Nicaraven protects against endotoxemia-induced inflammation and organ injury through modulation of AMPK/Sirt1 signaling in macrophages.

Endotoxemia is a disease characterized by systemic inflammatory responses and organ injury caused by lipopolysaccharide (LPS) infection, with high mortality. Nicaraven (AVS), a potent hydroxyl radical scavenger, has been proven to regulate the inflammatory response in tumors. To investigate the protective effects and mechanisms of AVS in endotoxemia, mice were injected intraperitoneally with LPS to induce endotoxemia. AVS treatment significantly decreased the levels of pro-inflammatory cytokines in the serum, reduced neutrophil infiltration, attenuated multiple organ injury, and increased the survival rate in LPS-challenged mice. In the LPS-induced inflammatory model of macrophages, AVS inhibited macrophage activation, suppressed nitric oxide (NO) production, and inhibited the expression and secretion of pro-inflammatory cytokines. Mechanistically, AVS treatment up-regulated silence information regulator transcript-1 (Sirt1) expression in a time- and dose-dependent manner. AVS treatment activated the AMP-dependent protein kinase (AMPK)/Sirt1 signaling pathway and suppressed the activation of nuclear factor kappa B (NF-κB) in macrophages exposed to LPS. However, the anti-inflammatory effects of AVS could be reversed by the AMPK, the Sirt1 inhibitor, or the histone deacetylase inhibitor. We confirmed that the AMPK inhibitor inhibited AVS-mediated AMPK/Sirt1 activation and NF-κB p65 acetylation. These results suggested that AVS alleviated endotoxemia by activating the AMPK/Sirt1 signaling pathway in macrophages.

Exosomal microRNA-551b-3p from bone marrow-derived mesenchymal stromal cells inhibits breast cancer progression via regulating TRIM31/Akt signaling.

Mesenchymal stromal cells (MSCs) play an important role in the development of human cancer. Meanwhile, exosomes released by MSCs can mediate cell-cell communication by delivering microRNAs (miRNAs/miRs). Hence, this study aimed to explore the role of bone marrow mesenchymal stromal cell (BMSC)-derived exosomal miR-551b-3p in breast cancer. In this study, we found that upregulation of miR-551b-5p suppressed the proliferation and migration and induced the apoptosis of breast cancer cells via downregulating tripartite motif-containing protein 31 (TRIM31). In addition, miR-551b-5p could be transferred from BMSCs to breast cancer cells via exosomes; BMSC-derived exosomal miR-551b-3p suppressed the proliferation and migration and promoted the apoptosis and oxidative stress of MDA-MB-231 cells via inhibiting TRIM31. Furthermore, a xenograft mouse model was used to explore the role of BMSC-derived exosomal miR-551b-3p in vivo. We found that BMSC-derived exosomal miR-551b-3p inhibited tumor growth in a mouse xenograft model of breast cancer in vivo. Collectively, these findings indicated that BMSC-derived exosomal miR-551b-3p could suppress the development of breast cancer via downregulating TRIM31. Thus, miR-551b-3p could serve as a potential target for the treatment of breast cancer.

Oncofertility Knowledge and Communication: Comparison Between Medical and Surgical Oncologists and Breast Cancer Patients in Academic Chinese Centers.

Background: As cancer has become a major public health issue in China, fertility preservation remains limited despite the wide application of Assisted Reproductive Technology (ART) throughout the country. Objective: This study aimed to identify gaps in knowledge and communication as well as referrals in the previous year regarding oncofertility among medical and surgical oncologists and breast cancer patients (BCPs) in Chinese academic settings to target areas of needed improvement. Materials and Methods: A WeChat online questionnaire was designed, distributed, and compared between medical and surgical oncology specialists and reproductive age BCPs in academic teaching settings in Shanghai. Results: Sixty-one medical and surgical oncologists and 125 BCPs responded to the survey. 63.3% of oncologists were familiar with the term "oncofertility" compared to 25.6% of BCPs (p < 0.001). Oncologists were more likely to correctly know the costs associated with treatment (59.0 vs. 32.0%, p < 0.001); patient did not have to be married to undergo oncofertility treatment (50.8 vs. 24.8%, p < 0.001). Both oncologists and BCPs were similarly unlikely to know when patients could utilize cryopreserved tissue in the future (37.7 vs. 22.2%, p = 0.056). While oncologists reported they discussed all oncofertility options (41.0%) and offered psychological counseling (98.4%), significantly fewer BCPs reported receiving information on all options and offered counseling (3.2%, p < 0.001 and 85.6%, p < 0.01). Knowledge of oncofertility was the most important predictor for providing and receiving counseling from oncologists [OR = 6.44 (95% CI = 1.59-26.1, p = 0.009] and BCPs (OR = 3.73 95% CI: = 1.36-10.2, p = 0.011). Overall, 57.4% of oncologists referred <10 patients and none referred more than 25 patients in the past year. Conclusion: Data suggests a significant knowledge gap and ineffective communication/comprehension exists between academic Chinese oncologists and BCPs. Continued education and raised awareness are needed to optimize utilization of oncofertility services in China.

Hypoxia in Breast Cancer-Scientific Translation to Therapeutic and Diagnostic Clinical Applications.

Breast cancer has been the leading cause of female cancer deaths for decades. Intratumoral hypoxia, mainly caused by structural and functional abnormalities in microvasculature, is often associated with a more aggressive phenotype, increased risk of metastasis and resistance to anti-malignancy treatments. The response of cancer cells to hypoxia is ascribed to hypoxia-inducible factors (HIFs) that activate the transcription of a large battery of genes encoding proteins promoting primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, cell motility, local tissue invasion, metastasis, and maintenance of the cancer stem cell properties. In this review, we summarized the role of hypoxia specifically in breast cancer, discuss the prognostic and predictive value of hypoxia factors, potential links of hypoxia and endocrine resistance, cancer hypoxia measurements, further involved mechanisms, clinical application of hypoxia-related treatments and open questions.

The Clinical Relevance and Function of Krüppel-Like Factor 16 in Breast Cancer.

BACKGROUND: Krüppel-like factor 16 (KLF16), a member of the KLF family, is involved in metabolism and regulation of the endocrine system and has emerging roles in tumor progression. However, the expression of KLF16 and its role in breast cancer are elusive. METHODS: We investigated the expression and prognostic value of KLFs in breast cancer using data acquired from the TCGA BRCA dataset and the Kaplan-Meier plotter dataset. The protein levels of KLF16 in breast specimens were detected by immunohistochemistry (IHC). KLF16 silencing using shRNAs was performed to explore the effects of KLF16 on breast cancer cell growth, migration, and invasion. The expression of EMT markers in cells manipulated for KLF16 expression was assessed by Western blotting. RESULTS: Using publicly available dataset and specimens from breast cancer patients, we found that the expression levels of KLF16 were significantly higher in tumor tissues and that high levels of KLF16 were associated with poor prognosis in breast cancer patients. Moreover, KLF16 expression levels had relation to several clinicopathological parameters of breast cancer, including the molecular subtype and histological grade. Importantly, knockdown of KLF16 dramatically suppressed cell proliferation both in vitro and in vivo. Also, KLF16 deletion impaired migration, and invasion in breast cancer cells, and suppressed epithelial-mesenchymal transition (EMT). CONCLUSION: Our results suggest that KLF16 has important oncogenic functions in breast cancer and that the expression levels of KLF16 are associated with prognosis in breast cancer patients. Our findings also suggest that KLF16 is involved in proliferation, migration, and invasion in breast cancer cells. Thus, KLF16 might be a promising prognostic marker and a therapeutic target for breast cancer.

Asiatic acid suppresses neuroinflammation in BV2 microglia via modulation of the Sirt1/NF-κB signaling pathway.

Asiatic acid, a triterpenoid derived from Centella asiatica, has been found to exhibit multiple bioactivities. In this study, we investigated the effects of asiatic acid on lipopolysaccharide (LPS)-induced neuroinflammation and explored the mechanism of its action in BV2 microglia. We found that asiatic acid (0.1 to 100 µM) treatment significantly attenuated nitric oxide (NO) production and inhibited inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner following LPS exposure. Asiatic acid reduced LPS-induced expression and secretion of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in BV2 cells. In addition, asiatic acid enhanced Sirt1 expression, reduced NF-κB p65 acetylation, and suppressed NF-κB activation after LPS stimulation. However, EX-527, an inhibitor of Sirt1, abolished the inhibitory effects of asiatic acid on LPS-stimulated microglia activation. These findings suggest that asiatic acid prevents LPS-induced neuroinflammation via regulating the Sirt1/NF-κB signaling pathway.