Osteoclast hyperactivity is a key factor in the pathogenesis of several skeletal disorders, including inflammatory bone loss, periprosthetic osteolysis, and rheumatoid arthritis. The ubiquitin-proteasome system (UPS) is pivotal in bone homeostasis and disease pathogenesis, modulating critical osteogenic and osteolytic signaling cascades. Our study identified Spautin-1, an inhibitor of ubiquitin-specific protease 10 (USP10), with the capacity to suppress osteoclastogenesis and the expression of genes associated with osteoclast activity, triggered by the nuclear factor-κB (NF-κB) ligand (RANKL) in bone marrow-derived macrophages (BMMs). Spautin-1 also effectively inhibited RANKL-induced bone resorption in vitro assays. At the molecular level, Spautin-1 reduced the expression of JNK interacting protein 1 (JIP1) by impeding USP10-mediated JIP1 deubiquitination, consequently dampening the RANKL-activated c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) signaling axis and curbing nuclear factor of activated T cells 1 (NFATc1) activation. Consistent with this mechanism, silencing of USP10 similarly reduced the expression of osteoclast‑related genes, mirroring the effects observed with Spautin‑1 treatment, whereas overexpression of JIP1 reversed these inhibitory effects. Additionally, Spautin-1 was found to ameliorate lipopolysaccharide (LPS)-induced bone loss in murine models. Notably, a positive correlation was observed between USP10 and JIP1 expression levels in bone tissues from osteoporotic patients. Collectively, our results position Spautin-1 as a potential therapeutic agent for osteoclast-mediated bone diseases.

RIG-I and STING are critical for mediating the RIG-I and cGAS-STING signaling pathways that guard against viral infection. Here, we report that ubiquitin-specific peptidase 39 (USP39) positively regulates the RIG-I and cGAS-STING pathways to induce antiviral innate immunity in vitro and in vivo. The USP39 deficiency impaired the antiviral immune response of macrophages, leading to low type I IFNs expression, and high RNA and (e.g., VSV, H1N1 PR8) DNA virus (e.g., HSV-1) replication. Moreover, USP39-deficient mice were more sensitive to VSV or HSV-1 infection than control mice. Conversely, USP39 overexpression promoted the antiviral immune response. Mechanistically, we found that USP39 regulates RIG-I protein expression by promoting pre-RIG-I mRNA splicing and maturation. In addition, we also revealed that USP39 interacts with and stabilizes STING protein by deubiquitinating K48-linked polyubiquitin of STING at K288. These data show that USP39 positively regulates RNA and DNA-virus-induced RIG-I and cGAS-STING signaling, respectively, by promoting post-transcriptional control of RIG-I and stabilization of STING. These data provide new insights and potential therapeutic targets to control viral infections.

Glioblastoma multiforme (GBM), an aggressive brain tumor with a dismal prognosis, lacks robust prognostic biomarkers. In this study, we aimed to identify novel biomarkers using integrative bioinformatics, radiomics, and experimental validation. Using the GEO, TCGA, and CGGA datasets, we screened 387 differentially expressed genes (DEGs) and identified five hub genes (LOX, VEGFA, SERPINH1, SLC12A5, and VSNL1) linked to poor outcomes. Among these, SLC12A5 exhibited unique downregulation in GBM, in contrast to its upregulation in most other cancers. Functional analyses revealed that SLC12A5 suppressed the JAK-STAT3, E2F, and MYC pathways, whereas single-cell sequencing highlighted its predominant expression in astrocytes and microglia. Western blotting and immunohistochemistry validated that SLC12A5 downregulation correlated with increased brain edema volume (negative correlation, * p < 0.05) and activated MMP9/STAT3 signaling. Radiomics analysis demonstrated that SLC12A5 expression was associated with MRI features predictive of the IDH genotypes, offering non-invasive prognostic insights. Drug sensitivity screening identified six small molecules (PD0325901, ERK-6604, paclitaxel, ribociclib, TAF1, and lapatinib) that targeted SLC12A5-related pathways. Crucially, multivariate Cox regression analysis confirmed that SLC12A5 was an independent prognostic factor (HR p = 0.04). This study established SLC12A5 as a novel biomarker for GBM, uniquely bridging molecular dysregulation, edema pathogenesis, and radiomics with implications for prognosis and targeted therapy.

Cuproptosis, a novel copper-dependent form of cell death, induces proteotoxic stress by targeting lipoylated mitochondrial proteins, offering a new strategy to overcome cancer therapy resistance. ferredoxin 1 (FDX1) is the core regulator of cuproptosis, and its expression exhibits significant heterogeneity across cancer types. This review systematically summarizes the multi-layered regulatory network governing FDX1, including protein interactions, non-coding RNA targeting, and epigenetic modifications. Targeting strategies are categorized based on expression differences: developing inhibitors to block its pro-tumorigenic effects in cancers with high FDX1 expression, or activating FDX1 expression/function to induce cuproptosis in cancers with low FDX1 expression. While novel nanomaterial-based combination therapies show therapeutic potential, key challenges hindering clinical translation include the lack of FDX1-specific drugs, incomplete understanding of its dynamic regulatory network, and unclear feedback mechanisms. This review provides a theoretical foundation and translational directions for cancer therapy targeting the FDX1-cuproptosis axis.

Intestinal fibrosis, as a late-stage complication of inflammatory bowel disease (IBD), leads to bowel obstruction and requires surgical intervention, significantly lowering the quality of life of affected patients. SAA3, a highly conserved member of the serum amyloid A (SAA) apolipoprotein family in mice, is synthesized primarily as an acute phase reactant in response to infection, inflammation and trauma. An increasing number of evidence suggests that SAA3 exerts a vital role in the fibrotic process, even though the underlying mechanisms are not yet fully comprehended. This study utilized dextran sulfate sodium (DSS) to establish an IBD mouse model and observed that the SAA3-deficient mice exhibited more severe intestinal fibrosis. Our results further indicated that SAA3 genetic disruption in fibroblasts enhanced cell activation to myofibroblasts through HSPB1/NF-κB/TGF-β1/Smads signaling cascade, exacerbating the pathological phenotype of intestinal fibrosis. Collectively, our results shed novel lights on regulating SAA3 in intestinal fibrosis and indicate the potential to develop therapeutic strategies for IBD patients.

BACKGROUND: DMD gene has been implicated in the progression and development of several tumors, but its specific contribution to gastric cancer (GC) has not been fully elucidated. METHODS: We validated DMD gene expression levels in the TIMER2.0 database and human gastric cancer tissue microarrays and constructed gastric precancerous lesion mouse models and DMD gene knockout and overexpression cell lines to investigate the role of DMD gene in gastric cancer development. RESULTS: In this study, we found that DMD gene is significantly downregulated in GC cells and tissues. Mechanistic analysis revealed that DMD gene deletion increased intracellular calcium levels, disrupted mitochondrial homeostasis, and promoted a metabolic shift towards glycolysis, impacting GC cell proliferation and migration. CONCLUSIONS: Taken together, our results shed light on the novel role of DMD gene in gastric cancer development and provide valuable insights into potential therapeutic strategies.

The E3 ubiquitin ligase usually regulates the substrate proteins ubiquitination and degradation, but the study of itself post-translational modification and stability is still elusive. Here, we reveal that E3 ubiquitin ligase ring finger protein 2 (RNF2) is deubiquitinated and stabilized by ubiquitin specific peptidase 43 (USP43) through interactome and quantitative ubiquitinome mass spectrometry analysis. This study demonstrated that USP43, as a deubiquitinating enzyme, negatively regulates the expression of type I interferon (IFN) and the Usp43 deficient enhances antiviral innate immune response against VSV infection both in vitro and in vivo. Mechanistically, USP43 negatively regulates antiviral immunity by promoting RNF2-mediated TBK1 ubiquitination and degradation. USP43 stabilizes RNF2 by removing K48-linked ubiquitination of RNF2 at Lys239 and Lys249, while RNF2 promotes TBK1 degradation by increasing K48-linked ubiquitination of TBK1 at Lys670. These findings uncover the E3 ubiquitin ligase RNF2 post-translational ubiquitination modification and stability regulation, and reveals a novel mechanism that the USP43/RNF2 axis in regulating antiviral innate immunity.

PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.

Drug-target interaction (DTI) prediction is vital for drug discovery and repurposing. Hypergraph is utilized in DTI prediction for modeling higher-order relationships in biomedical networks. Although the strategies of modeling hypergraph-based drug-related interactions with multi-channel and utilizing self-supervised learning task to improve DTI prediction performance have been proven promising, current researches fail to effectively model feature interaction across different channels and fully exploit cross-channel information for self-supervised task. In this study, we propose a hypergraph-based self-supervised multi-channel interaction framework HSMI-DTI for DTI prediction. HSMI-DTI aims to extract hypergraph features effectively and model cross-channel correlations, leveraging hierarchical self-supervised learning to uncover the discover correlations between different channels. We compare HSMI-DTI with advanced baselines, and experiment results show our model outperforms existing methods, thereby optimizing DTI prediction performance.

Treatments of inflammatory bowel disease (IBD) are diverse, but their efficacy is limited, and it is therefore urgent to find better therapies. Controlling mucosal inflammation is a must in IBD drug treatment. The occurrence of anti-tumor necrosis factor α (TNF-α) monoclonal antibodies has provided a safer and more efficacious therapy. However, this kind of treatment still faces failure in the form of loss of response. β-Carboline alkaloids own an anti-inflammatory pharmacological activity. While Kumujan B contains β-carboline, its biological activity remains unknown. In this study, we attempted to determine the anti-inflammatory effects of Kumujan B using both the TNF-α- induced in vitro inflammation and DSS-induced in vivo murine IBD models. Our data show that Kumujan B attenuated the expression of interleukin 1β (IL-1β) and interleukin 6 (IL-6) induced by TNF-α in mouse peritoneal macrophages. Kumujan B suppressed c-Jun N-terminal protein kinases (JNK) signaling, especially c-Jun, for anti-inflammatory response. Furthermore, Kumujan B promoted K11-linked ubiquitination and degradation of c-Jun through the proteasome pathway. In an in vivo study, Kumujan B inhibited the expression of IL-1β, IL-6, and TNF-α and improved the colon barrier function in dextran sulfate sodium salt (DSS)-induced experimental mice colitis. Kumujan B exhibited in vivo and in vitro anti-inflammatory effects, making it a potential therapeutic candidate for treating IBD.

Accurate and efficient prediction of drug-target interaction (DTI) is critical to advance drug development and reduce the cost of drug discovery. Recently, the employment of deep learning methods has enhanced DTI prediction precision and efficacy, but it still encounters several challenges. The first challenge lies in the efficient learning of drug and protein feature representations alongside their interaction features to enhance DTI prediction. Another important challenge is to improve the generalization capability of the DTI model within real-world scenarios. To address these challenges, we propose CAT-DTI, a model based on cross-attention and Transformer, possessing domain adaptation capability. CAT-DTI effectively captures the drug-target interactions while adapting to out-of-distribution data. Specifically, we use a convolution neural network combined with a Transformer to encode the distance relationship between amino acids within protein sequences and employ a cross-attention module to capture the drug-target interaction features. Generalization to new DTI prediction scenarios is achieved by leveraging a conditional domain adversarial network, aligning DTI representations under diverse distributions. Experimental results within in-domain and cross-domain scenarios demonstrate that CAT-DTI model overall improves DTI prediction performance compared with previous methods.

Despite significant breakthroughs in immunotherapy, the limitations of inadequate immune stimulation and stubborn immune resistance continue to present opportunities and challenges. Therefore, a two-pronged approach, encompassing the activation of immunogenic cell death (ICD) and blocking the indoleamine 2,3-dioxygenase (IDO)-mediated pathway, is devised to elicit systemic anti-tumor immunity and alleviate immunosuppression. Herein, a tumor microenvironment (TME)-specific driven nanoagent is composed of a tetrasulfide bond-bridged mesoporous silica layer (MON) coated up-conversion nanoparticles as a nano-carrier, combines Fe2+, curcumin, and indoximod for operating chemodynamic therapy/chemotherapy/immunotherapy. The consumption of glutathione (GSH) caused by MON degradation, the Fenton reaction of Fe2+, and curcumin triggering mitochondrial damage collectively exacerbate the oxidative stress, leading to a violent immunoreaction and reversal of the immunosuppressive TME through a combination of IDO-inhibitors. Meanwhile, upconversion luminescence (UCL) imaging serves as a significant guiding tool for drug delivery and the treatment of nanoagents. In vivo and in vitro experiment results demonstrate that the nanosystem not only effectively inhibits the growth of primary tumors but also induces immune priming and memory effects to reject re-challenged tumors. The strategy as a complementary approach displays great potential for future immunotherapy along with other multimodal treatment modes.

Background: The elevated Cyclin B1 expression contributes to various tumorigenesis and poor prognosis. Cyclin B1 expression could be regulated by ubiquitination and deubiquitination. However, the mechanism of how Cyclin B1 is deubiquitinated and its roles in human glioma remain unclear. Methods: Co-immunoprecipitation and other assays were performed to detect the interacting of Cyclin B1 and USP39. A series of in vitro and in vivo experiments were performed to investigate the effect of USP39 on the tumorigenicity of tumor cells. Results: USP39 interacts with Cyclin B1 and stabilizes its expression by deubiquitinating Cyclin B1. Notably, USP39 cleaves the K29-linked polyubiquitin chain on Cyclin B1 at Lys242. Additionally, overexpression of Cyclin B1 rescues the arrested cell cycle at G2/M transition and the suppressed proliferation of glioma cells caused by USP39 knockdown in vitro. Furthermore, USP39 promotes the growth of glioma xenograft in subcutaneous and in situ of nude mice. Finally, in human tumor specimens, the expression levels of USP39 and Cyclin B1 are positively relevant. Conclusion: Our data support the evidence that USP39 acts a novel deubiquitinating enzyme of Cyclin B1 and promoted tumor cell proliferation at least in part through Cyclin B1 stabilization, represents a promising therapeutic strategy for tumor patients.

The generation and stock of construction and demolition (C&D) waste is increasing, which makes the environmental and economic problems serious. In recent years, China has also launched many policies to encourage and guide C&D waste recycling. However, most of these policies are aimed at contractors and recycling utilization parties, while the lack of publicity and promotion has led to the acceptance in the market is generally low. People may have a negative stereotype of this recycled material recycled from C&D waste. In order to explore a measure that can alleviate this problem, this study used experimental research methods from psychology and neuroscience to investigate the mechanisms of different presentation forms of counter-stereotype intervention materials. This study included two experiments: the pretest experiment verified the implicit-explicit stereotype and neuronal image representation of C&D recycling products through single category implicit association test (SC-IAT), semantic difference scale and functional near-infrared (fNIRS). The posttest experiment was based on the counter-stereotype intervention method and intergroup contact theory. A within-participants design was used to investigate the effectiveness of counter-stereotype intervention and the differences in two intervene presentation forms based on the pretest experiment. The results showed that the counter-stereotype intervention was effective in suppressing the activation of stereotypes. The effects of the intervention were similar for both the video and graphic formats. In the neuron imaging representation of the posttest experiment, the significantly activated brain region shifted from the right dorsolateral prefrontal cortex (R-dlPFC) to the left dorsolateral prefrontal cortex (L-dlPFC). L-dlPFC is highly associated with the modulation of cognition, indicating that after the counter-stereotype intervention, the necessity of C&D waste recycling and the credibility of the recycling product influenced the participants. So when the stereotype was reactivated, the signal in the L-dlPFC was suppressed, weakening the expression of the stereotype. This also suggests that the mechanism of counter-stereotype intervention is to strengthen the brain regulatory system rather than to inhibit the activation of stereotypes at the source.

IκBα is a critical protein that inhibits NF-κB nuclear translocation and impairs NF-κB-mediated signaling. The abundance of IκBα determines the activation and restoration of the inflammatory response. However, posttranslational regulation of IκBα remains to be fully understood. In this study, we identified ubiquitin-specific protease 39 (USP39) as a negative regulator in the NF-κB inflammatory response by stabilizing basal IκBα. The expression of USP39 in macrophages was reduced under LPS-induced inflammation. Knockdown or knockout of USP39 in macrophages significantly increased the expression and secretion of proinflammatory cytokines upon exposure to LPS or Escherichia coli, whereas reexpression of exogenous USP39 in USP39-deficient macrophages rescued the effect. Moreover, USP39-defective mice were more sensitive to LPS or E. coli-induced systemic sepsis. Mechanistically, USP39 interacted with and stabilized IκBα by reducing K48-linked polyubiquination of IκBα. Taken together, to our knowledge, our study for the first time revealed the inhibitory function of USP39 in the NF-κB inflammatory response, providing a previously unknown mechanism for control of inflammatory cytokine induction in the cellular anti-inflammatory response.

The NLRP3 inflammasome plays a critical role in the innate immune response, and its excessive activation will cause pyroptotic cell death and be associated with the onset of inflammatory diseases. However, NLRP3 inflammasome targeting therapies are still to be implemented in the clinic setting. Here, we first isolated, purified and characterized a novel Vitenegu acid from V. negundo L. herb that specifically inhibits NLRP3 inflammasome activation, without affecting NLRC4 or AIM2 inflammasomes. Vitenegu acid blocks the oligomerization of NLRP3, thus inhibiting NLRP3 inflammasome assembly and activation. In vivo data show that Vitenegu acid exerts therapeutic effects on NLRP3 inflammasome-dependent inflammation. Taken together, our results suggest that Vitenegu acid is a candidate therapeutic agent for treating NLRP3 inflammasome related diseases.

The construction industry makes a major contribution to the growth of cities and yet produces enormous waste. Construction and demolition wastes can be recycled and reused, but their products are still challenged by the market. Many researchers blame the negative stereotype of cycled products, however, people show supportive opinions on recycled products in questionnaires. This study designed a single-category implicit association test (SC-IAT) and deployed functional near-infrared spectroscopy (fNIRS) device for direct measurement. The SC-IAT response times, semantic survey scores, and fNIRS blood oxygen concentration were used to quantitatively reflect the implicit impression of the recycled products. The calibrated beta value based on the general linear regression analysis and D-scores were used to capture the cognitive conflicts and assess the implicit stereotypes. After a predesigned experiment, a negative stereotype was observed based on the prolonged response time. The high HbO concentration level in the right dorsolateral prefrontal cortex and the frontal oculomotor area also suggests a cognitive conflict in the "positive words + self words" group. These outcomes demonstrate that fNIRS can supplement the SC-IAT and reveals the implicit cognitive attitudes toward recycled products.

神经胶质瘤是人脑中最常见的原发性肿瘤,占中枢神经系统恶性肿瘤的81％,当前标准疗法仍是手术切除及术后放化疗.因神经胶质瘤具有高侵袭性、分子异质性、治疗后耐药肿瘤干细胞可再生,以及化疗药物难以通过血脑屏障(BBB)达到足够高的治疗浓度等特点,导致其预后非常差,患者中位存活期仅为15个月.近年来,新兴的溶瘤病毒免疫疗法治疗神经胶质瘤的研究备受关注并取得一定进展,但依然面临诸如BBB、免疫"冷"微环境、宿主抗病毒反应和肿瘤高度异质性等挑战.这些问题限制了溶瘤病毒疗法的深入发展及进一步应用,但也给基础与临床研究者带来新的研究机遇.因此,本文从穿越BBB、改善肿瘤微环境(TME)、调控溶瘤病毒介导的宿主免疫反应和适应肿瘤异质性等四个方面,阐述溶瘤病毒在抗神经胶质瘤治疗研究中的存在问题及对策.