CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.

Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.

Systematic Characterization of DNA Methyltransferases Family in Tumor Progression and Antitumor Immunity.

Objective: DNA methylation is an essential epigenetic marker governed by DNA methyltransferases (DNMTs), which can influence cancer onset and progression. However, few studies have provided an integrated analysis of the relevance of DNMT family genes to cell stemness, the tumor microenvironment (TME), and immunotherapy biomarkers across diverse cancers. Methods: This study investigated the impact of five DNMTs on transcriptional profiles, prognosis, and their association with Ki67 expression, epithelial-mesenchymal transition signatures, stemness scores, the TME, and immunological markers across 31 cancer types from recognized public databases. Results: The results indicated that DNMT1/DNMT3B/DNMT3A expression increased, whereas TRDMT1/DNMT3L expression decreased in most cancer types. DNMT family genes were identified as prognostic risk factors for numerous cancers, as well as being prominently associated with immune, stromal, and ESTIMATE scores, as well as with immune-infiltrating cell levels. Expression of the well-known immune checkpoints, PDCD1 and CILA4, was noticeably related to DNMT1/DNMT3A/DNMT3B expression. Finally, we validated the role of DNMT1 in MCF-7 and HepG2-C3A cell lines through its knockdown, whereafter a decrease in cell proliferation and migration ability in vitro was observed. Conclusion: Our study comprehensively expounded that DNMT family genes not only behave as promising prognostic factors but also have the potential to serve as therapeutic targets in cancer immunotherapy for various types of cancer.

Caveolin-1 promotes glioma progression and maintains its mitochondrial inhibition resistance.

BACKGROUND: Glioma is a lethal brain cancer and lacking effective therapies. Challenges include no effective therapeutic target, intra- and intertumoral heterogeneity, inadequate effective drugs, and an immunosuppressive microenvironment, etc. Deciphering the pathogenesis of gliomas and finding out the working mechanisms are urgent and necessary for glioma treatment. Identification of prognostic biomarkers and targeting the biomarker genes will be a promising therapy. METHODS: From our RNA-sequencing data of the oxidative phosphorylation (OXPHOS)-inhibition sensitive and OXPHOS-resistant cell lines, we found that the scaffolding protein caveolin 1 (CAV1) is highly expressed in the resistant group but not in the sensitive group. By comprehensive analysis of our RNA sequencing data, Whole Genome Bisulfite Sequencing (WGBS) data and public databases, we found that CAV1 is highly expressed in gliomas and its expression is positively related with pathological processes, higher CAV1 predicts shorter overall survival. RESULTS: Further analysis indicated that (1) the differentiated genes in CAV1-high groups are enriched in immune infiltration and immune response; (2) CAV1 is positively correlated with tumor metastasis markers; (3) the methylation level of CAV1 promoters in glioma group is lower in higher stage than that in lower stage; (4) CAV1 is positively correlated with glioma stemness; (5) higher expression of CAV1 renders the glioma cells' resistant to oxidative phosphorylation inhibitors. CONCLUSION: Therefore, we identified a key gene CAV1 and deciphered its function in glioma progression and prognosis, proposing that CAV1 may be a therapeutic target for gliomas.

Diagnosis, Treatment, and Prognosis of Patients with Primary Familial Gastrointestinal Stromal Tumor: A Case Report and Literature Review.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.

Histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury.

Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury. However, a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established. Here, we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury. Disease-specific histone mark alterations were mainly found in H3K27me3-, H3K27ac-, and H3K4me1-marked regions 24 and 48 h after I/R. Genes differentially modified by H3K27ac, H3K4me1 and H3K27me3 were involved in immune response, heart conduction or contraction, cytoskeleton, and angiogenesis. H3K27me3 and its methyltransferase polycomb repressor complex 2 (PRC2) were upregulated in myocardial tissues after I/R. Upon selective inhibition of EZH2 (the catalytic core of PRC2), the mice manifest improved cardiac function, enhanced angiogenesis, and reduced fibrosis. Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro. This study delineates a landscape of histone modifications in myocardial I/R injury, and identifies H3K27me3 as a key epigenetic modifier in I/R process. The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.

Optimization of surgical exposure for harvesting gracilis-semitendinosus tendons.

PURPOSE: This study was conducted to provide anatomical data and surface markers for the safe and efficient exposure of surgical incisions for harvesting gracilis tendons (GT) and semitendinosus tendons (STT) while avoiding technical pitfalls and nerve injury during harvest for ligament reconstruction. METHODS: Seventy-four Chinese cadaveric lower limbs were dissected to expose the infrapatellar branch of the saphenous nerve (IPBSN) and pes anserinus (PA). Measurements of the borders and accessory bands of the PA tendons were taken. The arrangement of PA tendons and distribution of the IPBSN were assessed. RESULTS: The PA was roughly shaped like a quadrangle, with its superior border at the horizontal plane of the tibial tuberosity (TT). The GT and STT bifurcation point was located on the medial border of the PA. From medial side to lateral side, the sartorius tendons (ST), GT, and STT fused gradually and formed the lateral border of the PA at the distal end. The tendon arrangement of the PA was primarily affected by ST, which commonly covered GT and STT completely. Variant tendons were found in 41.9% of specimens. The insertion of the accessory bands was distal but close to the inferior border of the PA. Accessory bands were observed only in STT and ST, and STT accounted for the most. The width of the first accessory band of STT was similar to the width of the STT. Additionally, most of the IPBSNs were proximal to the horizontal plane of the TT. CONCLUSION: For clearly exposing the GT and STT, it is crucial to expose the GT and STT bifurcation point on the medial border of the PA, whether directly or indirectly through the incision.The influence of ST insertion and the variability of tendons within the PA must be paid attention to during the operation. To protect IPBSNs highly, the incision should not be higher than the TT level.

SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation.

Anthracyclines including doxorubicin (DOX) are still the most widely used and efficacious antitumor drugs, although their cardiotoxicity is a significant cause of heart failure. Despite considerable efforts being made to minimize anthracycline-induced cardiac adverse effects, little progress has been achieved. In this study, we aimed to explore the role and underlying mechanism of SNX17 in DOX-induced cardiotoxicity. We found that SNX17 was downregulated in cardiomyocytes treated with DOX both in vitro and in vivo. DOX treatment combined with SNX17 interference worsened the damage to neonatal rat ventricular myocytes (NRVMs). Furthermore, the rats with SNX17 deficiency manifested increased susceptibility to DOX-induced cardiotoxicity (myocardial damage and fibrosis, impaired contractility and cardiac death). Mechanistic investigation revealed that SNX17 interacted with leiomodin-2 (LMOD2), a key regulator of the thin filament length in muscles, via its C-TERM domain and SNX17 deficiency exacerbated DOX-induced cardiac systolic dysfunction by promoting aberrant LMOD2 degradation through lysosomal pathway. In conclusion, these findings highlight that SNX17 plays a protective role in DOX-induced cardiotoxicity, which provides an attractive target for the prevention and treatment of anthracycline induced cardiotoxicity.