SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/ß-Catenin and JAK-2/STAT-3 Signaling Pathways.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/ß-catenin (wingless-int1/ß-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of ß-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/ß-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

CP41, a novel curcumin analogue, induces apoptosis in endometrial cancer cells by activating the H3F3A/ proteasome-MAPK signaling pathway and enhancing oxidative stress.

AIMS: Curcumin is a natural compound and has good antitumor properties, but its clinical use is limited by its low bioavailability. We constructed the derivative CP41 (3,5-bis(2-chlorobenzylidene)-1-piperidin-4-one) by enhancing the bioavailability of curcumin while retaining its antitumor properties. MAIN METHODS: CCK-8 (Cell Counting Kit-8) was used to detect the effect of CP41 on cell proliferation; Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay were used to evaluate the expression of subcutaneous tumor-related molecules in cells and mice. KEY FINDINGS: Our results showed that CP41 inhibited the proliferation of endometrial cancer cells by suppressing the proliferation of AN3CA and HEC-1-B cells. We found that CP41 significantly increased H3F3A and inhibited proteasome activity, which activated MAPK signaling and led to apoptosis. Further experiments showed that H3F3A is a potential target of CP41. Correlation analysis showed that H3F3A was positively correlated with the sensitivity to chemotherapeutic agents in endometrial cancer. CP41 significantly induced reactive oxygen species (ROS) levels and activated endoplasmic reticulum stress, which led to apoptosis. The safety profile of CP41 was also evaluated, and CP41 did not cause significant drug toxicity in mice. SIGNIFICANCE: CP41 showed stronger antitumor potency than curcumin, and its antitumor activity may be achieved by inducing ROS and activating H3F3A-mediated apoptosis.

Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling.

OBJECTIVE: Curcumin has been shown to have anti-tumor proliferative properties, but its clinical application is limited by its low bioavailability, etc. Derivatives of curcumin have been developed and tested to improve its therapeutic efficacy. Derivative NL01 could induce ferroptosis through the HCAR1/MCT1 pathway. METHOD: CCK-8 was used to detect curcumin and derivative IC50, crystalline violet staining was used to detect the proliferation inhibition effect of NL01 in ovarian cancer, western blot and qPCR were used to detect downstream related molecular expression changes, Transwell and survival curve assays were used to detect malignant phenotypic. RESULTS: NL01 inhibited cell growth of Anglne and HO8910PM ovarian cancer cells by 13 times more potent than curcumin and induced ferroptosis of these two cells. we found that NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 pathway. Knock-down HCAR1 expression revealed similar phenotype and pathway alterations to NL01 treatment. HCAR1 overexpression promoted a malignant phenotype and resistance to cisplatin in both cancer cells, whereas knockdown of HCAR1 showed the opposite phenotype. Subcutaneous transplantation tumor experiments in nude mice also showed that NL01 induced iron death and inhibited ovarian cancer proliferation. Further study showed that NL01 promoted the downregulation of GPX4 expression, which is related to ferroptosis, and that addition of ferrostatin-1 partially reversed NL01-mediated inhibition of the growth of two cell lines. CONCLUSION: NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

The Immune Subtypes and Landscape of Advanced-Stage Ovarian Cancer.

Immunotherapy has played a significant role in the treatment of a variety of hematological and solid tumors, but its application in ovarian cancer (OC) remains unclear. This study aimed to identify immune subtypes of OC and delineate an immune landscape for selecting suitable patients for immunotherapy, thereby providing potent therapeutic targets for immunotherapy drug development. Three immune subtypes (IS1-IS3) with distinctive molecular, cellular, and clinical characteristics were identified from the TCGA and GSE32062 cohorts. Compared to IS1, IS3 has a better prognosis and exhibits an immunological "hot". IS3, in contrast, exhibits an immunological "cold" and has a worse prognosis in OC patients. Moreover, gene mutations, immune modulators, CA125, CA199, and HE4 expression, along with sensitivity either to immunotherapy or chemotherapy, were significantly different among the three immune subtypes. The OC immune landscape was highly heterogeneous between individual patients. Poor prognosis was correlated with low expression of the hub genes CD2, CD3D, and CD3E, which could act not only as biomarkers for predicting prognosis, but also as potential immunotherapy targets. Our study elucidates the immunotyping and molecular characteristics of the immune microenvironment in OC, which could provide an effective immunotherapy stratification method for optimally selecting patients, and also has clinical significance for the development of new immunotherapy as well as rational combination strategies for the treatment of OC patients.

Bisphenol F blocks Leydig cell maturation and steroidogenesis in pubertal male rats through suppressing androgen receptor signaling and activating G-protein coupled estrogen receptor 1 (GPER1) signaling.

Bisphenol F (BPF) is a new analog of bisphenol A (BPA). BPA has deleterious effects on the male reproductive system, but the effect of BPF has not been studied in detail. In this study we focus on the effect of BPF on Leydig cell maturation. Male Sprague-Dawley rats were gavaged with 0, 1, 10, or 100 mg/kg BPF from postnatal days 35-56. BPF significantly reduced serum testosterone levels and sperm count in cauda epididymis at dose ≥1 mg/kg. It significantly down-regulated the expression of steroidogenic enzymes, while increasing FSHR and SOX9 levels at 10 and 100 mg/kg. Further studies showed that BPF reduced NR3C4 expression in Leydig and Sertoli cells without affecting its levels in peritubular myoid cells. BPF markedly increased GPER1 in Leydig cells at 100 mg/kg, and it significantly reduced SIRT1 and PGC1α levels in the testes at 100 mg/kg. BPF significantly inhibited testosterone production by immature Leydig cells at 50 µM after 24 h of treatment, which was completely reversed by NR3C4 agonist 7α-methyl-19-nortestosterone and partially reversed by GPER1 antagonist G15 not by ESR1 antagonist ICI 182,780. In conclusion, BPF negatively affects Leydig cell maturation in pubertal male rats through NR3C4 antagonism and GPER1 agonism.

Dysregulated pseudogene BNIP3P1 inhibited cell proliferation and promoted cell apoptosis in preeclampsia by acting as a competing endogenous RNA for BNIP3.

Long noncoding RNAs (lncRNAs) have been reported as critical modulators in many diseases including preeclampsia. Since the association between lncRNA BNIP3P1 and its cognate gene BNIP3 in preeclampsia has been revealed previously, this study aimed to further explore the function and mechanism of BNIP3P1 in preeclampsia. EdU and TUNEL assays revealed that BNIP3P1 or BNIP3 overexpression inhibited trophoblast cell proliferation and enhanced cell apoptosis in preeclampsia. As suggested by western blot analysis, the protein levels of apoptotic markers in the cells were affected by BNIP3P1 or BNIP3 overexpression. The binding between miR-128-3p and BNIP3P1 (or BNIP3) was explored by luciferase reporter assays. Mechanistically, BNIP3P1 bound to miR-128-3p to upregulate BNIP3 expression by acting as a competing endogenous RNA (ceRNA). Importantly, BNIP3P1 was found to inactivate the mTOR signaling pathway. In conclusion, BNIP3P1 inhibited trophoblast cell proliferation and enhanced cell apoptosis in preeclampsia by targeting the miR-128-3p/BNIP3/mTOR signaling pathway.

[A cost-effectiveness analysis of comprehensive rehabilitation treatment of hand burn].

OBJECTIVE: To observe the effect of comprehensive rehabilitation treatment on hand burn, and to make a cost-effectiveness analysis. METHODS: Sixty-two patients with ninety-eight affected hands were divided into rehabilitation group (32 cases, 48 hands) and control group (30 cases, 50 hands). Patients in rehabilitation group received comprehensive rehabilitation treatment at early stage after burn; patients in control group were given instructions for function training at the same time. The functions of the hands to be restored including grasp, hold, pinch, nip, forearm pronation and supination, fetching, laying, and writing abilities of patients in both groups were quantitatively evaluated with Carroll's upper extremity function test before treatment and 5 months after. Direct medical costs of patients in both groups within 5 months were respectively added up to make a cost-effectiveness analysis. RESULTS: In rehabilitation group, function of digital opposition, palmar opposition, holding, and pinching of 37 hands recovered well, with which patients could pick food, put on clothes, go to toilet, and self-care etc. independently. Function of digital opposition, palmar opposition, holding, pinching half recovered in 7 hands, accompanied with well recovered of metacarpophalangeal function, but recovery of function of interphalangeal joint was less satisfactory. Although patients could grasp and hold, they were still poor in fine and harmonized activities. Joint ranges of motion of 4 hands were poor with limited function, and this was resulted from not strictly following treatment for remaining granulation wound. In control group, 23 hands received reconstructive surgery, 14 of them recovered with good function, but were poor in most of fine and harmonized activities. Severe claw hands were found in 13 hands. The ratio between total mean cost value and total function increment value in rehabilitation group (181 +/- 11) was obviously lower than that in control group (298 +/- 30, P < 0.01). CONCLUSIONS: Comprehensive rehabilitation treatment at early stage after hand burn has a good effect on prevention and treatment of hand deformity, promoting recovery of hand function and improving hand appearance. It is also less costly.