Low salinity influences the dose-dependent transcriptomic responses of oysters to cadmium.

Species in estuaries tend to undergo both cadmium (Cd) and low salinity stress. However, how low salinity affects the Cd toxicity has not been fully understood. Investigating the impacts of low salinity on the dose-response relationships between Cd and biological endpoints has potential to enhance our understanding of the combined effects of low salinity and Cd. In this work, changes in the transcriptomes of Pacific oysters were analyzed following exposure to Cd (5, 20, 80 µg/L Cd2+) under normal (31.4 psu) and low (15.7 psu) salinity conditions, and then the dose-response relationship between Cd and transcriptome was characterized in a high-throughput manner. The benchmark dose (BMD) of gene expression, as a point of departure (POD), was also calculated based on the fitted dose-response model. We found that low salinity treatment significantly influenced the dose-response relationships between Cd and transcripts in oysters indicated by altered dose-response curves. In details, a total of 219 DEGs were commonly fitted to best models under both normal and low salinity conditions. Nearly three quarters of dose-response curves varied with salinity condition. Some monotonic dose-response curves in normal salinity condition even were replaced by nonmonotonic curves in low salinity condition. Low salinity treatment decreased the PODs of differentially expressed genes induced by Cd, suggesting that gene differential expression was more prone to being triggered by Cd in low salinity condition. The changed sensitivity to Cd in low salinity condition should be taken into consideration when using oyster as an indicator to assess the ecological risk of Cd pollution in estuaries.

Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics.

During the past decade, "membrane lipid therapy", which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of "membrane lipid therapy" for tumors.

CENPE and LDHA were potential prognostic biomarkers of chromophobe renal cell carcinoma.

BACKGROUND: Most sarcomatoid differentiated renal cell carcinoma was differentiated from Chromophobe renal cell carcinoma (KICH) and related to a bad prognosis. Thus, finding biomarkers is important for the therapy of KICH. METHODS: The UCSC was used for determining the expression of mRNA and miRNA and clinical data in KICH and normal samples. KEGG and GO were used for predicting potential function of differently expressed genes (DEGs). Optimal prognostic markers were determined by Lasso regression. Kaplan-Meier survival, ROC, and cox regression were used for assessing prognosis value. GSEA was used for predicting potential function of markers. The relations between markers and immune cell infiltration were determined by Pearson method. The upstream miRNA of markers was predicted in TargetScan and DIANA. RESULTS: The 6162 upregulated and 13,903 downregulated DEGs were identified in KICH. Further CENPE and LDHA were screened out as optimal prognostic risk signatures. CENPE was highly expressed while LDHA was lowly expressed in KICH samples, and the high expressions of 2 genes contributed to bad prognosis. The functions of CENPE and LDHA were mainly enriched in proliferation related pathways such as cell cycle and DNA replication. In addition, the correlation of 2 genes with immune infiltrates in KICH was also observed. Finally, we found that has-miR-577 was the common upstream of 2 genes and the binding sites can be predicted. CONCLUSION: CENPE and LDHA were identified as the important prognostic biomarkers in KICH, and they might be involved in the proliferation of cancer cell.

Development and validation of a urinary microRNA biomarker panel as a tool for early detection of prostate cancer in a Chinese population.

INTRODUCTION: Urinary microRNAs (miRNAs) may serve as promising biomarkers for non-invasive early detection of prostate cancer (PCa). We aimed to identify multi-miRNA urinary biomarker panel for early detection of PCa. METHODS: Urine samples from 83 PCa patients and 88 healthy control subjects in a Chinese population were collected for miRNA profiling. The absolute expression of 360 unique miRNAs were measured in each sample using a highly sensitive and robust RT-qPCR workflow. Candidate urinary miRNA biomarkers were identified based on differential expression between PCa patients and healthy controls. Multi-miRNA biomarker panels were optimised for detection of PCa using three regression algorithms (Lasso, Stepwise, Exhaustive) to identify an optimal biomarker panel with best detection performance and least number of miRNAs. RESULTS: A total of 312 miRNAs were detected in urine samples, 10 candidate urinary miRNA biomarkers differentially expressed between PCa and healthy samples were identified. A panel comprising these 10 miRNAs detected PCa with an area under the curve (AUC) of 0.738. Optimization of multi-miRNA panels resulted in a 6-miRNA biomarker panel (hsa-miR-375, hsa-miR-520d-5p, hsa-miR-199b-5p, hsa-miR-518e-5p, hsa-miR-31-3p and hsa-miR-4306) that had an AUC of 0.750. CONCLUSION: We identified a urinary miRNA biomarker panel for early detection of PCa in a Chinese population.

Combined toxic effects of nanoplastics and norfloxacin on mussel: Leveraging biochemical parameters and gut microbiota.

Antibiotics and nanoplastics (NPs) are among the two most concerned and studied marine emerging contaminants in recent years. Given the large number of different types of antibiotics and NPs, there is a need to apply efficient tools to evaluate their combined toxic effects. Using the thick-shelled mussel (Mytilus coruscus) as a marine ecotoxicological model, we applied a battery of fast enzymatic activity assays and 16S rRNA sequencing to investigate the biochemical and gut microbial response of mussels exposed to antibiotic norfloxacin (NOR) and NPs (80 nm polystyrene beads) alone and in combination at environmentally relevant concentrations. After 15 days of exposure, NPs alone significantly inhibited superoxide dismutase (SOD) and amylase (AMS) activities, while catalase (CAT) was affected by both NOR and NPs. The changes in lysozyme (LZM) and lipase (LPS) were increased over time during the treatments. Co-exposure to NPs and NOR significantly affected glutathione (GSH) and trypsin (Typ), which might be explained by the increased bioavailable NOR carried by NPs. The richness and diversity of the gut microbiota of mussels were both decreased by exposures to NOR and NPs, and the top functions of gut microbiota that were affected by the exposures were predicted. The data fast generated by enzymatic test and 16S sequencing allowed further variance and correlation analysis to understand the plausible driving factors and toxicity mechanisms. Despite the toxic effects of only one type of antibiotics and NPs being evaluated, the validated assays on mussels are readily applicable to other antibiotics, NPs, and their mixture.

Toxicological mechanism of cadmium in the clam Ruditapes philippinarum using combined ionomic, metabolomic and transcriptomic analyses.

Cadmium (Cd) contamination in marine environment poses great risks to the organisms due to its potential adverse effects. In the present study, the toxicological effects and mechanisms of Cd at environmentally relevant concentrations (5 and 50 µg/L) on clam Ruditapes philippinarum after 21 days were investigated by combined ionomic, metabolomic, and transcriptomic analyses. Results showed that the uptake of Cd significantly decreased the concentrations of Cu, Zn, Sr, Se, and Mo in the whole soft tissue from 50 µg/L Cd-treated clams. Significantly negative correlations were observed between Cd and essential elements (Zn, Sr, Se, and Mo). Altered essential elements homeostasis was associated with the gene regulation of transport and detoxification, including ATP-binding cassette protein subfamily B member 1 (ABCB1) and metallothioneins (MT). The crucial contribution of Se to Cd detoxification was also found in clams. Additionally, gene set enrichment analysis showed that Cd could interfere with proteolysis by peptidases and decrease the translation efficiency at 50 µg/L. Cd inhibited lipid metabolism in clams and increased energy demand by up-regulating glycolysis and TCA cycle. Osmotic pressure was regulated by free amino acids, including alanine, glutamate, taurine, and homarine. Meanwhile, significant alterations of some differentially expressed genes, such as dopamine-ß-hydroxylase (DBH), neuroligin (NLGN), NOTCH 1, and chondroitin sulfate proteoglycan 1 (CSPG1) were observed in clams, which implied potential interference with synaptic transmission. Overall, through integrating multiple omics, this study provided new insights into the toxicological mechanisms of Cd, particularly in those mediated by dysregulation of essential element homeostasis.

Bioaccumulation and human health implications of trace metals in oysters from coastal areas of China.

This study recompiled a national dataset to characterize the pollution level and health risk of cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) in oysters along the coastal areas of China. Results showed that the median concentrations of Cd, Cu, Pb and Zn in nationwide oysters were 5.5, 335, 1.3 and 1280 mg/kg dry weight, respectively. Generally, oysters from the north coasts presented lower metal pollution and higher quality than those from the south. The regional characteristics of trace metals in oysters might be contributed by the interspecific differences. Nationally, the noncarcinogenic risk posed by these four metals in oysters was relatively low, with the risk only occurring in a few hotspots such as the Pearl River Estuary and the Jiulong River Estuary. However, more attention should be paid to the carcinogenic risk of Cd, and priority should be given to formulating control measures to mitigate Cd pollution.

Meta-analysis reveals the species-, dose- and duration-dependent effects of cadmium toxicities in marine bivalves.

Cadmium (Cd) is a typical pollutant in marine environment. Increasing studies have focused on the toxicological effects of Cd in marine bivalves. However, there were many conflicting findings of toxicological effects of Cd in marine bivalves. An integrated analysis performed on the published data of Cd toxicity in marine bivalves is still absent. In this study, a meta-analysis was performed on the toxic endpoints in bivalves exposed to aqueous-phase Cd from 87 studies screened from 1519 papers. Subgroup analyses were conducted according to the categories of species, tissue, exposure dose and duration. The results showed significant species-, duration- and dose-dependent responses in bivalves to aqueous-phase Cd exposure. In details, clams were more sensitive to Cd than oysters, mussels and scallops, indicated by the largest effect size in clams. Gill, hepatopancreas and hemolymph were top three tissues used to indicate Cd-induced toxicity and did not present a significant tissue-specific manner among them. With regard to toxicological effect subgroups, oxidative stress and detoxification were top two subgroups indicating Cd toxicities. Detoxification and genotoxicity subgroups presented higher response magnitudes. What is more, toxicological effect subgroups presented multiple dose- and duration-dependent curves. Oxidative stress and genotoxicity related endpoints presented significant increase trends with Cd exposure dose and were preferable biomarkers to marine Cd pollution. Detoxification and energy metabolism related endpoints showed inverted U-shaped and U-shaped dose-response curves, both of which could be explained by hormesis. The linear decrease in oxidative stress and energy metabolism related endpoints over time suggested their involvement into the adaptive mechanism in bivalves. Overall, this study provided not only a better understanding the responsive mechanisms of marine bivalves to Cd stress, but also a selection reference for biomarkers to aqueous-phase Cd pollution in marine environment.

Case report: Apalutamide-induced severe lethal cutaneous adverse effects in China.

Introduction: Apalutamide is a novel agent for castration-resistant prostate cancer while skin rashes are the most common untoward reactions. Up to now, most of the reported dermatologic adverse events (dAEs) allocated to mild and moderate with a fair prognosis. Herein, we report a case series of severe dAEs in China caused by apalutamide. Case presentation: The four patients all developed severe and lethal drug eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis with a mean incubation period of 40 days. On the basis of the medical condition, all the patients were suggested to withdraw apalutamide and three of them recovered. Of note, attempts of rechallenges of apalutamide may be fatal. Discussion: The incidence of dAEs in previously conducted clinical trials exceeded 20%, with maculopapular rashes being the most common feature. However, the incidence and severity varied in different geographic regions and ethnicities. Inadequate attention was paid to severe cutaneous adverse reactions. Long latency may easily lead to the misdiagnosis of dAEs, and immediate withdrawal of apalutamide is the cornerstone of therapies. Conclusion: Special and adequate attention should be paid to apalutamide-attributed severe cutaneous adverse effects. Besides, the prognosis of severe drug eruptions may be disappointing, and in-time withdrawal is vital.

Serum SALL4 as a predictive biomarker for the prognosis of patients with hepatocellular carcinoma who underwent nonsurgical treatment.

To investigate the role of serum spalt like transcription factor 4 (SALL4) in the hepatocellular carcinoma (HCC) patients with nonsurgical treatment. Serum samples were collected from 101 patients with HCC without surgical treatment, then the SALL4 was detected by enzyme linked immunosorbent assay. According to subsequent treatment, patients were divided into 2 groups, best supportive care (BSC) (58 cases) and nonsurgical anticancer treatment (NSAT) (48 cases). Kaplan-Meier survival analysis and Cox multivariate regression analysis were applied to evaluate the relationship between SALL4 and survival time of 2 groups. In BSC group, there was no significant difference of the survival time between 2 groups (SALL4 < 800 ng/mL or SALL4 ≥ 800 ng/mL) (P = .339). In NSAT group, the survival time of patients with low SALL4 concentration was significantly longer than patients with high SALL4 concentration (P = .005). SALL4 have no predictive effect in BSC patients with HCC. But for patients received NSAT, low SALL4 concentration in serum may indicate longer survival.

Critical target identification and human health risk ranking of metal ions based on mechanism-driven modeling.

Huge amounts of metals have been released into environment due to various anthropogenic activities, such as smelting and processing of metals and subsequent application in construction, automobiles, batteries, optoelectronic devices, and so on, resulting in widespread detection in environmental media. However, some metal ions are considered as "Environmental health hazards", leading to serious human health concerns through affecting critical targets. Hence, it is necessary to quickly and effectively recognize the key target of metal ions in living organisms. Fortunately, the development of high-throughput analysis and in silico approaches offer a promising tool for target identification. In this study, the key oncogenic target (tumor suppressor protein, p53) was screened by network analysis based on the comparative toxicogenomics database (CTD). Some metal ions could bind to p53 core domain, impair its function and induce the development of cancer risk, but its mechanisms were still unclear. Therefore, a quantitative structure-activity relationship (QSAR) model was constructed to characterize the binding constants (Ka) between DNA binding domain of p53 (p53 DBD) and nine metal ions (Mg2+, Ca2+, Cu2+, Zn2+, Co2+, Ni2+, Mn2+, Fe3+ and Ba2+). It had good robustness and predictive ability, which could be used to predict the Ka values of other six metal ions (Li+, Ag+, Cs+, Cd2+, Hg2+ and Pb2+) within application domain. The results showed strong binding affinity between Cd2+/Hg2+/Pb2+ and p53 DBD. Subsequent mechanism analyses revealed that first hydrolysis constant (|logKOH|) and polarization force (Z2/r) were key metal ion-characteristic parameters. The metal ions with weak hydrolysis constants and strong polarization forces could readily interact with N-containing histidine and S-containing cysteine of p53 DBD, which resulted in high Ka values. This study identified p53 as potential target for metal ions, revealed the key characteristics affecting the actions and provide a basic understanding of metal ions-p53 DBD interaction.

Toxicological responses of juvenile Chinese shrimp Fenneropenaeus chinensis and swimming crab Portunus trituberculatus exposed to cadmium.

Cadmium (Cd) is one of the typical metal pollutants in the Bohai Sea. To evaluate the acute toxicological effects of Cd on marine crustaceans, juvenile Fenneropenaeus chinensis and Portunus trituberculatus were exposed to Cd at environmentally relevant concentrations (5 and 50 µg/L) for 96 h. Cd accumulation, antioxidants and metabolite profiles were characterized to elucidate the responses of juvenile crustaceans to Cd stress. Significant Cd accumulation was observed in both juvenile crustaceans in 50 µg/L Cd-treated group. Results showed that Cd exposure induced hormesis based on the alterations of GSH, SOD and CAT activities (i.e. increased levels in the low concentration of Cd treatment and recovered levels in the high concentration of Cd treatment) in juvenile P. trituberculatus. Similarly, the responses of GSH contents presented hormesis pattern in Cd-treated juvenile F. chinensis. Na+-K+-ATPase contents were significantly elevated in 50 µg/L Cd-treated group. In addition, untargeted NMR-based metabolomics indicated Cd caused the disturbance in osmotic regulation and energy consumption in both juvenile F. chinensis and P. trituberculatus via different pathways. The immunotoxicity and movement disorder were uniquely demonstrated in juvenile P. trituberculatus after Cd exposure.

A diagnostic test: diagnostic value of gastrointestinal endoscopy narrow-band imaging (NBI) for colorectal laterally spreading tumor (LST) and submucosal invasion.

Background: Endoscopic ultrasonography is an effective endoscopic examination method for determining the depth of colorectal cancer invasion. Narrow-band imaging (NBI) techniques increase the contrast of vascular structures and more clearly highlight subtle structures on mucosal surfaces, thereby improving the accuracy of endoscopic assessment. This study investigated the diagnostic efficacy of NBI in colorectal laterally spreading tumor (LST) and its submucosal invasion. Methods: A total of 224 patients with colorectal LST admitted to the Affiliated Hospital of Putian University from January 2015 to December 2021 were enrolled in this study. The patients were divided into NBI and endoscopic ultrasonography groups according to the different examination methods they received. Subsequently, the clinicopathological characteristics of the patients were collected, and the rates of submucosal invasion of the four subtypes (LST-G-H, LST-G-NM, LST-NG-F, LST-NG-PD) were compared between the two groups. Also, the accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of judging the depth of LST lesions of the two examination methods were compared, taking the results of pathological tissue examination as the gold standard. Results: This study enrolled 224 patients with LST (mean onset age: 57.98±6.48 years), including 123 males and 101 females. In terms of tumor location, 21 cases were located in the cecum, 22 cases in the ascending colon, 38 cases in the transverse colon, 11 cases in the descending colon, 12 cases in the descending sigmoid junction, 23 cases in the sigmoid colon, and 97 cases in the rectum. The sizes of the tumors ranged from 18.81 to 52.88 mm. Moreover, there were 21 cases of lesion infiltration into the submucosa, and the infiltration rate was 9.38%. Furthermore, the accuracy of NBI in diagnosing colorectal LST was significantly higher than that of endoscopic ultrasonography (87.05% vs. 57.14%); NBI was more accurate than endoscopic ultrasonography in the preoperative diagnosis of LST lesion depth in the rectal, non-rectal, granular (LST-G), non-granular (LST-NG), <40, and ≥40 mm groups. Conclusions: Gastrointestinal NBI has a superior accuracy rate and value than endoscopic ultrasonography in diagnosing colorectal LST, tumor lesion depth, and submucosal invasion. Therefore, gastrointestinal NBI deserves to be promoted in clinical work.

Analysis of Voiding Impairment after Prostate Biopsy and the Effect of Doxazosin Treatment: Outcomes from a Regional Cancer Center.

INTRODUCTION: The aim of this study was to investigate the association of transrectal ultrasound (TRUS)-guided prostate biopsy with voiding impairment and the efficacy of doxazosin treatment. METHODS: A prospective observational study including 200 male patients undergoing TRUS-guided prostate biopsy was performed between May 2020 and December 2020. One hundred patients underwent biopsy with doxazosin (doxazosin group). The remaining 100 patients underwent biopsy without doxazosin (control group). All patients were questioned regarding post-biopsy voiding difficulty and acute urinary retention. The International Prostate Symptom Score (IPSS), maximal urinary flow rate (Qmax), and residual urine volume were recorded before biopsy and at 7 and 30 days after biopsy. RESULTS: There were no significant differences in baseline parameters between the two groups. The rate of post-biopsy voiding difficulty in the doxazosin group was significantly lower than that in the control group. Compared with baseline values, doxazosin treatment significantly improved IPSS, quality of life scores, and Qmax after biopsy (p < 0.05). The baseline values of IPSS and prostate size may be risk factors for post-biopsy voiding difficulty. CONCLUSION: TRUS-guided prostate biopsy causes transient voiding impairments, which may be improved by doxazosin treatment.

Toxicity pathways of lipid metabolic disorders induced by typical replacement flame retardants via data-driven analysis, in silico and in vitro approaches.

Endocrine-disrupting chemicals can interfere with hormone action via various pathways, thereby increasing the risk of adverse health outcomes. Organophosphorus ester (OPEs) retardants, a group of new emerging endocrine disruption chemicals, have been referred to as metabolism disruptors and reported to induce chronic health problems. However, the toxicity pathways were mainly focused on nuclear receptor signaling pathways. Significantly, the membrane receptor pathway (such as G protein-coupled estrogen receptor 1 (GPER) signaling pathway) had been gradually realized as the important role in respond more effective to lipid metabolism disorder than traditional nuclear receptors, whereas the detailed mechanism was unclear yet. Therefore, this study innovatively integrated the bibliometric analysis, in silico and in vitro approach to develop toxicity pathways for the mechanism interpretation. Bibliometric analysis found that the typical OPEs - triphenyl phosphate was a major concern of lipid metabolism abnormality. Results verified that TPP could damage the structures of cell membranes and exert an agonistic effect of GPER as the molecular initiating event. Then, the activated GPER could trigger the PI3K-Akt/NCOR1 and mTOR/S6K2/PPARα transduction pathways as key event 1 (KE1) and affect the process of lipid metabolism and synthesis (CPT1A, CPT2, SREBF2 and SCD) as KE2. As a result, these alterations led to lipid accumulation as adverse effect at cellular-levels. Furthermore, the potential outcomes (such as immunity damage, weight change and steatohepatitis) at high biological levels were expanded. These findings improved knowledge to deeply understand toxicity pathways of phosphorus flame retardants and then provided a theoretical basis for risk assessments.

Dose-dependent responses of metabolism and tissue injuries in clam Ruditapes philippinarum after subchronic exposure to cadmium.

Marine cadmium (Cd) pollution has been globally occurring, which creates a pressing need to characterize toxicological effects and develop biomarkers for Cd. However, the dose-response relationships challenge toxicity characterization and biomarkers selection. Metabolic processes have been frequently targeted by Cd. In this work, we investigated the dose-dependent effects of Cd on metabolic endpoints in whole soft tissues as well as gill and hepatopancreas injuries in clam Ruditapes philippinarum, aiming to better understand the metabolic responses and develop biomarkers. Nuclear magnetic resonance (NMR)-based metabolomic analysis was conducted on clam whole soft tissues to identify metabolites. The enzymes and metabolites associated with tricarboxylic acid (TCA) cycle, glycolysis, and oxidative phosphorylation showed both monotonic and non-monotonic curves with the increase of Cd dose. In details, glutamine, glucose-1-phosphate, hexokinase (HK), and citrate synthase (CS) presented monotonic decreases with the increase of Cd dose, among which glutamine and CS were preferable biomarkers to Cd exposure based on lower benchmark dose (BMD) values. The monotonic decreases of HK and CS activities suggested Cd exposure potentially disrupted glycolysis and TCA cycle via inhibiting rate-limiting enzymes. In contrast, the non-monotonic responses of succinate dehydrogenase (SDH), alanine aminotransferase (ALT), and their substrates (succinate and alanine) were approximate to U- or J-shaped curves, suggesting the adaptive strategy of metabolic responses to different degrees of Cd stress, like induction of anaerobiosis as energy compensation. Especially, the alterations of succinate and SDH presented typical hormetic dose-response curves. What is more, clam hepatopancreas was more sensitive to Cd than gill in terms of injury occurrence. Overall, characterization of dose-dependent effect of Cd on metabolism and tissue injuries provides a new insight into understanding the metabolic adaptation in marine clams and risk assessment of Cd pollution.

Hypoxia-Induced Autophagy Enhances Cisplatin Resistance in Human Bladder Cancer Cells by Targeting Hypoxia-Inducible Factor-1α.

PURPOSE: To investigate the effect of hypoxia on chemoresistance and the underlying mechanism in bladder cancer cells. METHODS: BIU-87 bladder cancer cell line was treated with cisplatin under hypoxic and normoxic conditions and tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting. All the data were expressed as mean ± standard error from three independent experiments and analyzed by multiple t-tests. RESULTS: Apoptosis of bladder cancer cells caused by cisplatin was attenuated in hypoxic conditions. Hypoxia enhanced autophagy caused by cisplatin. The autophagy inhibitor and HIF-1α inhibitor can reverse the chemoresistance in hypoxic condition. Apoptosis and autophagy of bladder cancer cells were downregulated by HIF-1α inhibitor YC-1. Hypoxia-induced autophagy enhanced chemoresistance to cisplatin via the HIF-1 signaling pathway. CONCLUSION: Resistance to cisplatin in BIU-87 bladder cancer cells under hypoxic conditions can be explained by activation of autophagy, which is regulated by HIF-1α-associated signaling pathways. The hypoxia-autophagy pathway may be a target for improving the efficacy of cisplatin chemotherapy in bladder cancer.

Stress responses in expressions of microRNAs in mussel Mytilus galloprovincialis exposed to cadmium.

MicroRNAs (miRNAs) are known to have complicated functions in aquatic species, but little is known about the role of miRNAs in mollusk species under environmental stress. In this study, we performed small RNA sequencing to characterize the differentially expressed miRNAs in different tissues (whole tissues, digestive glands, gills, and gonads) of blue mussels (Mytilus galloprovincialis) exposed to cadmium (Cd). In summary, 107 known miRNAs and 32 novel miRNAs were significantly (p < 0.01) differentially expressed after Cd exposure. The peak size of miRNAs was 22 nucleotides. Target genes of these differentially expressions of miRNAs related to immune defense, apoptosis, lipid and xenobiotic metabolism showed significant changes under Cd stress. These findings provide the first characterization of miRNAs in mussel M. galloprovincialis and expressions of many target genes in response to Cd stress.

Global characterization of dose-dependent effects of cadmium in clam Ruditapes philippinarum.

Cadmium (Cd) is being frequently detected in marine organisms. However, dose-dependent effects of Cd challenged unraveling the toxicological mechanisms of Cd to marine organisms and developing biomarkers. Here, the dose-dependent effects of Cd on clams Ruditapes philippinarum following exposure to 5 doses of Cd (3, 9, 27, 81, 243 µg/L) were investigated using benchmark dose (BMD) method. By model fitting, calculation of BMD values was performed on transcriptomic profiles, metals concentrations, and antioxidant indices. Cd exposure induced not only significant Cd accumulation in clams, but also marked alterations of essential metals such as Ca, Cu, Zn, Mn, and Fe. Gene regulation posed little influence on essential metal homeostasis, indicated by poor enrichment of differentially expressed genes (DEGs) associated with metal binding and metal transport in lower concentrations of Cd-treated groups. BMD analysis on biological processes and pathways showed that peptide cross-linking was the most sensitive biological process to Cd exposure, followed by focal adhesion, ubiquitin mediated proteolysis, and apoptosis. Occurrence of apoptosis was also confirmed by TUENL-positive staining in gills and hepatopancreas of clams treated with Cd. Furthermore, many DEGs, such as transglutaminases (TGs), metallothionein (MT), STEAP2-like and laccase, which presented linear or monotonic curves and relatively low BMD values, were potentially preferable biomarkers in clams to Cd. Overall, BMD analysis on transcriptomic profiles, metals concentrations and biochemical endpoints unraveled the sensitiveness of key events in response to Cd treatments, which provided new insights in exploring the toxicological mechanisms of Cd in clams as well as biomarker selection.