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Background: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. Methods: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. Results: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. Conclusion: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the role of circular RNAs (circRNAs) in the pathogenesis of ameloblastoma (AB), identifying potential novel targets for future targeted therapy. Materials and Methods: CircRNA and microRNA (miRNA) profiling in AB were built with microarrays. Six novel circRNAs were validated, circ‐miRNA networks were delineated. Hsa‐miR‐608 was filtered over cross‐comparison between database screening, miRNA microarray and validated. Circ‐miRNA binding sponge was validated via luciferase reporter assay. Downstream mRNAs were screened. Regulation between miRNAs and mRNAs was confirmed in vitro. Gene interaction networks and circRNA–miRNA–mRNA interaction pathway enrichment analyses were established. Results: Six differentially expressed circRNAs were selected and validated. According to miRNAs and pathways predicted, six correlated miRNAs were selected, hsa‐miR‐608 was filtered and validated. The hsa_circ_0089153/hsa‐miR‐608 binding sponge was validated. Downstream gene interaction networks showed that EGFR and p53 had the strongest co‐expression. In vitro transfection results confirmed the suppressive function of miR‐608 and EGFR p53. Hsa_circ_0089153/hsa‐miR‐608/EGFR p53 interaction pathway enrichment analysis confirmed functions mainly enriched in MAPK and related signaling pathways regulating AB progression. Conclusions: Six novel circRNAs were identified. Hsa_circ_0089153/hsa‐miR‐608 sponging was validated, hsa‐miR‐608 downregulated EGFR and p53, which might further regulate cell proliferation, differentiation, apoptosis, and cell cycle processes via the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

The treatment of traumatic spinal cord injury (SCI) remains challenging as the neuron regeneration is impaired by irregular cavity and apoptosis. An injectable in situ gelling hydrogel is therefore developed for the local delivery of cannabidiol (CBD) through a novel method based on polyelectrolyte (PEC) interaction of sodium carboxymethylcellulose (CMC) and chitosan (CS). It can be injected into the spinal cord cavity with a 26-gauge syringe before gelation, and gelled after 110 ± 10 s. Of note, the in-situ forming hydrogel has mechanical properties similar to spinal cord. Moreover, the CBD-loaded hydrogels sustain delivery of CBD for up to 72 h, resulting in reducing apoptosis in SCI by enhancing mitochondrial biogenesis. Importantly, the CBD-loaded hydrogels raise neurogenesis more than pure hydrogels both in vivo and in vitro, further achieving significant recovery of motor and urinary function in SCI rats. Thus, it suggested that CMC/CS/CBD hydrogels could be used as promising biomaterials for tissue engineering and SCI. CBD-loaded CMC/CS PEC hydrogels with injectable and in situ gelling are developed. It can be injected into the injury site to perfectly match the lesion cavity. Moreover, the hydrogels can enhance mitochondrial biogenesis, inhibit apoptosis and promote neurogenesis, thus achieving significant locomotor and urinary function restoration in SCI rats. [Display omitted] • A cannabidiol-loaded hydrogel (CMC/CS/CBD) was fabricated as a novel material for treatment of spinal cord injury. • The CMC/CS/CBD hydrogel significantlypromotes the recovery of motor and urinary function in SCI rats. • The CMC/CS/CBD hydrogel not only shows good injectability, in-situ gelling, and biocompatibility but also acts as a drug carrier. • The CMC/CS/CBD hydrogel significantly promoted filopodia extension of neural stem cells • The CMC/CS/CBD hydrogel promotes spinal cord injury repair by upregulating of PGC-1α/NRF2 pathway [ABSTRACT FROM AUTHOR]

Abstract: Glycogen synthase kinase-3β (GSK3β) is a major negative modulator of cardiac hypertrophy. Here we report that GSK3β physically and functionally interacts with Smad3. The interaction between GSK3β and Smad3 may participate in the negative regulation of transforming growth factor β1 (TGF-β1) and Angiotensin II-induced transcription and apoptosis. GSK3β interacted directly with Smad3 to sequester it outside the nucleus and prevent its nuclear translocation. This resulted in the suppression of Smad3-mediated transcriptional activity and gene expression. GSK3β counteracted the pro-apoptotic effect of Smad3 and attenuated Angiotensin II-induced apoptosis in cardiac myocytes. Furthermore, stimulation of these cells with TGF-β1 and Angiotensin II led to the endogenous Smad3 disassociating from GSK3β and inactivating GSK3β by phosphorylation of its Ser9. These results uncovered a novel mechanism for the GSK3β negative regulation of TGF-β1/Smad3 and Angiotensin II/Smad3-mediated transcription and apoptosis by the identification of a crosstalk between GSK3β and Smad3 signal pathway. [ABSTRACT FROM AUTHOR]

Treatments for triple-negative breast cancer (TNBC) are limited; intermediate-conductance calcium-activated potassium (SK4) channels are closely involved in tumor progression, but little is known about these channels in TNBC. We aimed to investigate whether SK4 channels affect TNBC. First, by immunohistochemistry (IHC) and western blotting (WB), increased SK4 protein expression in breast tumor tissues was detected relative to that in non-tumor breast tissues, but there was no apparent expression difference between various subtypes of breast cancer (p>0.05). Next, functional SK4 channels were detected in the TNBC cell line MDA-MB-231 using WB, real-time PCR, immunofluorescence and patch-clamp recording. By employing SK4 specific siRNAs and blockers, including TRAM-34 and clotrimazole, in combination with an MTT assay, a colony-formation assay, flow cytometry and a cell motility assay, we found that the suppression of SK4 channels significantly inhibited cell proliferation and migration and promoted apoptosis in MDA-MB-231 cells (p<0.05). Further investigation revealed that treatment with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) caused MDA-MB-231 cells to undergo the epithelial-mesenchymal transition (EMT) and to show increased SK4 mRNA expression. In addition, the down-regulation of SK4 expression inhibited the EMT markers Vimentin and Snail1. Collectively, our findings suggest that SK4 channels are expressed in TNBC and are involved in the proliferation, apoptosis, migration and EMT processes of TNBC cells. [ABSTRACT FROM AUTHOR]