Background: Obesity is an important risk factor for osteoarthritis (OA), but the mechanisms associated with OA progression are still not fully understood. The aim of this study was to investigate the role of cyclin-dependent kinase 5 (CDK5) in regulating the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-κB (NF-κB) signaling pathway and its effect on obesity-related OA.
Methods: By analyzing tissue samples from obese and nonobese patients with OA in conjunction with a high-fat diet (HFD)-induced obese mouse model of OA, we investigated the expression level of CDK5 and its effects on inflammation and apoptosis. The role of CDK5 in macrophage polarization and chondrocyte apoptosis was further explored by gene knockdown and pharmacological intervention.
Results: CDK5 levels were found to be significantly elevated in obese patients with OA, promoting M1 macrophage infiltration and chondrocyte apoptosis. In the model, CDK5 knockdown attenuated cartilage damage and inhibited PPARγ phosphorylation and NF-κB signaling. In vitro experiments showed that overexpression of CDK5 facilitated M1 macrophage polarization and chondrocyte apoptosis, and PPARγ agonists reversed these effects. Mechanically, CDK5 binds to PPARγ to regulate the NF-κB signaling pathway.
Conclusion: CDK5 promotes the progression of obesity-associated OA through the PPARγ/NF-κB pathway and is a potential therapeutic target in OA, especially in obese patients.
Background: Radiotherapy for malignant tumor treatment and irradiation (IR)-related diagnosis damage lymphocytes, which inevitably suppresses immunity and leads to unwanted clinical outcomes. However, a few agents have been approved by the Food and Drug Administration (FDA) to alleviate IR-induced injury. Here, the radioprotective effect and underlying mechanism of a new steroidal compound optimized from estradiol (E0703) were investigated.
Methods: Mice were exposed to γ-ray IR to establish an in vivo model of radiation injury, and human peripheral blood B lymphocytes (AHH-1) were employed to investigate injury in lymphocytes. Protein level changes in cell and tissue samples were detected by western blot and immunofluorescence. DNA damage was assessed by the comet assay and γH2AX staining. RNA sequencing was used to screen the critical genes mediating the radioprotective effect of E0703. To determine the direct target of E0703, cellular thermal shift (CETSA), drug affinity responsive target stability (DARTS), molecular docking, and surface plasmon resonance (SPR) assays were adopted. GLI3 transactivation by estrogen receptor β (ERβ) was determined by the chromatin immunoprecipitation (ChIP) assay, while protein interactions were detected by coimmunoprecipitation (Co-IP). IP products were subjected to label-free proteomics assay to screen GLI3 conjugates.
Results: E0703 significantly improved survival and tissue injury in mice exposed to IR damage. In lymphocytes, IR-induced DNA damage was ameliorated with E0703 in an ataxia-telangiectasia mutated protein (ATM)-checkpoint kinase 2 (CHK2)-dependent manner. ERβ but not ERα was a direct target of E0703, wherein ERβ enhancement on the promoter region of GLI3 triggered by E0703 could sustain its protein expression. The interaction between GLI3 and eIF4G1 favored by E0703 was critical for the formation of the eIF4F translation-initiation complex. eIF4F assembly was indispensable for the stimulation of ATM-CHK2 signaling involved in DNA damage repair.
Conclusions: E0703 alleviated IR-induced DNA damage in lymphocytes by selectively targeting ERβ. The formation of the eIF4F complex in a GLI3-dependent manner was critical for ATM-CHK2 activation triggered by E0703. Our study provides an alternative countermeasure to alleviate IR-induced lymphopenia in individuals undergoing radiotherapy or IR-related diagnosis.
The human Y chromosome (ChrY), which confers male sex determination, contains a relatively small number of protein-coding genes compared to other chromosomes; consequently, its functional impact on adult physiology was once severely unappreciated. While the repetitive structure of the ChrY once impeded sequencing, technological advances have now made it possible to identify its contents. Despite the historical view of ChrY as a virtual wasteland, we now know that it encodes a variety of genes which are hugely consequential to both human health and disease. The extreme downregulation of ChrY gene expression, resulting from partial or total loss of ChrY (LOY), is a common characteristic observed in various disease states in men, including cardiovascular, neurodegenerative, immunological health issues, and ,most notably, cancer. Additionally, mosaic LOY (mLOY) is sometimes found in primary cancerous tissues and is associated with poorer clinical outcome. Although, the reasons for these associations were once elusive, they are now understood to be linked to the activity of several ChrY genes, as well as the pleiotropic effects of their loss. In this review, we critically analyze contemporary and historic scientific literature which evaluate the clinical LOY trends seen in male exclusive/predominant cancers as well as explore the now identified mechanisms of ChrY alteration in cancer initiation, progression, and metastasis. Moreover, we discuss recent research studies which have uncovered novel mechanisms through which LOY may induce the physiological and molecular changes in the tumor microenvironment (TME) associated with malignant transformation and the evasion of innate immunity. Interestingly, the TME formed by malignant cells with LOY appears to contribute to early T cell exhaustion in infiltrating immune cells and consequent compromised tumor clearance; a phenomenon which has been profusely observed in patient samples. Furthermore, we describe the tumor-suppressive activities of the ChrY demonstrated in previous studies, as well as its newly identified roles in cancer immunology.
Background: The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking.
Methods: Candidate lncRNA IGFL2-AS1 and its downstream target, the HSPA1A and RAP1 cascade, were identified using RNA sequencing. In vitro functional assays, including proliferation, clonal formation, Transwell migration, sphere formation, and drug sensitivity test, were conducted to explore the function of the IGFL2-AS1/HSPA1A axis in lung cancer. For in vivo functional validation, subcutaneous implantation and tail vein injection of luciferase-tagged lung cancer cells were performed in mouse models. Moreover, RNA pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and point/truncated mutations were utilized to dissect the mechanisms underlying the activation of the YBX1-mediated IGFL2-AS1/HSPA1A axis. Pharmacological inhibition of HSPA1A was performed to restore chemotherapy sensitivity and attenuate lung cancer cell metastasis in vivo. Finally, tissue microarray staining was employed to evaluate the expression of the YBX1/IGFL2-AS1/HSPA1A/RAP1 axis in lung cancer specimens and its correlation with prognosis.
Results: IGFL2-AS1, stimulated by C/EBPβ, was aberrantly upregulated in chemoresistant cell lines and lung cancer specimens. IGFL2-AS1 promoted lung cancer proliferation, metastasis, drug resistance, and stemness by upregulating HSPA1A expression both in vitro and in vivo. Mechanistically, IGFL2-AS1 recruited YBX1 to the HSPA1A promoter, facilitating its transcription. Pharmacological inhibition of HSPA1A restored the sensitization of A549 cells resistant to cisplatin and 5-fluorouracil via the downstream RAP1 signaling cascade. Notably, the YBX1/IGFL2-AS1/HSPA1A axis was consistently activated in lung cancer specimens and correlated with poor patient prognosis.
Conclusions: This study demonstrated that the YBX1-modulated IGFL2-AS1/HSPA1A/RAP1 axis is aberrantly activated in lung cancer cells and is associated with unfavorable prognosis, highlighting its potential as a novel therapeutic target in clinical settings.
Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this review, we explore the role of ISGylation in a variety of related phenotypes in the tumor context, including apoptosis regulation, autophagy regulation, immune escape, metabolic reprogramming, cancer stem cell maintenance, and DNA damage repair. ISGylation plays a dual role in apoptosis, promoting either pro-survival or pro-death pathways depending on contexts. It also regulates autophagy by promoting tumor adaptation or by regulating immune responses. Moreover, ISGylation contributes to the immune escape mechanism by regulating the stability of PD-L1 and immune cell infiltration. In addition, ISGylation is involved in metabolic reprogramming, supporting tumor growth and therapeutic resistance by regulating key metabolic pathways. It also plays a key role in maintaining the properties of cancer stem cells by stabilizing essential metabolic and signaling proteins. In sum, this review examines the functions and mechanisms of ISG15 and ISGylation in various tumor-associated phenotypes, enhancing our understanding of their role in tumorigenesis and disease progression.
Background: Rapid and efficient epithelial regeneration is fundamental for tissue homeostasis and proper function. As the outermost ocular structure, the cornea is transparent, multilayered, and vital for clear vision. Due to its exposed position, the cornea frequently undergoes various forms of injury affecting either the epithelium itself or its surrounding microenvironment, including corneal innervation and the tear film. Corneal abrasion, occurring commonly through trauma or as part of refractive surgical procedures, is typically viewed as a minor event since it usually resolves rapidly. Consequently, the cornea serves as an excellent model for studying epithelial wound healing. However, complications such as persistent epithelial defects or corneal opacity can develop, underscoring critical gaps in understanding the underlying molecular mechanisms.
Methods: Utilizing a unilateral corneal abrasion mouse model, we conducted a comprehensive multi-omics analysis, integrating transcriptomics, proteomics, and epitranscriptomics, to dissect the dynamic molecular responses post-injury in both wounded and contralateral tissues. To elucidate the role of the tear film, we performed additional studies involving lacrimal gland ablation combined with corneal injury. We applied RNA sequencing to profile transcriptomic changes in corneal and lacrimal gland tissues, and mass spectrometry to study tear proteomics and epitranscriptomic modifications.
Results: We revealed a major modulation of the cornea transcriptome after abrasion, suggesting a regulation of pathways including JAK-STAT, Wnt and TGF-β, and a reduction of nucleoside modifications. The lacrimal gland transcriptome and tears proteome were also significantly affected. Plus, we highlighted a bilateralization, both in the cornea transcriptome and tears proteome. In the tear-deficient conditions, the wound closure rate and molecular responses were altered, and the bilateralization was impacted, with an increased matrix remodeling and a modulation of keratins expression.
Conclusions: Our multi-omics analyses revealed extensive epithelial cellular plasticity as a key mechanism driving rapid wound closure, characterized by profound remodeling of transcriptional networks and RNA modifications. Importantly, we uncovered a previously underappreciated role of the lacrimal gland and tear film in mediating bilateral molecular responses following unilateral injury, emphasizing their pivotal roles in tissue regeneration. Additionally, we identified novel regulatory roles for RNA methylation events and critical signaling pathways implicated in epithelial healing.
Background: Disarray in microRNA (miRNA) strand selection is associated with multiple tumors. However, the mechanisms underlying miRNA strand selection-driven temozolomide (TMZ) resistance in glioblastoma (GBM) remain unexplored.
Approach and results: Here, we observed that the strand selection disarray of miR-92b contributes to enhancing TMZ resistance. The pattern of higher expression of miR-92b-3p and lower expression of miR-92b-5p is significantly correlated with TMZ resistance. In TMZ-resistant GBM cells, miR-92b-3p and miR-92b-5p increased the enrichment of H3K27ac in the COL7A1 promoter region by divergently targeting HDAC9 and FOXP3, thereby elevating COL7A1 expression and mediating collagen deposition. In addition, TUT4 regulated strand selection of pre-miR-92b through uridylation, promoting preference for the 3' strand (3p). The TUT4 inhibitor aurothioglucose hydrate (ATG-H) blocked the miR-92b strand selection disarray and restored TMZ sensitivity in TMZ-resistant GBM cells.
Conclusions: Our study demonstrates that TUT4-mediated elevation of the miR-92b-3p/-5p ratio promotes COL7A1 transcription via silencing HDAC9 and alleviation of FOXP3 targeting, leading to collagen deposition and heightened TMZ resistance. Our results suggest that targeting miR-92b strand selection may serve as a potential therapeutic strategy for sensitizing GBM to TMZ.
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