The Bifunctional Effects of Lactoferrin (LFcinB11) in Inhibiting Neural Cell Adhesive Molecule (NCAM) Polysialylation and the Release of Neutrophil Extracellular Traps (NETs).

The expression of polysialic acid (polySia) on the neuronal cell adhesion molecule (NCAM) is called NCAM-polysialylation, which is strongly related to the migration and invasion of tumor cells and aggressive clinical status. Thus, it is important to select a proper drug to block tumor cell migration during clinical treatment. In this study, we proposed that lactoferrin (LFcinB11) may be a better candidate for inhibiting NCAM polysialylation when compared with CMP and low-molecular-weight heparin (LMWH), which were determined based on our NMR studies. Furthermore, neutrophil extracellular traps (NETs) represent the most dramatic stage in the cell death process, and the release of NETs is related to the pathogenesis of autoimmune and inflammatory disorders, with proposed involvement in glomerulonephritis, chronic lung disease, sepsis, and vascular disorders. In this study, the molecular mechanisms involved in the inhibition of NET release using LFcinB11 as an inhibitor were also determined. Based on these results, LFcinB11 is proposed as being a bifunctional inhibitor for inhibiting both NCAM polysialylation and the release of NETs.

Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.

Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.

Angiotoxic effects of chlorinated polyfluorinated ether sulfonate, a novel perfluorooctane sulfonate substitute, in vivo and in vitro.

Chlorinated polyfluorinated ether sulfonate (Cl-PFESA), a substitute for perfluorooctane sulfonate (PFOS), has been widely used in the Chinese electroplating industry under the trade name F-53B. The production and use of F-53B is keep increasing in recent years, consequently causing more emissions into the environment. Thus, there is a growing concern about the adverse effects of F-53B on human health. However, related research is very limited, particularly in terms of its toxicity to the vascular system. In this study, C57BL/6 J mice were exposed to 0.04, 0.2, and 1 mg/kg F-53B for 12 weeks to assess its impact on the vascular system. We found that F-53B exposure caused aortic wall thickening, collagen deposition, and reduced elasticity in mice. In addition, F-53B exposure led to a loss of vascular endothelial integrity and a vascular inflammatory response. Intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were found to be indispensable for this process. Furthermore, RNA sequencing analysis revealed that F-53B can decrease the repair capacity of endothelial cells by inhibiting their proliferation and migration. Collectively, our findings demonstrate that F-53B exposure induces vascular inflammation and loss of endothelial integrity as well as suppresses the repair capacity of endothelial cells, which ultimately results in vascular injury, highlighting the need for a more thorough risk assessment of F-53B to human health.

Role of Contrast-Enhanced Ultrasound With the Enhancement Pattern and Qualitative Analysis for Differentiating Hypovascular Solid Renal Lesions.

OBJECTIVE: The aim of the work described here was to explore the clinical value of contrast-enhanced ultrasound (CEUS) with the enhancement pattern and qualitative analysis in distinguishing different types of hypovascular solid renal lesions. METHODS: A total of 140 patients with 140 renal tumors (all diagnosed by pathology), which manifested hypo-enhancement on CEUS, were included in this study. We compared conventional ultrasound (US) and CEUS features in five common hypovascular renal tumors, including renal angiomyolipoma (RAML), clear cell renal cell carcinoma (ccRCC), renal pelvic urothelial carcinoma (RPUC), papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC). The diagnostic value of conventional US and qualitative parameters of CEUS for differentiating hypovascular solid renal lesions were evaluated. RESULTS: The mean age of patients with a benign renal lesion was younger than that of patients with a malignant renal lesion (p < 0.05). Echogenicity and qualitative parameters such as wash-out, perfusion defects and perilesional rim-like enhancement (PRE) in the two groups differed significantly (all p values <0.05). Benign renal lesions exhibited mainly slow wash-out, whereas malignant renal lesions exhibited predominantly fast wash-out on CEUS (p < 0.05). There were significant differences in echogenicity, such as between RAML and ccRCC, between RAML and RPUC and between RAML and pRCC (all p values <0.05). The rates of appearance of perfusion defect in ccRCC (48%, 13/27) and pRCC (53%, 10/19) were significantly higher than the rate in RAML (14%, 6/43) (p < 0.05). The rates of appearance of PRE in ccRCC (15%, 4/27), pRCC (26%, 5/19) and chRCC (24%,4/17) were significantly higher than the rate in RAML (9%, 4/43) (p < 0.05). CONCLUSION: CEUS with the enhancement pattern and qualitative analysis may be helpful in distinguishing malignant from benign hypovascular renal lesions.

The NMR studies of CMP inhibition of polysialylation.

The overexpression of polysialic acid (polySia) on neural cell adhesion molecules (NCAM) promotes hypersialylation, and thus benefits cancer cell migration and invasion. It has been proposed that the binding between the polysialyltransferase domain (PSTD) and CMP-Sia needs to be inhibited in order to block the effects of hypersialylation. In this study, CMP was confirmed to be a competitive inhibitor of polysialyltransferases (polySTs) in the presence of CMP-Sia and triSia (oligosialic acid trimer) based on the interactional features between molecules. The further NMR analysis suggested that polysialylation could be partially inhibited when CMP-Sia and polySia co-exist in solution. In addition, an unexpecting finding is that CMP-Sia plays a role in reducing the gathering extent of polySia chains on the PSTD, and may benefit for the inhibition of polysialylation. The findings in this study may provide new insight into the optimal design of the drug and inhibitor for cancer treatment.

Tandem oxidative and thermal cracking of polypropylene at low temperatures.

Polypropylene waste was upcycled into terminal functionalized long-chain chemicals with the aid of anionic surfactants. The reaction only needs to be heated at 80 °C for 5 min by coupling exothermic oxidative cracking with endothermic thermal cracking. This work opens a new way to rapidly convert plastic waste into high-value-added chemicals under mild conditions.

Identification of faecal extracellular vesicles as novel biomarkers for the non-invasive diagnosis and prognosis of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies that is usually detected late in the clinic. The currently available diagnostic tools for CRC are either invasive or insensitive to early lesions due to the dearth of reliable biomarkers. In this study, we discovered that the extracellular vesicles (EVs) in the faeces of CRC patients can act as a potent biomarker for the non-invasive diagnosis and prognosis of CRC. This finding is based on the identification of two transmembrane proteins-CD147 and A33-on faeces-derived EVs (fEVs) that are intrinsically associated with CRC. The detection results show that the levels of CD147 and A33 on fEVs were upregulated in the CRC patients (n = 48), dramatically distinguishing them from the healthy donors (n = 16). The CD147/A33-enriched EVs offer a clinical sensitivity of 89%, much higher than that (40%) of carcinoembryonic antigen (CEA), a clinically-established serum biomarker for CRC diagnosis. In addition, the analysis of longitudinal faeces samples (n = 29) demonstrated that the CD147/A33-enriched fEVs can be utilized to track the prognosis of CRC. Due to the high compliance of faeces-based detection, the CD147/A33-enriched fEVs could serve as new-generation CRC biomarkers for large-scale, non-invasive CRC screening as well as real-time monitoring of patient outcomes during clinical interventions.

EPSTI1 promotes monocyte adhesion to endothelial cells in vitro via upregulating VCAM-1 and ICAM-1 expression.

Atherosclerosis is a chronic inflammatory disease of arterial wall, and circulating monocyte adhesion to endothelial cells is a crucial step in the pathogenesis of atherosclerosis. Epithelial-stromal interaction 1 (EPSTI1) is a novel gene, which is dramatically induced by epithelial-stromal interaction in human breast cancer. EPSTI1 expression is not only restricted to the breast but also in other normal tissues. In this study we investigated the role of EPSTI1 in monocyte-endothelial cell adhesion and its expression pattern in atherosclerotic plaques. We showed that EPSTI1 was dramatically upregulated in human and mouse atherosclerotic plaques when compared with normal arteries. In addition, the expression of EPSTI1 in endothelial cells of human and mouse atherosclerotic plaques is significantly higher than that of the normal arteries. Furthermore, we demonstrated that EPSTI1 promoted human monocytic THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs) via upregulating VCAM-1 and ICAM-1 expression in HUVECs. Treatment with LPS (100, 500, 1000 ng/mL) induced EPSTI1 expression in HUVECs at both mRNA and protein levels in a dose- and time-dependent manner. Knockdown of EPSTI1 significantly inhibited LPS-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. Moreover, we revealed that LPS induced EPSTI1 expression through p65 nuclear translocation. Thus, we conclude that EPSTI1 promotes THP-1 cell adhesion to endothelial cells by upregulating VCAM-1 and ICAM-1 expression, implying its potential role in the development of atherosclerosis.

Association between rs735482 polymorphism and risk of cancer: A meta-analysis of 10 case-control studies.

Several studies have inspected the relationship between rs735482 polymorphism and the risk of some human cancers, but the findings remain controversial. We designed this meta-analysis to validate the association between rs735482 polymorphism and cancer risk. All articles were published before September 1, 2018 and searched in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang, and Chinese BioMedical databases, STATA 12.0 software was used for statistical analysis, which provides reasonable data and technical support for this article. A total of 10 studies were included in the meta-analysis, including 2652 cancer cases and 3536 rs735482 polymorphic controls. Data were directly extracted from these studies and odds ratios with 95% confidence intervals were computed to estimate the strength of the association. By pooling all eligible studies, the rs735482 polymorphism showed no significant association with susceptibility of several cancers in all the five genetic models (the allelic model: OR = 1.019, 95% CI: 0.916-1.134, P = .731). In addition, another adjusted OR data showed a significant increased risk between the rs735482 and susceptibility of several cancers (the codominant model BB vs AA: OR = 1.353, 95% CI: 1.033-1.774, P = .028) and the stratification analysis by ethnicity indicated the rs735482 is associated with an increased risk of cancer in Chinese group (BB vs AA, OR = 1.391, 95% CI = 1.054-1.837, P = .020; AB+BB vs AA OR = 1.253, 95% CI = 1.011-1.551, P = .039). However, the ERCC1 rs735482 is associated with a decreased risk of cancer in Italian group (AB vs AA, OR = 0.600, 95% CI = 0.402-0.859, P = .012; AB + BB vs AA, OR = 0.620, 95% CI = 0.424-0.908, P = .014). The results of this meta-analysis do not support the association between rs735482 polymorphism and cancer risk. But stratified analysis showed that rs735482 significantly increased the risk of cancer in Chinese while decreased the risk of cancer in Italian. Because of the limited number of samples, larger and well-designed researches are needed to estimate this association in detail.

Stimuli-Mediated Specific Isolation of Exosomes from Blood Plasma for High-Throughput Profiling of Cancer Biomarkers.

Exosomes, ranging from 30-150 nm in diameter, have emerged as promising non-invasive biomarkers for the diagnosis and prognosis of numerous diseases. However, current research on exosomes is largely restricted by the lack of an efficient method to isolate exosomes from real samples. Herein, the first stimuli-mediated enrichment and purification system to selectively and efficiently extract exosomes from clinical plasma for high-throughput profiling of exosomal mRNAs as cancer biomarkers is presented. This novel isolation system relies on specific installation of the stimuli-responsive copolymers onto exosomal phospholipid bilayers, by which the enrichment and purification are exclusively achieved for exosomes rather than the non-vesicle counterparts co-existing in real samples. The stimuli-mediated isolation system outperforms conventional methods such as ultracentrifugation and polyethylene glycol-based precipitation in terms of isolation yield, purity, and retained bioactivity. The high performance of the isolation system is demonstrated by enriching exosomes from 77 blood plasma samples and validated the clinical potentials in profiling exosomal mRNAs for cancer diagnosis and discrimination with high accuracy. This simple isolation system can boost the development of extracellular vesicle research, not limited to exosomes, in both basic and clinical settings.

Long non-coding RNA ACTA2-AS1 inhibits the cisplatin resistance of non-small cell lung cancer cells through inhibiting autophagy by suppressing TSC2.

Long non-coding RNA (lncRNA) ACTA2-AS1 has been reported to play an important role in the progression of multiple human malignancies. The article aims to explore the role of ACTA2-AS1 on the cisplatin resistance of non-small cell lung cancer (NSCLC). RT-qPCR was performed to investigate the expression of ACTA2-AS1 in cisplatin-resistant NSCLC cell lines. Western blot was used to investigate the effects of ACTA2-AS1 on autophagy-related protein expression. RIP assay and RNA pull down were used to analyze the combination of ACTA2-AS1 and enhancer of zeste homolog 2 (EZH2), and CHIP was used to analyze the combination of tuberous sclerosis complex-2 (TSC2) gene promoter and Lys-27 of histone H3 (H3K27me3). In this study, ACTA2-AS1 was downregulated in cisplatin-resistant NSCLC cell lines. ACTA2-AS1 negatively regulated the cell viability and positively regulated the cell apoptosis of cisplatin-resistant NSCLC cell lines. Furthermore, our results demonstrated that ACTA2-AS1 promoted cisplatin-resistant NSCLC cells apoptosis through inhibiting autophagy. The regulation of ACTA2-AS1 to the cisplatin-resistant NSCLC cell autophagy was reversed by TSC2 increasing. Importantly, our results displayed that ACTA2-AS1 bound with EZH2, and TSC2 gene promoter combined with H3k27me3. The inhibition of ACTA2-AS1 to TSC2 expression was recused by EZH2 silencing. In conclusion, ACTA2-AS1 inhibited the cisplatin resistances of NSCLC cell lines through suppressing TSC2 expressing by recruiting EZH2 to TSC2 gene promoter.

pH-Mediated Clustering of Exosomes: Breaking Through the Size Limit of Exosome Analysis in Conventional Flow Cytometry.

Exosomes have recently emerged as some of the most promising biomarkers for disease diagnosis. Due to their small sizes and composition heterogeneity, exosomes are difficult to detect by currently available platforms. Here, we report a pH-mediated assembly system that converts single nanosized exosomes into microsized clusters, which can be directly analyzed by conventional flow cytometry (FCM), breaking through the size limit of exosome analysis. We demonstrated the clinical utility of the pH-mediated clustering system by profiling the exosomal proteins from blood plasma samples of 33 cancer patients and 11 benign controls. The results indicated that the combination of MUC-1 and PD-L1 could serve as a new biomarker panel for the early diagnosis of liver cancer with high clinical accuracy. This pH-mediated assembly strategy allows rapid, sensitive, and high-throughput analysis of exosome biomarkers by conventional FCM, which can be easily refined for use in both basic and clinical settings.

TRPV4 induces apoptosis via p38 MAPK in human lung cancer cells.

Lung cancer is one of the most common cancers worldwide. TRPV4 belongs to the 'transient receptor potential' (TRP) superfamily. It has been identified to profoundly affect a variety of physiological processes, including nociception, heat sensation, and inflammation. Unlike other TRP superfamily channels, its roles in cancers are unknown. Here, we elucidated the effects of TRPV4 and molecular mechanisms in human lung cancer cells. The levels of TRPV4 were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay. Cell apoptosis was determined by FACS assay. The results demonstrated that low levels of TRPV4 were detected in clinical lung carcinoma specimens. Over-expression of TRPV4 induced cell death and inhibited cell proliferation and migration in A549 cells and H460 cells. Moreover, over-expression of TRPV4 enhanced the activation of p38 MAPK signal pathway. Inhibition of p38 MAPK abolished the effects of TRPV4 on cell proliferation, apoptosis, and migration in A549 cells. Collectively, our findings indicated that TRPV4 induced apoptosis via p38 MAPK in human lung cancer cells and suggested that TRPV4 was a potential target for therapy of human lung cancers.

Prognostic significance of excision repair cross complementation group 1 rs2298881 in patients with gastric cancer receiving platinum-based chemotherapy: A PRISMA-compliant meta-analysis.

BACKGROUND: Gastric cancer (GC) is a strong cause of global cancer mortality. Nucleotide excision repair (NER) can modulate platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. Some studies have found a link between excision repair cross complementation group 1 (ERCC1) rs2298881, one gene in NER pathway, and response to chemotherapy. However, the results have been disputed. METHODS: We conducted a meta-analysis to reevaluate the association between polymorphisms of NER gene (ERCC1 rs2298881) and the clinical outcomes in gastric cancer patients receiving platinum-based chemotherapy. Searching PubMed, Web of Science, EMBASE, Google Scholar, and China National Knowledge Infrastructure, 2 independent searchers found all pertinent literatures up to May 1, 2021. We enrolled studies according to consistent selection criteria, extracted and vitrified data. Crude odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were applied to evaluate the effect of ERCC1 rs2298881 on patients treated by platinum-based chemotherapy. RESULTS: By the data gathered from 6 independent studies, 1940 cases diagnosed with gastric cancer and treated with chemotherapy were included, containing 1208 Good-Responders and 732 Poor-Responders. With a comprehensive meta-analysis, we found that the patients with ERCC1 rs2298881A allele had a worse response to chemotherapy than those who with rs2298881C allele under allelic model (A vs C), with the pooled OR of 0.780 (95% CI: 0.611-0.996, P = .046). And our analysis indicated that AA genotype was associated with unfavorable overall survival (HR = 1.540, 95% CI = 1.106-2.144, P = .011) compared with CC genotype. CONCLUSIONS: ERCC1 rs2298881 is suggested as a marker of clinical outcome in gastric cancer patients treated by platinum-based chemotherapy.

Evaluation of the reporting quality of clinical practice guidelines on melanoma using the RIGHT checklist.

BACKGROUND: The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) instrument was launched in 2016 to improve the reporting of clinical practice guidelines (CPGs). We aimed to systematically evaluate the reporting quality of CPGs on melanoma using RIGHT. METHODS: We systematically searched electronic databases, guideline databases and medical society websites until November 2020 to identify guidelines for melanoma published since 2018. The reporting quality of included guidelines was assessed by calculating the percentages of the 35 items of the RIGHT checklist that were appropriately reported. We stratified the results by selected characteristics to describe the correlation of these factors with reporting quality. RESULTS: A total of 20 guidelines were identified and analyzed. The mean reporting rate was greater than 50% in five of the seven domains of the RIGHT checklist; the remaining two domains (Other information, Review and quality assurance) both had a mean reporting rate of 35.0%. The mean overall reporting rate was 63.7%. No CPG considered equity, feasibility or acceptability of the recommendations (item 14c), and only one CPG described the role of funders (item 18b). Guidelines that reported funding or were published in higher-impact journals tended to have a higher reporting quality, whereas the reporting rate in the one included Chinese-language CPG was low. CONCLUSIONS: Reporting quality of melanoma CPGs tends to be relatively good. The CPGs developed in China were however an exception. The use of the 2016 RIGHT tool in guideline development should be encouraged to support rigorous and transparent reporting.

Molecular Mechanism of Inhibition of Polysialyltransferase Domain (PSTD) by Heparin.

The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. It has been proposed that NCAM polysialylation could be inhibited by two types of heparin inhibitors, low molecular heparin (LMWH) and heparin tetrasaccharide (DP4). This review summarizes how the interactions between Polysialyltransferase Domain (PSTD) in ST8SiaIV and CMP-Sia, and between the PSTD and polySia take place, and how these interactions are inhibited by LMWH and DP4. Our NMR studies indicate that LMWH is a more effective inhibitor than DP4 for inhibition of NCAM polysialylation. The NMR identification of heparin-binding sites in the PSTD may provide insight into the design of specific inhibitors of polysialylation.

Ubenimex Suppresses the Ability of Migration and Invasion in Gastric Cancer Cells by Alleviating the Activity of the CD13/NAB1/MAPK Pathway.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in China. Most GC patients are diagnosed at an advanced stage, for that the prognosis is dismal and metastasis is common. Although there have been increasing numbers of studies indicating that Ubenimex can suppress metastasis in GC, the underlying mechanism is still unknown. METHODS: Herein, the inhibitory effect of Ubenimex on GC metastasis, in which the underlining mechanism was determined using Gene chip analysis, high content screening (HCS), transwell assays, wound healing assays and Western blot assays. RESULTS: The results obtained from wound healing assays and transwell assays indicated that Ubenimex, an inhibitor of CD13, suppressed the migration and invasion of MKN-28, MGC-803, BGC-823 and SGC-790 cells, by downregulating CD13 expression. In addition, the findings acquired from Gene chip analysis and HCS demonstrated that NGFI-A-binding protein 1 (NAB1) was a putative target downstream of CD13. Furthermore, the results obtained from Western blot assays showed that Ubenimex not only inhibits NAB1 expression by targeting CD13, but also inhibits GC metastasis by mitigating the activity of the MAPK signaling pathway. These findings indicated a possible mechanism via the CD13/NAB1/MAPK pathway of which activity was restrained. CONCLUSION: Ubenimex exert the inhibitory effect on GC metastasis by targeting CD13, in which NAB1 expression and the activation of MAPK signaling pathway were both suppressed. This study identified a promising target for the inhibition of GC metastasis.

The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis.

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.

Activation of forkhead box O3a by mono(2-ethylhexyl)phthalate and its role in protection against mono(2-ethylhexyl)phthalate-induced oxidative stress and apoptosis in human cardiomyocytes.

Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of di(2-ethylhexyl)phthalate (DEHP), is known to exert cardiotoxicity. The aim of the present study was to investigate the role of forkhead box O3a (FOXO3a) in MEHP-induced human AC16 cardiomyocyte injuries. MEHP reduced cell viability and mitochondrial membrane potential (ΔΨm), whereas it increased lactate dehydrogenase (LDH) leakage, production of reactive oxygen species (ROS), and apoptosis in cardiomyocytes. The expression of FOXO3a and its target genes, mitochondrial superoxide dismutase (Mn-SOD) and apoptosis repressor with caspase recruitment domain (ARC), increased after MEHP exposure, but the expression of p-FOXO3a protein was decreased. Overexpression of FOXO3a decreased the production of ROS and the apoptosis rate induced by MEHP, and the expression of Mn-SOD and ARC was further increased after MEHP exposure. In contrast, knockdown of FOXO3a resulted in increased ROS production and apoptosis and suppressed the expression of Mn-SOD and ARC in the presence of MEHP. However, overexpression or knockdown of FOXO3a did not affect MEHP-induced loss of ΔΨm. In conclusion, the loss of ΔΨm and apoptosis are involved in MEHP-induced cardiomyocyte toxicity. Activation of FOXO3a defends against MEHP-induced oxidative stress and apoptosis by upregulating the expression of Mn-SOD and ARC in AC16 cardiomyocytes.

TRPV4 induces apoptosis via p38 MAPK in human lung cancer cells

Lung cancer is one of the most common cancers worldwide. TRPV4 belongs to the 'transient receptor potential' (TRP) superfamily. It has been identified to profoundly affect a variety of physiological processes, including nociception, heat sensation, and inflammation. Unlike other TRP superfamily channels, its roles in cancers are unknown. Here, we elucidated the effects of TRPV4 and molecular mechanisms in human lung cancer cells. The levels of TRPV4 were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay. Cell apoptosis was determined by FACS assay. The results demonstrated that low levels of TRPV4 were detected in clinical lung carcinoma specimens. Over-expression of TRPV4 induced cell death and inhibited cell proliferation and migration in A549 cells and H460 cells. Moreover, over-expression of TRPV4 enhanced the activation of p38 MAPK signal pathway. Inhibition of p38 MAPK abolished the effects of TRPV4 on cell proliferation, apoptosis, and migration in A549 cells. Collectively, our findings indicated that TRPV4 induced apoptosis via p38 MAPK in human lung cancer cells and suggested that TRPV4 was a potential target for therapy of human lung cancers.