Novel Signaling Pathway and NSC689534 as a Potential Drug Candidate for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC. METHODS: In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line. RESULTS: Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC. CONCLUSIONS: NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

HSC70-JNK-BAG3 complex is critical for cardiomyocyte protection of BAG3 through its PXXP and BAG structural domains.

Notwithstanding previous studies have proved the anti-apoptotic effect of Bcl-2 associated athanogene3 (BAG3) in myocardium, the structural domains PXXP and BAG responsible for its protection are not reformed. Since BAG3 in cardiomyocytes is a new target for inhibiting apoptosis induced by hypoxia/reoxygenation (H/R) stress, we demonstrated that over-expression of BAG3 reduced the injury induced by H/R in either neonatal or adult rat cardiomyocytes (NRCMs and ARCMs, respectively) and PXXP and BAG domains play an important role in cellular protection in H/R stress. Apoptosis in cardiomyocytes induced by hypoxia-reperfusion was evaluated with propidium iodide (PI) staining, cleaved caspase-3, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining in cultured NRCMS. Either increasing expression of BAG3 or its mutants was performed to manipulate the level of BAG3. Co-immunoprecipitation (Co-IP) was used to demonstrate the complex that BAG3 is binding to HSC70 and JNK. PXXP and BAG domains of BAG3 played an essential role in BAG3 attenuating cardiomyocytes apoptosis induced by H/R through the JNK signalling pathway. The cellular protection of BAG3 with its structural domain PXXP or BAG is associated with the binding with HSC70 and JNK. These results showed that the protective effect of BAG3 on apoptosis induced by H/R stress is closely related to its structural domains PXXP and BAG. The mechanism may provide a new therapeutic strategy for the patients suffering from ischemic cardiomyopathy and may be a critical role of its PXXP and BAG3 domains.

[Neurodevelopmental features of preterm infants at the corrected age of 1 year].

OBJECTIVE: To investigate the neurodevelopmental level of preterm infants at the corrected age of 1 year and the effect of complications on neurodevelopment. METHODS: The clinical data and follow-up data of hospitalized preterm infants were retrospectively studied. The Bayley Scales of Infant Development was used to assess the neurodevelopmental level. Preterm infants were divided into groups according to gestational age, birth weight, and the presence or absence of complications. The mental development index (MDI) and psychomotor development index (PDI) were compared between groups. RESULTS: At the corrected age of 1 year, compared with the late preterm infants, the early preterm infants had significantly lower MDI and PDI (P<0.05) and significantly higher rates of retarded intellectual and psychomotor development (P<0.01). Compared with the normal birth weight group, the low birth weight group had significantly lower MDI and PDI (P<0.01) and significantly higher rates of retarded intellectual and psychomotor development (P<0.01). The preterm infants with hyperbilirubinemia, birth asphyxia or neonatal respiratory distress syndrome (NRDS) had significantly lower MDI and PDI than those without such complications (P<0.05). CONCLUSIONS: Lower gestational age and birth weight are associated with worse intellectual and psychomotor development in preterm infants. Complications, such as hyperbilirubinemia, birth asphyxia and NRDS, have adverse effects on neurodevelopment of preterm infants.

Mitochondrial energy metabolism dysfunction involved in reproductive toxicity of mice caused by endosulfan and protective effects of vitamin E.

The experiment was designed to study the mechanism of reproductive toxicity caused by endosulfan in mice and protective effects of vitamin E. The experiment was composed of three groups: the control group did not receive any endosulfan and vitamin E; the endosulfan exposed group received 0.8 mg/kg/d endosulfan and 0mg/kg/d vitamin E; and the endosulfan+vitamin E group received 0.8 mg/kg/d endosulfan and 100mg/kg/d vitamin E. The results showed that vitamin E significantly reversed the decline of the concentration and motility rate of sperm, and inhibited the increase of sperm abnormality rate caused by endosulfan. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and lactate dehydrogenase-C4 (LDH-C4) and the level of adenosine triphosphate (ATP) in the endosulfan+vitamin E group were higher while the malondialdehyde (MDA) content was significantly lower than those of the endosulfan exposed group. The results from pathology and electron microscope observed showed vitamin E decreased the cavities formation by desquamating of spermatogenic cells, stopped the ruptures and disappearances of mitochondrial cristaes in spermatogenic cells, and prevented the breakages and partial dissolvings of sperm tails induced by endosulfan. It is likely that endosulfan could directly damage sperm structures by oxidative stress, leading to a decrease in sperm quantity and quality. It also could indirectly cause a decline in reproductive function by damaging the structure of mitochondria, resulting in energy metabolism dysfunction, which could be one of the mechanisms behind the reproductive toxicity induced by endosulfan. It was inferred that vitamin E helps maintain the structural integrities of sperm architecture and prevent mitochondrial dysfunction through inhibiting oxidative stress, and thereby prevent the reproductive dysfunctions caused by endosulfan.