MIOX inhibits autophagy to regulate the ROS -driven inhibition of STAT3/c-Myc-mediated epithelial-mesenchymal transition in clear cell renal cell carcinoma.

The specific mechanism of clear cell renal cell carcinoma (ccRCC) progression, a pathological type that accounts for the highest proportion of RCC, remains unclear. In this study, bioinformatics analysis of scRNA-seq dataset in ccRCC revealed that MIOX was a gene specifically down-regulated in tumor epithelial cells of ccRCC. Analysis of the TCGA database further validated the association between decreased MIOX mRNA levels and ccRCC malignant phenotype and poor prognosis. Immunohistochemistry indicated the down-regulation of MIOX in ccRCC tissues compared to paired adjacent renal tissues, with further down-regulation of MIOX in the primary tumors of patients with primary metastasis compared to those without metastasis. Also, patients with low expression of MIOX showed shorter metastasis-free survival (MFS) compared to those with high MIOX expression. In vitro results showed that overexpression of MIOX in ccRCC cells inhibited the proliferation, migration and invasion and promoted apoptosis. Mechanistically, up-regulation of MIOX inhibited autophagy to elevate the levels of ROS, and thus suppressed STAT3/c-Myc-mediated epithelial-mesenchymal transition in ccRCC cells. In vivo data further confirmed that increased MIOX expression suppressed the growth and proliferation of RCC cells and reduced the ability of RCC cells to form metastases in the lung. This study demonstrates that MIOX is an important regulatory molecule of ccRCC, which is conducive to understanding the potential molecular mechanism of ccRCC progression.

Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer.

Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-ß, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor.

ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN-γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.

Reactive Oxygen Species- and Cell-Free DNA-Scavenging Mn3O4 Nanozymes for Acute Kidney Injury Therapy.

Reactive oxygen species (ROS) scavenging therapy toward acute kidney injury (AKI) is promising, but no effective ROS scavenging drug has been developed yet. Moreover, cell-free DNA (cfDNA) is also involved in AKI, but the corresponding therapies have not been well developed. To tackle these challenges, Mn3O4 nanoflowers (Nfs) possessing both ROS and cfDNA scavenging activities were developed for better AKI protection as follows. First, Mn3O4 Nfs could protect HK2 cells through cascade ROS scavenging (dismutating ·O2- into H2O2 by superoxide dismutase-like activity and then decomposing H2O2 by catalase-like activity). Second, Mn3O4 Nfs could efficiently adsorb cfDNA and then decrease the inflammation caused by cfDNA. Combined, remarkable therapeutic efficacy was achieved in both cisplatin-induced and ischemia-reperfusion AKI murine models. Furthermore, Mn3O4 Nfs could be used for the T1-MRI real-time imaging of AKI. This study not only offered a promising treatment for AKI but also showed the translational potential of nanozymes.

Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis.

BACKGROUND: Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. METHODS: Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. RESULTS: Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. CONCLUSIONS: This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.

circDHTKD1 promotes lymphatic metastasis of bladder cancer by upregulating CXCL5.

Lymph node (LN) metastasis is associated with unfavorable prognosis of bladder cancer (BCa). Although lymphangiogenesis is functionally important in LN metastasis of tumors, the potential mechanism in BCa remains unclear. Here, we clarified a regulatory mechanism of circRNA-mediated lymphangiogenesis and LN metastasis in BCa based on next-generation sequencing data. We revealed that circDHTKD1 was positively associated with LN metastasis and significantly upregulated in BCa. By analyzing the co-expression patterns of circDHTKD1 and differentially expressed mRNAs, we identified that circDHTKD1 facilitated lymphangiogenesis by upregulating CXCL5. Mechanistically, circDHTKD1 directly interacted with miR-149-5p, and antagonized the repression of miR-149-5p on CXCL5. Furthermore, circDHTKD1-induced CXCL5 expression recruited and activated neutrophils, which participated in lymphangiogenesis by secreting VEGF-C. Our study supports circDHTKD1 as a promising diagnostic and therapeutic target for LN metastasis in BCa.

Design of a Controlled-Release Delivery Composite of Antibacterial Agent Gatifloxacin by Spherical Silica Nanocarrier.

In this study, a spherical silica nanoparticle was explored as a gatifloxacin carrier synthesized by the chemical precipitation method. It was found that there was no new chemical bond formation during the loading process between gatifloxacin and silica, which implies that the binding was driven by physical interaction. In addition, the drug loading and encapsulation efficiency could be improved by appropriately increasing nano-silica content in the loading process. Meanwhile, the release rate of gatifloxacin after loading nano-silica was also improved, suggesting the successful design of a controlled-release delivery composite. The silica nanocarrier could significantly improve the antibacterial performance of Escherichia coli by 2.1 times, which was higher than the pure gatifloxacin. The 24 h bacteriostatic rate was higher than that of a simple mixture of silica nanoparticles and gatifloxacin. Strong reactive oxygen species (ROS) in GAT-SiO2 NPs suggests that ROS might be associated with bactericidal activity. The synergy between the physicochemical effect and ROS production of this material is proposed as the mechanism of its antibacterial activity, which can also be confirmed by the cell membrane damage observed under electron microscopy and DNA damage experiments. Collectively, our finding indicates that nano-silica microspheres could serve as a promising carrier for the sustained release of gatifloxacin, thereby providing a new carrier design scheme for the improvement of the antibacterial effect.

The role of sex and femininity in preferences for unfamiliar infants among Chinese adults.

Guided by parental investment theory and social role theory, this study aimed to understand current contradictory results regarding sex differences in response to infant faces by considering the effect of gender role orientation. We recruited 300 adults in China and asked them to complete an Interest in Infants questionnaire and a Bem Sex Role Inventory and then administered a behavioral assessment that used unfamiliar infant faces with varying expressions (laughing, neutral, and crying) as stimuli to gauge three components of motivation towards infants (i.e., liking, representational responding, and evoked responding). The results demonstrated that sex differences emerged only in self-reported interest in infants, but no difference was found between the sexes in terms of their hedonic reactions to infant faces. Furthermore, femininity was found to correlate with preferences for infants in both verbal and visual tests, but significant interactive effects of feminine traits and sex were found only in the behavioral test. The findings indicated that men's responses to infants were influenced more by their feminine traits than were women's responses, potentially explaining the greater extent to which paternal (vs. maternal) investment is facultative.

Alleviating effects of noni fruit polysaccharide on hepatic oxidative stress and inflammation in rats under a high-fat diet and its possible mechanisms.

Non-alcoholic fatty liver disease is associated with gut microbiota, oxidative stress, and inflammation. We aimed to investigate the possible mechanism by which noni fruit polysaccharide (NFP) improved hepatic oxidative stress and inflammation in rats under a high-fat diet (HFD) by modulating short-chain fatty acids (SCFAs), the intestinal barrier, and gut microbiota. Hepatic oxidative stress, inflammation, and gut dysbiosis in rats were induced through HFD feeding for 4 weeks, followed by intervention with NFP treatment (100 mg per kg bw) for 5 weeks. The results showed that NFP reduced body weight gain and improved lipid metabolism, hepatic oxidative stress, and inflammation in rats under a HFD. Aside from these beneficial effects, NFP positively affected the SCFA production and reversed the HFD-induced gut dysbiosis as indicated by improved microbiota diversity and composition. The levels of Lactobacillus, Ruminococcaceae_UCG_014, Parasutterella, [Eubacterium]_coprostanoligenes_group, and Ruminococcus_1 improved, whereas the levels of Prevotella_9, Collinsella, Bacteroides, and Turicibacter decreased. Furthermore, NFP maintained the colonic barrier integrity (increased the mRNA relative expression of CCL5, ZO-1, and occludin in the colon, and decreased the serum CCL5 level), and decreased the serum lipopolysaccharide level. Thus, NFP may modulate the gut microflora and SCFA production and reduce the permeability of the colonic barrier and metabolic endotoxemia, thereby alleviating hepatic oxidative stress and inflammation in rats under a HFD.

Bystander Attitudes to Prevent Sexual Assault: A Study of College Students in the United States, Japan, India, Vietnam, and China.

College women are at a high risk of sexual assault. Although programs that aim to change bystander behaviors have been shown to be potentially effective in preventing sexual assault on campuses in the United States, little is known about bystander behaviors outside of the United States. The purpose of this study was to explore and compare factors affecting bystander behaviors regarding sexual assault intervention and prevention among undergraduate students in the United States, Japan, India, Vietnam, and China. A total of 1,136 students participated in a self-reported survey. Results demonstrate substantial variations across countries. Bystander behaviors are associated with multilevel factors, including gender, knowledge of individuals who have experienced a sexual assault, and knowledge about campus or community organizations.

Knowledge and perceptions of breast health among free clinic patients.

BACKGROUND: Breast cancer is a significant women's health problem in the United States. However, critical information on specific populations is still lacking. In particular, it is not well known how free clinic patients perceive breast health. The purpose of this study was to assess knowledge and perceptions of breast health among uninsured women utilizing a free clinic that serves as a safety net for the underserved. METHODS: A self-administrated survey that included knowledge and perceptions of breast health was conducted for female free clinic patients aged 40 or older in fall 2012. There were 146 participants. The participants were classified into three groups for comparison; U.S. citizen English speakers, non-U.S. citizen English speakers, and Spanish speakers. RESULTS: Spanish speakers had the highest average score on the knowledge of breast health, whereas the non-U.S. citizen English speakers had the lowest average score. Free clinic patients may consider breast health screening if recommended by health care providers. The non-U.S. citizen English speakers and Spanish speakers were more likely to have negative perceptions of breast health compared with the U.S. citizen English speakers. CONCLUSIONS: Promoting knowledge about breast health is important for free clinics. Recommendation by a health care provider is a key to increasing attendance at health education programs and breast health screening. Non-U.S. citizens and non-English speakers would need culturally competent interventions. Free clinics have limited human and financial resources. Such characteristics of free clinics should be considered for practice implementations.