Background: Chemoresistance is a major challenge in cancer treatment.miR-506 is a potent inhibitor of the epithelial-tomesenchymal transition (EMT), which is also associated with chemoresistance.We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. Methods:We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents.We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity.All statistical tests were two-sided.Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001;TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04).MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51.Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36 ± 0.05g vs 0.07 ± 0.02g, P < .001;control miRNA plus olaparib vs miR-506 plus olaparib: 0.32 ± 0.13g vs 0.05 ± 0.02g, P = .045,respectively), thus recapitulating the clinical observation.Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy. MTT AssayTwenty-four hours after transfection with 20 nm miR-506, miR-Ctrl, or anti-miR-LNA, cells were seeded onto 96-well
Abstract Objectives. Deletion of Fscn2 gene in mice has been linked to progressive hearing loss and degeneration of cochlear cells. Cisplatin, an antitumor drug, can cause various side effects, including ototoxicity. The aim of this study was to investigate the effects of Fscn2 on cisplatin-induced hearing impairment in mice and to explore the possible mechanism. Methods. Two-week-old Fscn2 +/+ mice and Fscn2 -/- mice were treated with two doses of cisplatin, with a 3-day recovery period in between. ABR (auditory evoked brain stem response) thresholds were measured and cochlear pathology was observed at 3 weeks of age. Results. Both Fscn2 +/+ and Fscn2 -/- mice showed hearing loss under the effect of cisplatin, but the impairment was more severe in Fscn2 -/- mice. Further experiments showed that the percentages of outer hair cell (OHC) and spiral ganglion neuron (SGN) loss were significantly higher in cisplatin-treated Fscn2 -/- mice compared to Fscn2 +/+ mice. Additionally, knockdown of Fscn2 in HEI-OC1 cells worsened cisplatin-induced cell apoptosis. Conclusion. FSCN2 mediates reduction of CDDP induced ototoxicity by inhibiting cell apoptosis
To investigate the effects of hydrogen sulfide (H2S) on vascular inflammation and blood pressure in spontaneously hypertensive rats (SHR).Four weeks old male SHR rats were treated with saline (control, n = 7), sodium hydrosulfide (NaHS, a H2S donor, n = 7) and propargylglycine (PPG, endogenous H2S production inhibitor, n = 6) for 5 weeks. Age-natched male Wistar Kyoto (WKY) rats served as normotensive controls (n = 8). Five weeks later, systolic blood pressure (SBP) was measured in conscious and quiet rats by means of the standard tail-cuff method. The protein expressions of intercellular adhesive molecule-1 (ICAM-1), nuclear transcriptional factor-kappaB p65 (NF-kappaB p65) and inhibitor of nuclear transcriptional factor-kappaB (IkappaB-alpha) in thoracic aorta of rats were detected by immunohistochemical assay, while the expression of ICAM-1 mRNA in thoracic aorta of rats were investigated by in situ hybridization.SBP of control SHR rats was significantly higher than that of WKY rats (P < 0.05) accompanied by significantly upregulated expressions of ICAM-1 mRNA, ICAM-1 protein, NF-kappaB p65 protein in aortic endothelial cells (all P < 0.01), while the expression of IkappaB-alpha protein in aortic endothelial cells in SHR control group was significantly lower than that of WKY control group (P < 0.01). NaHS treated SHR rats showed significantly reduced SBP and downregulated expressions of ICAM-1 mRNA, ICAM-1, NF-kappaB p65 in aortic endothelial cells and upregulated expression of IkappaB-alpha protein in aortic endothelial cells compared to untreated control SHR rats (all P < 0.05). In SHR rats treated with PPG, the expressions of ICAM-1 mRNA, ICAM-1 protein, NF-kappaB p65 protein in aortic endothelial cells were further increased while the expression of IkappaB-alpha protein further decreased compared with control SHR rats (all P < 0.05).H2S might attenuate the development of hypertension through by attenuating vascular inflammation reactions.
Chinese shrimp(Fenneropenaeus chinensis)is distributed mainly along Chinese inshore areas,and is one of the most important farmed shrimp in China.The studies on innate immune responses of shrimps,especially on immune defense against the main crustacean pathogens,will provide more knowledge of shrimp immunity to prevent infectious diseases.Invertebrates do not possess an adaptive immune system based on highly specific antibodies and antigen receptors.They must rely on efficient immune defenses capable of protecting them against invading microorganisms.The chief issue of crustacean immunity should concern non-self-recognition mechanisms.Proteins that specifically bind to certain carbohydrate components on the surface of microorganisms play an important role in non-self-recognition and cleaning up of the invading microorganisms.Such proteins are known as pattern recognition receptors(PRRs).Lectins exist in almost all living organisms.Due to their ability of binding to terminal sugars on glycoproteins and glycolipids,lectins are primary candidates for pattern recognition receptors in innate immunity.C type Lectin is regarded as a potential molecule involved in immune recognition and phagocytosis through opsonization in crustacean.In the preliminary study,a novel C-type lectin was cloned from hemocytes of Chinese shrimp,(Fenneropenaeus chinensis).It contains two tandem carbohydrate recognition domains(CRDs)/C-type lectin-like domains.Both of the CRDs contain a QPD(Gln-Pro-Asp)motif that has a predicted binding specificity for galactose-type sugar.In this research,two recombinant target proteins(rFclectin-CRD1 and rFclectin-CRD2)were expressed by prokaryotic expression system.The result showed that fusion protein was expressed in the form of inclusion bodies.The LC-ESI-MS analysis showed that two peptide fragments of rFclectin-CRD1 and rFclectin-CRD2 were identical with the corresponding sequence of F.chinensis C-type lectin.Recombinant protein was purified by immobilized-metal affinity chromatography and Ni-NTA technology.The concentrations of purified target proteins were 0.4 g/L.rFclectin-CRD1 and rFclectin-CRD2 had agglutinating and antimicrobial activity against main pathogens in aquaculture in a calcium-dependent manner.The agglutinating activity can be inhibited by multiple carbohydrates,such as galactose,peptidoglycan and lipopolysaccharide.These results suggest that Fclectin,as a Ca2+dependent carbohydrate-recognition protein,is one of the important PRRs.It might play a crucial role in the innate immunity of the shrimp and is expected to be applied in disease control.
Abstract Background Acute lymphoblastic leukemia (ALL) is a prevalent hematologic malignancy that primarily affects children. The diagnosis and treatment of pediatric ALL remain challenging. This study aimed to identify differential lipids and metabolites that may hold potential for improving ALL diagnosis. Methods Serum lipidome and metabolome alterations of ALL were analyzed by comparing pediatric patients with ALL with healthy controls based on liquid chromatography high-resolution mass spectrometry analysis of serum lipidomic and metabolomic signatures. Results We identified 2,298 lipid features in the serum. Among them, 72 (3.13%) differed significantly in pediatric patients with ALL compared to healthy controls. Notably, sphingolipids (ceramide and sphingomyelin) and phospholipids exhibited the most pronounced changes. Targeted analysis of ceramides revealed significantly elevated levels of Cer 18:0 and Cer 20:0 in the serum of pediatric patients with ALL. Additionally, gut microbial-related lipids (such as sulfonolipids and fatty acid esters of hydroxy fatty acids) showed significant alterations. Metabolomic analysis identified 15 differential metabolites, indicating disrupted nucleotide and amino acid metabolism. Furthermore, the dysregulated lipids and metabolites correlated with various blood indicators, with ceramide and nucleosides positively associated with white blood cell count but negatively correlated with hemoglobin and platelet. Conclusion These findings shed light on abnormal molecular signatures contributing to pediatric ALL and may serve as potential biomarker panel for diagnosis and therapy of ALL.
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