Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.

INTRODUCTION: Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. METHODS: We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 µg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. RESULTS: In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. CONCLUSION: Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.

Development of a multifunctional gold nanoplatform for combined chemo-photothermal therapy against oral cancer.

Aim: To design and fabricate a multifunctional drug-delivery nanoplatform for oral cancer therapy. Materials & methods: Polyethylene glycol-stabilized, PDPN antibody (PDPN Ab)- and doxorubicin (DOX)-conjugated gold nanoparticles (AuNPs) were prepared and evaluated for their cytotoxicity and antitumor efficacy in both chemotherapy and photothermal therapy. Results: The obtained (PDPN Ab)-AuNP-DOX system presents low toxicity, a high drug loading capacity and cellular uptake efficiency. Both in vitro and in vivo experiments demonstrate that (PDPN Ab)-AuNP-DOX has enhanced antitumor efficacy. Treatment with (PDPN Ab)-AuNP-DOX combined with laser irradiation exhibits superior antitumor effects. Conclusion: This (PDPN Ab)-AuNP-DOX system may be used as a versatile drug-delivery nanoplatform for targeted and combined chemo-photothermal therapy against oral cancer.

Tumor necrosis factor receptor-associated factor 6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been found to be involved in carcinogenesis in multiple cancers. However, the precise role of TRAF6 in cancer has not been extensively investigated and remains largely unknown. In this study, we aimed to investigate the biological function of TRAF6 and its underlying molecular mechanisms in cancer. A positive correlation between poor tumor differentiation and TRAF6 expression status was observed in both oral cancer and breast cancer. Overexpression of TRAF6 promoted proliferation, migration, and G0 /G1 to S phase transition in tumor cells. Tumor necrosis factor receptor-associated factor 6-mediated AKT ubiquitination and subsequent phosphorylation played an essential role in the control of tumor cell malignant behavior. In vivo treatment with TRAF6, but not the E3 ligase deficient TRAF6 mutant, facilitated tumor growth. Our findings indicate that TRAF6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation. Therefore, TRAF6 could serve as a therapeutic target in cancers.

Serum miR-626 and miR-5100 are Promising Prognosis Predictors for Oral Squamous Cell Carcinoma.

Although serum microRNAs (miRNAs) are currently being considered as promising noninvasive biomarkers for cancers, their role in the prognosis of oral squamous cell carcinoma (OSCC) has not been elucidated. Here we aimed to identify serum miRNA biomarkers that could be used as prognosis predictors of OSCC. Methods: A cohort of 260 serum miRNA samples was assessed in a three-step approach that included a screening stage, a training stage, and a testing stage. The correlation between prognosis of OSCC and the miRNAs expression was comprehensively analyzed. Results: A two-miRNA signature involving miR-626 and miR-5100 has been developed. Patients defined to be high-risk group by the two-miRNA signature had significantly shortened median survival time compared with the low-risk group. In multivariate analysis, this two-miRNA signature was independently predictive of survival, and achieved a superior predictive value compared with that of traditional clinicopathologic factors such as pathology grade as well as tumor and node metastasis (TNM) stage. An integrated prognostic model combining the TNM stage and miRNA signature displayed the highest prognostic performance (AUC value: 0.787, specificity: 0.884, sensitivity: 0.573) compared to the TNM stage-alone (AUC value: 0.630, specificity: 0.526, sensitivity: 0.733) or miRNA signature-alone model (AUC value: 0.771, specificity: 0.768, sensitivity: 0.773). In addition, we found that OSCC tumor cells not only expressed a high level of these two miRNAs, but also secreted certain miRNAs into the extracellular environment, suggesting these miRNAs may originate from tumor cells. Conclusion: In our study, we established a two-miRNA signature that was strongly and independently associated with prognosis in OSCC, and may serve as a promising prognosis predictor.

Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis.

Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets.Significance: These findings identify the ADAM10-p75NTR ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. Cancer Res; 78(9); 2262-76. ©2018 AACR.