The Efficacy and Safety of an Intra-articular Dual-Acting Antibacterial Agent (TNP-2092) for Implant Infection-Associated Methicillin-Resistant Staphylococcus aureus.

Owing to the presence of microbial biofilm on the implant, the eradication of biofilm-associated infections poses a challenge for antibiotic therapies. The study aimed to investigate the efficacy and safety of the novel antibiotic agent TNP-2092 in the context of implant infections. In vivo, rats with periprosthetic joint infection (PJI) treated with antibiotics showed an increase in body weight and decrease in swelling, temperature, and width of knee, compared with the control group. Meanwhile, inflammatory markers in synovium and serum were decreased in the TNP-2092 group, consistent with the pathological results. Moreover, TNP-2092 was effective in eliminating bacteria and disruption biofilm formation, and further alleviated the abnormal bone absorption and reactive bone changes around the prosthesis. In conclusion, intra-articular injection of TNP-2092 is safe and effective in treating knee PJI in a rat model. The study provides a foundation for the future utilization of TNP-2092 in the management of implant-related infections.

Current Status of Tissue Regenerative Engineering for the Treatment of Uterine Infertility.

With the recent developments in tissue engineering, scientists have attempted to establish seed cells from different sources, create cell sheets through various technologies, implant them on scaffolds with various spatial structures, or load scaffolds with cytokines. These research results are very optimistic, bringing hope to the treatment of patients with uterine infertility. In this article, we reviewed articles related to the treatment of uterine infertility from the aspects of experimental treatment strategy, seed cells, scaffold application, and repair criteria so as to provide a basis for future research.

Mitochondrial protein LETM1 and its-mediated CTMP are potential therapeutic targets for endometrial cancer.

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an important mitochondrial protein, while its function in endometrial cancer remains unknown. This study aimed to explore the function of LETM1 in endometrial cancer and reveal the underlying mechanisms involving carboxy-terminal modulator protein (CTMP). Immunohistochemistry was performed to detect the expression of LETM1 and CTMP in normal, atypical hyperplastic and endometrial cancer endometrial tissues. LETM1 and CTMP were silenced in two endometrial cancer cell lines (ISK and KLE), which were verified by western blot. Cell viability, colony number, migration and invasion were detected by cell counting kit-8, colony formation, wound healing and trans-well assays, respectively. A xenograft mouse model was established to determine the antitumor potential of LETM1/CTMP silencing in vivo . In addition, CTMP was overexpressed to evaluate its regulatory relationship with LETM1 in endometrial cancer cells. The expression of LETM1 and CTMP proteins were higher in endometrial cancer tissues than atypical hyperplastic tissues and were higher in atypical hyperplastic tissues than normal tissues. LETM1 and CTMP were also upregulated in ISK and KLE cells. Silencing of LETM1 or CTMP could decrease the viability, colony number, migration and invasion of endometrial cancer cells and the weight and volume of tumor xenografts. In addition, CTMP was downregulated by LETM1 silencing in KLE cells, and its overexpression enhanced the malignant characteristics of si-LETM1-transfected KLE cells. Silencing of LETM1 inhibits the malignant progression of endometrial cancer through downregulating CTMP.

In Vivo Studies of Mesenchymal Stem Cells in the Treatment of Meniscus Injury.

This review summarizes the literature of preclinical studies and clinical trials on the use of mesenchymal stem cells (MSCs) to treat meniscus injury and promote its repair and regeneration and provide guidance for future clinical research. Due to the special anatomical features of the meniscus, conservative or surgical treatment can hardly achieve complete physiological and histological repair. As a new method, stem cells promote meniscus regeneration in preclinical research and human preliminary research. We expect that, in the near future, in vivo injection of stem cells to promote meniscus repair can be used as a new treatment model in clinical treatment. The treatment of animal meniscus injury, and the clinical trial of human meniscus injury has begun preliminary exploration. As for the animal experiments, most models of meniscus injury are too simple, which can hardly simulate the complexity of actual meniscal tears, and since the follow-up often lasts for only 4-12 weeks, long-term results could not be observed. Lastly, animal models failed to simulate the actual stress environment faced by the meniscus, so it needs to be further studied if regenerated meniscus has similar anti-stress or anti-twist features. Despite these limitations, repair of the meniscus by MSCs has great potential in clinics. MSCs can differentiate into fibrous chondrocytes, which can possibly repair the meniscus and provide a new strategy for repairing meniscus injury.

The miRNA mir-582-3p suppresses ovarian cancer progression by targeting AKT/MTOR signaling via lncRNA TUG1.

Ovarian cancer (OC) is one of the most common malignancies of the female reproductive system. The miRNA miR-582-3p is associated with a variety of tumors, and the aim of this study was to investigate the role and mechanisms of miR-582-3p specifically in ovarian carcinogenesis and progression. Low expression of miR-582-3p was noted in OC tissue and cell lines, and lower expression of miR-582-3p correlated with lower overall survival in OC patients. Knockdown of miR-582-3p promoted the proliferation and migration of OC cells, while overexpression inhibited them. TUG1, a long non-coding RNA, was found to bind to miR-582-3p, and inhibition of lncRNA TUG1 decreased viability and migration and weakened the effect of miR-582-3p knockdown in OC cells. Implantation of OC cells with reduced miR-582-3p caused increased tumor growth, while lncRNA TUG1 knockdown suppressed tumor growth and relieved the impact of reduced miR-582-3p in vivo. Phosphorylation of AKT and mTOR were significantly enhanced with decreased miR-582-3p expression, but lncRNA TUG1 knockdown attenuated this trend in vitro and in vivo. The novel miR-582-3p represses the malignant properties of OC via the AKT/mTOR signaling pathway by targeting lncRNA TUG1. This axis may represent valuable prognostic biomarkers and therapeutic targets for OC.

Cisplatin remodels the tumor immune microenvironment via the transcription factor EB in ovarian cancer.

The mortality rate of ovarian cancer (OC) remains the highest among all gynecological malignancies. Platinum-based chemotherapies are effective in treating most OC cases. However, chemoresistance is still a major challenge for successful OC treatments. Emerging evidence has highlighted that the modulation of the tumor immune microenvironment is involved in chemoresistance, but the mechanism remains unclear. This study aimed to investigate whether resistance to cisplatin (CDDP), the standard treatment for OC, is due to the remodeling of the tumor immune microenvironment by the transcription factor EB (TFEB). We hypothesized that TFEB is not essential for tumor survival but is associated with CDDP resistance. We collected 20 tissue samples of OC patients who had not undergone chemotherapy or radiotherapy prior to surgery. We cultured OC cell lines and performed cell transfection and assays as well as analytical, fluorescence microscopy, and immunohistochemical techniques to explore a novel function of TFEB in remodeling the tumor immune microenvironment in OC. We found a positive correlation between TFEB and programmed cell death-ligand 1 (PD-L1), PD-L2, and HLA-A expression in OC cells and tissues. We also found that CDDP treatment induced TFEB nuclear translocation, thus increasing PD-L1 and PD-L2 expression to foster an immunosuppressive tumor microenvironment, which mediates tumor immune evasion and drug resistance. Interestingly, TFEB also regulated HLA-A expression, which increases the tumor immunogenicity of OC. Finally, in a syngenic murine model of OC, we observed the therapeutic benefit of CDDP plus programmed cell death-1 (PD-1) inhibitor, which enhanced the cytolytic activity of CD8+ T cells and inhibited tumor growth. Our study illustrates the important role of TFEB in regulating the tumor immune microenvironment in OC.

Alantolactone inhibits cervical cancer progression by downregulating BMI1.

Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer.

BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells.

BI2536 is a highly selective and potent inhibitor of polo-like kinase 1 (PLK1). In this study, we aimed to determine whether BI2536 and cisplatin can synergistically inhibit the malignant behavior of gastric cancer cells. For this purpose, the expression of PLK1 in gastric cancer cells was determined. The effects of BI2536, cisplatin, and the combination of BI2536 and cisplatin on gastric cancer cell viability, invasion, cell cycle arrest and apoptosis were assessed. Furthermore, the expression of cell cycle-regulated proteins was examined. Moreover, the differentially expressed proteins between the SGC-7901 and SGC-7901/DDP (cisplatin-resistant) cells, and the enriched signaling pathways were analyzed by protein pathway array following treatment with BI2536 (IC50) for 48 h. Our results revealed that PLK1 was upregulated in the SGC-7901/DDP (cisplatin-resistant) gastric cancer cells compared with the SGC-7901 cells. BI2536 enhanced the inhibitory effect of cisplatin on SGC-7901 cell viability and invasion. BI2536 induced G2/M arrest in SGC-7901 and SGC-7901/DDP cells. BI2536 promoted cisplatin-induced gastric cancer SGC-7901/DDP cell apoptosis. It also induced the differential expression of 68 proteins between the SGC-7901 and SGC-7901/DDP cells, and these differentially expressed proteins were involved in a number of cellular functions and signaling pathways, such as cell death, cell development, tumorigenesis, the cell cycle, DNA duplication/recombination/repair, cellular movement, and the Wnt/ß-catenin and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)/ribosomal S6 kinase 1 (RSK1) signaling pathways. On the whole, our findings suggest that BI2536 and cisplatin synergistically inhibit the malignant behavior of SGC-7901/DDP (cisplatin­resistant) gastric cancer cells.