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Background: Pancreatic cancer (PAAD) is a malignant tumor with a poor prognosis and lacks sensitive biomarkers for diagnosis and targeted therapy. Cuproptosis, a recently proposed form of cell death based on cellular copper ion concentration, plays a key role in cancer biology. This study is aimed at constructing a risk model for predicting the prognosis of PAAD patients based on cuproptosis-related genes., Methods: Pancreatic-related data from UCSC-TCGA and UCSC-GTEx databases were extracted for analysis, and TCGA-PAAD samples were randomly divided into the training and validation groups. Pearson correlation analysis was used to obtain cuproptosis-related genes coexpressed with 19 copper death genes. Univariate Cox and Lasso regression analyses were used to obtain cuproptosis-related prognostic genes. Multivariate Cox regression analysis was used to construct the final prognostic risk model. The risk score curve, Kaplan-Meier survival curves, and ROC curve were used to evaluate the predictive ability of the Cox risk model. Finally, the functional annotation of the risk model was obtained through enrichment analysis., Results: The Cox risk model has an eight prognostic cuproptosis-related gene signature. Kaplan-Meier survival curves demonstrated that the high-risk group had a shorter survival time. The ROC curve of the risk score was well created to predict one-, three-, and five-year survival rates, and AUC of the risk score was higher than other clinical characteristics. Cox regression analysis revealed that the risk score has an independent prognostic value for PAAD. GSEA reveals specific tumor pathways associated with the risk model (Myc targets v1, mTORC1 signaling, and E2F targets)., Conclusions: We constructed a prognostic model containing eight cuproptosis-related genes (AKR1B10, KLHL29, PROM2, PIP5K1C, KIF18B, AMIGO2, MRPL3, and PI4KB) that can accurately predict the prognosis of PAAD patients. The results will provide new perspectives for individualized outcome prediction and new therapy development for PAAD patients., Competing Interests: All authors declare that there is no conflict of interest., (Copyright © 2023 Yan Du et al.)

It was found recently that iron overload can cause osteoporosis in rats. Through in vitro and in vivo experimentations, the purpose of the present study was to validate and confirm the inhibitory effects of melatonin on iron death of osteoporosis and its role in bone microstructure improvements. Melatonin (100 mol/L) was administered to MC3T3-E1 cells induced by iron overload in vitro for 48 hours. The expression of cleaved caspase-3 and cleaved PARP and the production of ROS (reactive oxygen species) and mitochondrial damage were all exacerbated by iron overload. On the other hand, melatonin restored these impacts in MC3T3-E1 cells produced by iron overload. By evaluating the expression of PI3K/AKT/GSK-3 β /P70S6k signaling pathway-related proteins (RUNX2, BMP2, ALP, and OCN) using RT-PCR and Western blot, osteogenic-related proteins were identified. Alizarin red S and alkaline phosphatase were utilized to evaluate the osteogenic potential of MC3T3-E1 cells. Melatonin significantly improved the osteogenic ability and phosphorylation rates of PI3K, AKT, GSK-3 β , and P70S6k in iron overload-induced MC3T3-E1 cells. In vivo , melatonin treated iron overload-induced osteoporotic bone defect in rats. Rat skeletal microstructure was observed using micro-CT and bone tissue pathological section staining. ELISA was utilized to identify OCN, PINP, CTX-I, and SI in the serum of rats. We discovered that melatonin increased bone trabecular regeneration and repair in osteoporotic bone defects caused by iron overload. In conclusion, melatonin enhanced the osteogenic ability of iron overload-induced MC3T3-E1 cells by activating the PI3K/AKT/GSK-3 β /P70S6k signaling pathway and promoting the healing of iron overload-induced osteoporotic bone defects in rats., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Maoxian Ren et al.)

The trigeminal ganglion (TG) refers to sensory neurons bodies that innervate the spinal cord and peripheral axons that innervate teeth. The tetrodotoxin-sensitive sodium (NA) channels (Nav1.7) play important roles in the pathophysiology of pain. In this study, we investigated the TG expression of Nav1.7 and extracellular signal-regulated kinase (ERK) in a rat model of pulpitis to explore the correlation between these channels and inflammatory pain. Pulpitis was confirmed by hematoxylin-eosin staining. In this study, we demonstrated that the reflex of rats to mechanical stimulation increases after pulp exposure and that the exposed rat molar pulp can upregulate the expression of Nav1.7 and ERK in the rat TG. Three days after rat pulp exposure, the expression levels of the two ion channels in the TG increased. TG target injection of PF04856264, a Nav1.7 inhibitor, dose-dependently increased the mechanical pain threshold and was able to inhibit ERK expression. TG target injection of PD98059, an ERK inhibitor, dose-dependently increased the mechanical pain threshold. These factors simultaneously resulted in the highest production. In this study, with the established link to inflammatory pain, we found that Nav1.7 and ERK both play important roles in the induction of inflammatory pain caused by pulpitis. We also found a correlation between the expression levels of Nav1.7 and ERK and the degree of inflammatory pain. Furthermore, ERK signaling pathways were promoted by the Nav1.7 in TG after pulpitis.

Stem cell survival after transplantation determines the efficiency of stem cell treatment, which develops as a novel potential therapy for several central nervous system (CNS) diseases in recent decades. The engrafted stem cells face the damage of oxidative stress, inflammation, and immune response at the lesion point in host. Among the damaging pathologies, oxidative stress directs stem cells to apoptosis and even death through several signalling pathways and DNA damage. However, the in-detail mechanism of stem cell survival from oxidative stress has not been revealed clearly. Here, in this study, we used hydrogen peroxide (H 2 O 2 ) to induce the oxidative damage on neural stem cells (NSCs). The damage was in consequence demonstrated involving the activation of heat shock protein 90 (HSP90) and NF- κ B/p65 signalling pathways. Further application of the pharmacological inhibitors, respectively, targeting at each signalling indicated an upper-stream role of HSP90 upon NF- κ B/p65 on NSCs survival. Preinhibition of HSP90 with the specific inhibitor displayed a significant protection on NSCs against oxidative stress. In conclusion, inhibition of HSP90 would attenuate NF- κ B/p65 activation by oxidative induction and promote NSCs survival from oxidative damage. The HSP90/NF- κ B mechanism provides a new evidence on rescuing NSCs from oxidative stress and also promotes the stem cell application on CNS pathologies.