tissues from xenografts revealed significantly higher LMNB2 protein levels that were associated with poor patient prognosis. These comprehensive results establish LMNB2 as a critical oncogenic driver that promotes both primary tumor development and metastatic spread in prostate adenocarcinoma. LMNB2 promotes prostate cancer progression by activating the Wnt/β-catenin signaling pathway and inducing EMT, highlighting its potential as a prognostic biomarker and therapeutic target.

Electric field directed migration (electrotaxis) of immune cells and breast cancer cells has been previously demonstrated with important physiological and pathological relevance. However, whether an electrical current is necessary for electrotactic cell migration is unknown, which requires engineering innovation to enable experimental investigation. Addressing this fundamental question will lead to biological implications of the electromagnetic environment exposure and raise the possibility of wireless electrical control of cell trafficking in tissues, which motivated this research. To help address this question, we developed a useful wireless unidirectional electric field (Wi-uEF) device, in where the electrochemical field is manipulated to examine migratory responses of human peripheral blood neutrophils (hPBN) and high metastatic potential MDA-MB-231 breast cancer cells. Migration of immune and cancer cells responded differently under Wi-uEF; hPBN migration is biased toward the cathode while breast cancer cells maintain overall random migration patterns. Based on these observations, we hypothesized a random-walk-based mechanistic model to predict different cell migration outcomes in Wi-uEF, and in-silico simulation captured the key experimental results. Altogether, our work is the first demonstration of the differential migratory responses of hPBN and MDA-MB-231 cancer cells to Wi-uEF and suggests a possible biophysical mechanism. Additionally, our wireless bioelectronic platform is capably developed for examining various biological cell responses in real-time in a controlled electrochemical microenvironment.

Abstract SMARCA4, the ATPase component of the SWI/SNF chromatin remodeling complex, is integral to the regulation of gene expression through modulation of chromatin accessibility. Although SMARCA4 is frequently inactivated in lung adenocarcinoma (LUAD), a subset of tumors exhibits elevated SMARCA4 expression, suggesting a context-dependent oncogenic function. However, the molecular mechanisms by which elevated SMARCA4 exerts oncogenic functions in LUAD remain unclear. Here, using a SMARCA4-deficient LUAD cellular model, we show that SMARCA4 overexpression reorganizes enhancer landscapes and establishes a cooperative transcriptional network involving FOSL1, thereby promoting cancer cell proliferation and tumorigenic phenotypes. Integrative multi-omics analyses revealed that SMARCA4 directly cooperates with FOSL1 at active enhancers, leading to the activation of tumor-associated transcriptional programs. Functionally, genetic depletion of FOSL1 or pharmacological inhibition of SMARCA4 reduced cell proliferation and migration and suppressed tumor growth in vitro and in vivo. Importantly, high co-expression of SMARCA4 and FOSL1 was associated with poor clinical outcomes in LUAD patient cohorts. Together, these findings define an epigenetic regulatory axis between SMARCA4 and FOSL1 induced by SMARCA4 activation in SMARCA4-deficient LUAD cells, thereby providing mechanistic insight into how SMARCA4 activates oncogenic regulatory programs in this specific cellular context.

Objective: To investigate the potential molecular regulatory mechanism of interferon-α (IFN-α)-induced disulfidptosis occurrence in human liver cancer cells. Methods: Glucose starvation and IFN-α treatment models were constructed using human hepatocellular carcinoma cell lines HepG2 and Huh7, respectively. Western blotting (WB), NADPH content measurement, and immunofluorescence staining were employed to evaluate disulfidptosis-related phenotypes, such as intracellular disulfide bond accumulation, NADPH depletion, and filamentous actin (F-actin) skeleton collapse. The reversibility of the phenotypes was validated by combining the disulfidptosis inhibitor D-penicillamine (D-Pen). The expression of solute carrier family 7 member 11 (SLC7A11) was downregulated using siRNA interference to evaluate the dependence of IFN-α-induced disulfidptosis on the SLC7A11 pathway. Furthermore, the GEO transcriptome dataset was employed to conduct differential gene analysis for screening candidate molecules involved in the regulation of IFN-α-induced disulfidptosis. Quantitative data are presented as mean ± standard deviation (SD). Comparisons between two groups were performed using the independent-samples t test, while comparisons among multiple groups were analyzed by one-way analysis of variance (ANOVA), followed by Dunnett's t test for pairwise comparisons. Results: Compared with the control group, glucose starvation and IFN-α treatment both induced disulfidptosis-related phenotypes in HepG2 and Huh7 cells, characterized by increased intracellular disulfide bond levels, decreased NADPH content, and F-actin cytoskeleton collapse. Following IFN-α treatment, the accumulation of high-molecular-weight protein aggregates increased in a time- and dose-dependent manner. Compared with IFN-α treatment alone, combined D-Pen intervention partially alleviated intracellular disulfide accumulation, NADPH depletion, and F-actin cytoskeletal collapse. Under conditions of SLC7A11 knockdown, IFN-α-induced high-molecular-weight protein aggregation was further aggravated, suggesting that regulatory mechanisms independent of SLC7A11 may also be involved in this process. Transcriptomic differential expression analysis revealed that β2-microglobulin (B2M), ubiquitin-specific peptidase 18 (USP18) and proteasome activator subunit 1 (PSME1) were upregulated following IFN-α stimulation, among which PSME1 also showed increased protein expression after IFN-α treatment. Conclusion: IFN-α can induce disulfidptosis-related phenotypic changes in HepG2 and Huh7 human hepatocellular carcinoma cells. The upregulation of B2M, USP18, and PSME1 suggests that these molecules may be involved in this process; however, the specific underlying mechanisms require further investigation.

Background Arthralgia, an early manifestation preceding definite rheumatoid arthritis (RA), represents a critical window to identify high‐risk individuals and implement timely interventions. However, the immunopathological mechanisms underlying the transition from arthralgia to established RA remain incompletely defined. Methods We employed a multi‐omics strategy integrating peripheral immune cell phenotyping, serum proteomics, and autoantibody profiling to investigate the immunopathological continuum from preclinical to established RA. A prospective cohort of 346 patients with recent‐onset arthralgia was enrolled. Participants included healthy controls, self‐limiting arthralgia (SLA), arthralgia at risk of RA (ARI), early RA, and established RA. RA development in ARI was ascertained through 24‐month follow‐up. Results Compared with SLA, ARI showed immune dysregulation, including reduced Tregs and a lower Treg/Th17 ratio, with related changes persisting into early RA. Serum proteomics revealed upregulation of C5, A1BG, RPUSD4, WDR87 and FUBP2, which showed inverse associations with Tregs. Autoantibody profiling identified stage‐specific reactivity, with ARI showing elevated antibodies against stress‐related proteins. Within 24 months, 18.4% of ARI progressed to RA (converters). Baseline immunophenotypic differences between converters and non‐converters were comparable, while longitudinal paired analyses revealed a reduction in Tregs and Treg/Th17 ratio. Treg/Th17 ratio (AUC = 0.734) outperformed anti‐CCP (AUC = 0.611) in discriminating ARI from SLA, particularly in ACPA‐negative patients (AUC = 0.729). Combining Tregs, anti‐CCP and Treg/Th17 ratio improved classification performance (AUC = 0.783). Conclusions These findings delineate a critical transition from reversible immune dysregulation to established autoimmunity along the arthralgia‐RA continuum, suggesting that Treg‐related dysregulation may be associated with progression toward persistent inflammatory arthritis.

Clinical investigations have demonstrated that blood and immune cells are involved in the pathophysiological processes of dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). However, the causal relationships between these cellular components and the development of DCM and HCM remain uncertain. A two-sample Mendelian randomization analysis was performed to evaluate the causal effects of blood cells and immune cells on DCM and HCM. The primary analytical method was inverse variance weighting, supplemented by Mendelian randomization-Egger, weighted median, and MR-PRESSO approaches. Furthermore, immune cells were examined as mediators to assess their intermediary roles in the causal pathways linking blood cells with DCM and HCM. Significant causal associations were observed between red blood cells, monocytes, eosinophils, and platelets and DCM and HCM (P < .05). CD127 on CD8br, naive CD8br %CD8br, CD16- CD56 on natural killer cell, CD45 on T cell, and lymphocyte AC were identified as mediators in the causal pathways connecting various blood cell types to DCM and HCM. This study provides robust evidence for the causal roles of specific blood cell and immune cell phenotypes in the development of DCM and HCM. These findings open new avenues for investigating the hematological immune system in cardiomyopathy and present novel opportunities for therapeutic interventions targeting DCM and HCM.