ABSTRACT
Aquatic organisms are frequently exposed to various nanoparticles (NPs) in the natural environment. Thus, studies of NP bioaccumulation should include organisms that have been previously exposed to NPs. Our study investigated the effects of pre-exposure of Tetrahymena thermophila (T. thermophila) to Fe2O3 or TiO2 NPs on the protozoan's subsequent uptake of 55Fe-labeled Fe2O3 (55Fe2O3) NPs. Molecular mechanisms underlying the pre-exposure effects were explored in transcriptomic and metabolomic experiments. Pre-exposure to either NPs inhibited the subsequent uptake of 55Fe2O3 NPs. The results of the transcriptomic experiment indicated that NP pre-exposure influenced the expression of genes related to phagosomes and lysosomes and physiological processes such as glutathione and lipid metabolism, which are closely associated with the endocytosis of 55Fe2O3 NPs. The differentially expressed metabolites obtained from the metabolomic experiments showed an enrichment of energy metabolism and antioxidation pathways in T. thermophila pre-exposed to NPs. Together, these results demonstrate that the pre-exposure of T. thermophila to Fe2O3 or TiO2 NPs inhibited the protozoan's subsequent uptake of 55Fe2O3 NPs, possibly by mechanisms involving the alteration of endocytosis-related organelles, the induction of oxidative stress, and a lowering of the intracellular energy supply. Thus, NP pre-exposure represents a scenario which can inform increasingly realistic estimates of NP bioaccumulation.
Subject(s)
Nanoparticles , Titanium/pharmacology , Antioxidants/metabolism , Oxidative StressABSTRACT
Humans are exposed to a wide variety of natural and engineered nanoparticles (NPs) during their lifetime. However, the effects of pre-exposure to NPs on subsequent uptake of other NPs have not been investigated. In the present study, we investigated the effects of pre-exposure to three NPs (TiO2, Fe2O3, and SiO2 NPs) on the subsequent uptake of gold NPs (AuNPs) by hepatocellular carcinoma cells (HepG2). When HepG2 cells were pre-exposed to TiO2 or Fe2O3 NPs, but not SiO2 NPs for 2 days, their subsequent uptake of AuNPs was inhibited. Such inhibition was also observed in human cervical cancer (HeLa) cells, suggesting that this phenomenon is present in different cell types. The mechanisms underlying the inhibitory effect of NP pre-exposure include altered plasma membrane fluidity due to changes in lipid metabolism and reduced intracellular ATP production due to decreased intracellular oxygen. Despite the inhibitory effects of NP pre-exposure, full recovery was observed after transferring the cells to medium without NPs, even when the pre-exposure time was extended from 2 days to 2 weeks. Overall, the pre-exposure effects observed in the present study should be considered in the biological application and risk evaluation of NPs.
Subject(s)
Metal Nanoparticles , Nanoparticles , Humans , Titanium/toxicity , Gold , Metal Nanoparticles/toxicity , Nanoparticles/metabolism , HeLa Cells , Magnetic Iron Oxide NanoparticlesABSTRACT
BACKGROUND: At present, little is known about the risk factors of early postoperative death in patients with hepatocellular carcinoma (HCC). METHODS: We collected the data of patients who were diagnosed with primary liver cancer between 2010 and 2015 in the Surveillance, Epidemiology, and End Results database and further allocated them to the training set and validation set. Univariate and multivariate logistic regression analysis was used to determine the independent influencing factors of early postoperative death of HCC patients. Random forest and Least absolute shrinkage and selection operator regression analysis were used to screen out vital variables for the construction of the nomogram. It was evaluated by receiver operating characteristic curve, calibration curve and decision curve analysis. RESULTS: A total of 4154 patients were selected in this process, including 2647 patients with postoperative early death (outcome1) and 1507 patients with liver cancer-specific postoperative early death (outcome2). Surgery method, age category, marital status and tumor grade were the risk factors for early postoperative death. As for the liver cancer-specific early postoperative death, AJCC, surgery method, chemotherapy and tumor grade were independent prognostic factors. Early death and liver cancer-specific early death nomograms have an area under curves of 0.643 and 0.679 in the training set, respectively, and 0.617 and 0.688 in the validation set. The calibration curve and decision curve analysis shows that the nomograms have good performance. CONCLUSION: This model provides an intuitive and practical tool for future studies based on large-scale cohorts by exploring the risk factors of early death in patients with HCCs undergoing surgery.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/surgery , Liver Neoplasms/pathology , Retrospective Studies , Logistic Models , Nomograms , Algorithms , PrognosisABSTRACT
Although nanoparticles' (NPs) toxicity has been intensively studied, their effects on bacterial ingestion by protozoans (as an important component of the microbial loop) is unknown. This study investigated the effects of NPs of different chemical composition [hematite (HemNPs), anatase (AnaNPs), and silica (SiNPs) NPs] and size [SiNPs with particle size of 20 (Si-20), 100 (Si-100), and 500 (Si-500) nm] on the ingestion of Escherichia coli by the protozoan Tetrahymena thermophila. Potential differences between pre- vs. co-exposure were also assessed. Pre-exposure to HemNPs had no effects on bacterial ingestion but the other NPs caused a significant inhibition, due to their inhibition of ATP synthesis and the down-regulation of phagocytosis-related genes (ACT1 and CTHB). Contrastively, co-exposure to HemNPs and Si-20 didn't affect bacterial ingestion while co-exposure to AnaNPs (Si-100 and Si-500) induced (inhibited) ingestion. The stimulatory effect of AnaNPs was due to their induction of an increase in the intracellular Ca concentration of T. thermophila whereas the inhibitory effects of Si-100 and Si-500 were attributable to ATP synthesis reduction, enhanced bacterial cell aggregation, and competition between the bacterial cells and the NPs. These findings provide insights into the mechanisms underlying the environmental risks of NPs.
Subject(s)
Nanoparticles , Tetrahymena thermophila , Bacteria , Eating , Nanoparticles/toxicityABSTRACT
Microplastics (MPs) and nanoplastics (NPs) in the environment pose significant risks to organisms of different trophic levels. While the toxicity of MPs and NPs have been extensively investigated, it remains unknown whether these particles affect microbial transformation of organic pollutants. Here, we show that 20 and 100 nm polystyrene NPs (PS-NPs) can inhibit the transformation of tetrabromobisphenol A (TBBPA) by Gram-positive bacterium Rhodococcus jostii in a concentration-dependent manner. We found that smaller PS-NPs were more inhibitory than larger ones and that both PS-NPs affected biotransformation in several ways. PS-NPs adsorbed TBBPA on their surface and reduced the bioavailable concentration of TBBPA for transformation by R. jostii. Furthermore, PS-NPs induced oxidative stress, increased membrane permeability, and downregulated O-methyltransferase enzymes that transform TBBPA into their methylated derivatives. Our results demonstrate that PS-NPs can impact microbial transformation of organic pollutants, and these effects should be accounted for in future environmental risk assessments.
Subject(s)
Nanoparticles , Water Pollutants, Chemical , Polystyrenes , Microplastics , Plastics , Nanoparticles/toxicityABSTRACT
OBJECTIVE: To investigate the association between magnetic resonance imaging (MRI) classification and symptom relief after uterine artery embolization (UAE) in patients with adenomyosis. METHODS: Totally, 73 patients with symptomatic adenomyosis who underwent UAE were retrospectively analyzed. Preoperative MRI classification was defined as: type I, high signal on both T2-weighted images (T2WI) and T1-weighted images (T1WI); type III, high signal only on T2WI, and type II, high signal on neither T1WI nor T2WI. Dysmenorrhea was measured with the visual-analog scales and the degree of menorrhagia was measured according to the number of sanitary pads used in one menstrual cycle. Dysmenorrhea and menorrhagia were measured before UAE and 12 months after UAE. RESULTS: The number of the type I, II, III cases was 23, 37, and 13, respectively. The baseline characteristics of the three groups exhibited no significant difference. The alleviation rates of dysmenorrhea among type I, II, III cases were 73.9%, 89.2%, and 84.6%, respectively (P=0.455). The alleviation rates of menorrhagia for type I, II, III were 69.6%, 78.4%, and 92.3%, respectively (P=0.714). CONCLUSION: Pre-procedure MRI classification and symptom relief after UAE exhibited no significant association. UAE has a favorable mid-term control on dysmenorrhea and menorrhagia among patients with adenomyosis. Preoperative MRI classification might not indicate symptom relief. More research is needed before changing clinical practice.
Subject(s)
Adenomyosis/surgery , Magnetic Resonance Imaging/classification , Uterine Artery Embolization , Adult , Female , Humans , Retrospective Studies , Treatment OutcomeABSTRACT
In aquatic ecosystems, the calcium (Ca) concentration varies greatly. It is well known that Ca affects the aggregation of nanoparticles (NPs) and thus their bioaccumulation. Nevertheless, Ca also plays critical roles in various biological processes, whose effects on NP accumulation in aquatic organisms remain unclear. In this study, the effects of Ca on the uptake of polyacrylate-coated hematite NPs (HemNPs) by the aquatic ciliate Tetrahymena thermophila were investigated. At all of the tested Ca concentrations, HemNPs were well dispersed in the experimental medium, excluding the possibility of Ca to influence HemNP bioaccumulation by aggregating the NPs. Instead, Ca was shown to induce the clathrin-mediated endocytosis and phagocytosis of HemNPs. Manipulation of the Ca speciation in the experimental medium as well as the influx and intracellular availability of Ca in T. thermophila indicated that HemNP uptake was regulated by the intracellular Ca level. The results of the proteomics analyses further showed that the binding of intracellular Ca to calmodulin altered the activity of proteins involved in clathrin-mediated endocytosis (calcineurin and dynamin) and phagocytosis (actin). Overall, the biologically inductive effects of Ca on NP accumulation in aquatic organisms should be considered when evaluating the environmental risks of NPs.
Subject(s)
Nanoparticles , Tetrahymena thermophila , Calcium , Ecosystem , Magnetic Iron Oxide Nanoparticles , PlasticsABSTRACT
The potential effects of engineered nanoparticles (NPs) on metal bioaccumulation in aquatic organisms have been the focus of increasing research attention. However, while NPs typically aggregate, the role of aggregation in NP-mediated metal bioaccumulation is largely unknown. The present study investigated the effects of polyacrylate-coated TiO2 (anatase) NPs (AnaNPs) on Cd bioaccumulation in zebrafish. The Ca concentration in the experimental medium was manipulated to regulate AnaNP aggregation. At the low Ca concentration, the AnaNPs were well-dispersed and there was little bioaccumulation. Under this condition, Cd bioaccumulation was mainly via the uptake of free ions (Route 1), with only a minor contribution from NP-Cd complexes (Route 2). Therefore, AnaNPs decreased Cd bioaccumulation, as their inductive carrier effect could not offset the inhibition induced by the decrease in the free Cd ion concentration as a result of NP adsorption. At the high Ca concentration, the AnaNPs aggregated and their bioaccumulation increased. Accordingly, Cd bioaccumulation was equally accounted for by Routes 1 and 2 but the overall amount of Cd remained unchanged because the inductive effect of the AnaNPs offset their inhibitory effect. Thus, during risk evaluations of NPs, the contribution of aggregation to metal bioaccumulation should be considered.
Subject(s)
Nanoparticles , Water Pollutants, Chemical , Animals , Bioaccumulation , Cadmium/toxicity , Nanoparticles/toxicity , Titanium/analysis , Titanium/toxicity , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/toxicity , ZebrafishABSTRACT
Bacterial accumulation of engineered nanoparticles (NPs) result in their transfer along the food chain. However, there are a lot of NPs not associated with bacteria. Whether bacteria, as representative biotic particles, influence the biological uptake of these non-associated NPs in aquatic ecosystems is unclear. In the present study, we examined the effects of four bacterial species on the uptake kinetics of polyacrylate-coated hematite nanoparticles (HemNPs) by the ciliate Tetrahymena thermophila. The HemNPs were well dispersed. Their adsorption on the bacteria was low with negligible uptake by T. thermophila through bacterial ingestion. This result demonstrated the feasibility of examining the effects of bacteria on the uptake of non-associated HemNPs. Our study further showed that all four bacterial species inhibited the uptake of HemNPs by T. thermophila; however, the effects of the bacterial cells on the physiological activities of the ciliate with respect to its uptake of HemNPs were negligible. In the absence of phagocytosis by T. thermophila, none of the bacteria inhibited HemNP uptake. This observation suggested that bacterial cells competed with the HemNPs for uptake via phagocytosis. Therefore, in evaluations of the environmental risks of NPs, their competition with biotic particles should be taken into account.
Subject(s)
Tetrahymena thermophila , Bacteria , Ecosystem , Magnetic Iron Oxide Nanoparticles , PlasticsABSTRACT
PURPOSE: The burden of non-communicable diseases (NCDs) has increased in China. However, the contribution of dietary risks to the NCD burden has not been evaluated. This study aimed to estimate the burden of ischemic heart disease (IHD) and colorectal cancer (CRC) attributable to a diet low in fiber in China from 1990 to 2017. METHODS: China data from the Global Burden of Disease Study (GBD) 2017 were used to assess the age-, sex-, and province-specific mortality and disability-adjusted life-years (DALYs) of IHD and CRC related to a diet low in fiber. RESULTS: In 2017, a diet low in fiber contributed 170,143 [95% uncertainty interval (UI): 99,623-256,806] IHD deaths and 25,561 (95% UI: 13,726-39,215) CRC deaths, with the population attributable fractions (PAFs) were 9.7 and 13.7%, respectively. Males had higher risk-attributable mortality and DALY rates for IHD and CRC than females. An upward trend with age in rates of mortality and DALY was observed. All-age risk-attributable mortality and DALY rates increased significantly by 111.4 and 53.2% for IHD, and 94.4 and 59.6% for CRC from 1990 to 2017, respectively; however, the corresponding age-standardized rates for IHD and CRC showed relatively stable trends. Heilongjiang, Xinjiang, and Inner Mongolia were ranked as the top three provinces in terms of total risk-attributable NCD burden in 2017. CONCLUSIONS: China has a large and growing NCD burden attributable to a diet low in fiber. Greater priority in disease prevention and control should be given to male and older adults throughout China, particularly in some western provinces.
Subject(s)
Colorectal Neoplasms , Myocardial Ischemia , Aged , China/epidemiology , Colorectal Neoplasms/epidemiology , Cost of Illness , Diet , Female , Global Burden of Disease , Humans , Male , Myocardial Ischemia/epidemiology , Myocardial Ischemia/etiology , Risk FactorsABSTRACT
Microplastics (MPs) are an environmental hazard of growing concern, including their potential toxic effects on the biota of different trophic levels. Nevertheless, the molecular mechanisms underlying MP-induced toxicity remain largely unknown. In the present study, Tetrahymena thermophila was exposed to polystyrene nanoplastics (PS-NPs) and the responses of this relatively sensitive ciliate were then followed using transcriptome analysis together with several other verification methods. The results showed that PS-NPs perturbed calcium (Ca) homeostasis, by inducing the inositol-1,4,5-trisphosphate-dependent liberation of Ca from the endoplasmic reticulum into the cytosol. The high cytosolic concentration of Ca induced Ca accumulation in mitochondria, which increased mitochondrial permeability and the generation of reactive oxygen species, finally leading to growth inhibition. Such toxicity is the so-called direct effects of PS-NPs. By contrast, PS-NPs also inhibited the activity of multixenobiotic resistance transporter, by down-regulating the ATP-binding cassette transporter genes Abcb15 and Abcc52. This additional effect may alter cellular responses to other pollutants and implicates PS-NPs in the risks to the organism posed by subsequent toxic exposures, which was named as the indirect effects of PS-NPs. Our study highlights the importance of considering both direct and indirect biological effects of MPs in evaluations of their environmental and health risks.
Subject(s)
Nanoparticles , Tetrahymena thermophila , Water Pollutants, Chemical , Calcium , Homeostasis , Microplastics , Plastics , Polystyrenes , Tetrahymena thermophila/geneticsABSTRACT
The widespread use of nanoparticles (NPs) has drawn considerable attention because of their potential toxicity and the environmental consequences thereof. However, the effects of the exposure route and life stage of an organism on the bioaccumulation and toxicity of NPs are largely unknown. In the present study, we investigated the accumulation kinetics (uptake, assimilation, and efflux) and tissue distribution of waterborne and dietary hematite NPs (HemNPs) during three life stages (embryo, larva, and adult) of the zebrafish Danio rerio. For all zebrafish life stages, the waterborne accumulation of well-dispersed HemNPs increased linearly with exposure time but decreased after reaching a maximum. The increase in HemNPs accumulation followed the order embryo > larva > adult. Compared with the waterborne route, the dietary accumulation of HemNPs in larval and adult zebrafish fluctuated, reaching a maximum after each food refreshment and then decreasing until the next food addition. Similar to waterborne exposure, adult fish accumulated less dietary HemNPs than did larvae. Nevertheless, dietary HemNPs mostly accumulated in the intestinal tract, with smaller amounts in the truncus, head, and gills, as compared with their waterborne counterparts. Moreover, in the gonad no dietary HemNPs were detected whereas accumulation via waterborne HemNPs was significant. Despite the low assimilation efficiency of dietary HemNPs, biodynamic modeling showed that the diet was the main source of particle accumulation in zebrafish. Thus, both the life stage and the exposure route should be considered in evaluations of the environmental risks of NPs.
Subject(s)
Diet , Ferric Compounds , Nanoparticles , Water Pollutants, Chemical , Zebrafish , Animals , Ferric Compounds/metabolism , Nanoparticles/metabolism , Water Pollutants, Chemical/metabolism , Zebrafish/growth & development , Zebrafish/metabolismABSTRACT
The ligustrazine - betulin derivative (TB), TB amino acids derivatives (TB-01 - TB-09) and TB dipeptide derivatives (TB-10 - TB-18) were designed and synthesized. And their in vitro cytotoxic activities were evaluated against four cancer cell lines (Hela, HepG2, BGC-823 and HT-29) and normal cells MDCK by standard methylthiazol tetrazolium (MTT) assay. Most of them demonstrated better antitumor activity than the relevant material betulin. Among them, compound TB-01 showed the best anti-tumor effect on the cancer cells and the lowest toxicity on the normal cells. For example, the cytotoxicity of TB-01 against the cancer cells (mean IC50â¯=â¯4.86⯱â¯1.16⯵M) was 3-fold higher than that against the normal cells MDCK (IC50â¯=â¯16.11⯱â¯2.29⯵M). Moreover, TB-01 showed better cytotoxic than positive drug cisplatin (DDP) on tumor cells. Besides, the Zebrafish toxicity evaluation test showed that TB-01 demonstrated high biosafety. Subsequently, fluorescent staining, apoptosis detection and cell cycle analysis indicated that TB-01 induced early apoptosis in HepG2 cells and blocked the cell cycle in the G1 phase. In addition, the structure-activity relationships of these derivatives were briefly discussed.
Subject(s)
Amino Acids/pharmacology , Antineoplastic Agents/pharmacology , Dipeptides/pharmacology , Drug Design , Pyrazines/pharmacology , Triterpenes/pharmacology , Amino Acids/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dipeptides/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Male , Molecular Structure , Pyrazines/chemistry , Structure-Activity Relationship , Triterpenes/chemistry , ZebrafishABSTRACT
As for complex brain diseases involved with multiple pathogenic factors, it is extremely difficult to achieve curative effect by acting on a single target. Multi-approach drugs provide a promising prospect in the treatment of complex brain diseases and have been attracting more and more interest. Enlightened by synergetic effect of combination in traditional herb medicines, forty-two novel cinnamic acid derivatives were designed and synthesized by introducing capsaicin and/or ligustrazine moieties to enhance biological activities in both neurological function and neurovascular protection. Elevated levels of cell viability on human brain microvascular endothelium cell line (HBMEC-2) and human neuroblastoma cell line (SH-SY5Y) against free radical injury were observed in most of compounds. Among them, compound 14a exhibited the most potent activities with a significant EC50 value of 3.26⯱â¯0.16⯵M (HBMEC-2) and 2.41⯱â¯0.10⯵M (SH-SY5Y). Subsequently, the results of morphological staining and flow cytometry analysis experiments on both cell lines showed that 14a had the potential to block apoptosis, maintain cell morphological integrity and protect physiological function of mitochondria. Moreover, 14a displayed specific angiogenesis effect in the chick chorioallantoic membrane (CAM) assay; and the results of RT-PCR suggested that the mechanism for angiogenesis effect was associated with the enhancement of the expressions of VEGFR2 mRNA in chick embryo. Preliminary structure-activity relationship was analyzed. The above evidences suggested that conjunctures gained by combining active ingredients in traditional herb medicines deserved further study and might provide references in discovering dual-effective lead compounds for brain diseases.
Subject(s)
Angiogenesis Inducing Agents/pharmacology , Cinnamates/pharmacology , Drug Design , Neuroprotective Agents/pharmacology , Angiogenesis Inducing Agents/chemical synthesis , Angiogenesis Inducing Agents/chemistry , Apoptosis/drug effects , Capsaicin/chemistry , Capsaicin/pharmacology , Cell Line , Cell Survival/drug effects , Cinnamates/chemical synthesis , Cinnamates/chemistry , Dose-Response Relationship, Drug , Humans , Membrane Potential, Mitochondrial/drug effects , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Oxidative Stress/drug effects , Pyrazines/chemistry , Pyrazines/pharmacology , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/metabolism , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Glycyrrhetinic acid (GA) had been the star anticancer lead compound and appealed to many scientists all over the world; however, its antitumor activity was not potent enough. To improve GA's cytoxicity and explore the effect of bonding mode on antitumor activity, 32 compounds including GA-OH series (GO, esters in C-3 position) and GA-NH2 series (GN, with amide linkages in C-3 position) had been designed and synthesized. All the compounds were screened for in vitro cytotoxicity against A549, HepG2, MCF-7, Hela and MDCK cell lines. As a result, all the de-protected (without Boc group) derivatives showed much stronger cytotoxic activity than GA, and surprisingly enough, all the GN series of the compounds were more potent than GO series against various tumor cells. Among them, the compound 26 (amide linkages in C-3 position) exhibited stronger antitumor activity against A549â¯cell line (IC50â¯=â¯2.109⯱â¯0.11⯵M) than the positive drug cisplatin (IC50â¯=â¯9.001⯱â¯0.37⯵M). Further studies indicated that compound 26 could induce A549 apoptosis via nuclei fragmentation. The detection of apoptosis and cell cycle analysis indicated that compound 26 could induce the early apoptosis and prevent A549â¯cells transition from S to G2 phase. Furthermore, the structure-activity relationships were briefly discussed. Among which, current study displayed amide linkages in C-3 position could effectively enhance GA cytotoxicity, providing a new modification strategy for further study.
Subject(s)
Antineoplastic Agents/pharmacology , Glycyrrhetinic Acid/pharmacology , Madin Darby Canine Kidney Cells/drug effects , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glycyrrhetinic Acid/chemical synthesis , Glycyrrhetinic Acid/chemistry , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Rapid developments in nanotechnology have led to the release of substantial amounts of nanoparticles (NPs) into aquatic environments, where many types of biotic particles are present and could potentially interact with the NPs. Nevertheless, how biotic particles may affect the bioaccumulation and toxicity of NPs remains largely unknown. In the present study, we investigated the effects of the green alga Chlamydomonas reinhardtii on the accumulation kinetics (uptake, assimilation, efflux) and toxicity of polyacrylate-coated hematite NPs (HemNPs), using Daphnia magna as the test organism. As a biotic particle and daphnid food, C. reinhardtii reduced the accumulation and toxicity of HemNPs in D. magna. The HemNPs were well-dispersed with little adsorption to the alga. Their decreased accumulation could thus be partly explained by their low trophic transfer from the alga to the daphnid and by the inductive effects of the alga on HemNP efflux. However, the main cause was the direct inhibition of HemNP uptake from the water phase as a result of the reduced water-filtration activity of D. magna in the presence of C. reinhardtii. Overall, in bioaccumulation studies, the inhibitory effects of biotic particles on NP uptake from the water phase should be paid attention.
Subject(s)
Nanoparticles , Water Pollutants, Chemical , Animals , Daphnia , Ferric Compounds , WaterABSTRACT
Deoxynivalenol (DON, vomitoxin) is the most common mycotoxin in cereals and grains. DON contamination can cause a serious health threat to humans and farm animals. DON has been reported to exert significant toxicity effects on the male reproductive system. However, the causes and mechanisms underlying efforts of DON on sperm and testicular damage remain largely unclear. In the present study, we thoroughly investigated this issue. Eighty male BALB/c mice were randomly divided into a control group ( n = 40) and DON treatment group (2.4 mg/kg of body weight, n = 40). The ratio of testes and seminal vesicle to body, sperm survival and motility, and morphology of sperm and testis were observed in DON-treated and control mice. In addition, the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and glutathione (GSH), and also the expression levels of JNK/c-Jun signaling and apoptotic factors such as caspase-3, caspase-8, caspase-9, Bim, and Bid were analyzed and compared between the two groups. The results demonstrated that a single topical application of DON significantly increased the percentage of abnormal sperm and decreased the motility of sperm, indicating the sperms are damaged by DON. Additionally, the reduced relative body weight of testis and severe destruction of testicular morphology were observed. Moreover, the increased levels of ROS and MDA levels and decreased activities of SOD and GSH were found in testicular tissues, suggesting that oxidative stress is induced by DON treatment. Furthermore, DON upregulated the expression of stress-induced JNK/c-Jun signaling pathway proteins as well as JNK/c-Jun phosphorylation proteins. In addition, DON could enhance testicular apoptosis by increasing expression levels of apoptotic genes including Bim, cytochrome c, caspase 3, caspase 8, and caspase 9. These results suggest that DON exposure can cause sperm damage, oxidative stress, testicular apoptosis, and phosphorylation of JNK/c-Jun signaling pathway. The underlying mechanisms may be that DON induces sperm damage by exacerbating oxidative stress-mediated testicular apoptosis via JNK/c-Jun signaling pathway.
Subject(s)
Spermatozoa/drug effects , Testis/drug effects , Trichothecenes/toxicity , Animals , Caspase 3/metabolism , Glutathione/metabolism , MAP Kinase Signaling System/drug effects , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred BALB C , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Spermatozoa/cytology , Spermatozoa/metabolism , Superoxide Dismutase/metabolism , Testis/cytology , Testis/metabolismABSTRACT
PURPOSE: We aimed to identify predisposing factors that could help predict the therapeutic response of adenomyosis after uterine artery embolization (UAE). METHODS: This was a retrospective, single-center study of patients admitted to the hospital for adenomyosis between 2013 and 2015. Sixty-eight patients with adenomyosis who underwent UAE with tris-acryl gelatin microspheres were divided into two groups based on their therapeutic response (complete or incomplete necrosis of lesions), and pre- and postprocedural pelvic magnetic resonance imaging (MRI) data. Patients were followed up for 12 months after UAE. Improvements in dysmenorrhea and menorrhagia were evaluated based on the symptom relief criteria. Improvement rates in both groups were analyzed and compared. Multivariate logistic regression analysis was used to identify the predisposing factors from retrospectively gathered baseline data that might affect the therapeutic response, including MRI features, clinical symptoms, biochemical index, and accompanying diseases of adenomyosis. Then, a prognostic model was established, and the receiver operating characteristic (ROC) curve of identified factors was drawn to determine their predictive value. RESULTS: Following UAE, 46 patients (67.6%) showed complete necrosis, while 22 patients (32.4%) showed incomplete necrosis. At 12-month follow-up, dysmenorrhea symptom improvement was seen in 94.7% of complete necrosis and 50% of incomplete necrosis group (P < 0.001); menorrhagia symptom improvement was seen in 96.2% of complete necrosis and 57.1% of incomplete necrosis groups (P = 0.004). Multivariate logistic regression analysis determined serum cancer antigen 125 (CA125) levels (odds ratio [OR], 1.006; 95% confidence interval [CI], 1.002-1.010; P = 0.005) and accompanying endometriosis (OR, 6.869; 95% CI, 1.881-25.016; P = 0.004) as predisposing factors. The areas under the ROC curve of CA125, endometriosis, and these two indicators combined were 0.785, 0.708, and 0.845, which corresponded to sensitivities of 95.5%, 66.7%, and 68.2% and specificities of 52.2%, 80.0%, and 87.0% at optimal cutoff values, respectively. CONCLUSION: Symptom relief of dysmenorrhea and menorrhagia for patients with complete necrosis was significantly better than that for patients with incomplete necrosis. Serum CA125 levels and accompanying endometriosis can effectively distinguish complete necrosis from incomplete necrosis.
Subject(s)
Adenomyosis/blood , Adenomyosis/surgery , CA-125 Antigen/blood , Endometriosis/blood , Endometriosis/complications , Membrane Proteins/blood , Uterine Artery Embolization/methods , Adenomyosis/complications , Adult , Endometriosis/diagnostic imaging , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Middle Aged , Myometrium/diagnostic imaging , Myometrium/surgery , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new Heâ»pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 µM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 µM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 µM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structureâ»activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.
Subject(s)
Drug Design , Oleanolic Acid/analogs & derivatives , Pyrazines/chemical synthesis , Pyrazines/toxicity , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Death , Cell Line, Tumor , Cell Shape/drug effects , Cluster Analysis , Discriminant Analysis , Humans , Inhibitory Concentration 50 , Least-Squares Analysis , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/toxicity , Principal Component Analysis , Pyrazines/chemistry , Staining and Labeling , Structure-Activity RelationshipABSTRACT
Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMAâº) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 µM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMAâº), while it was minimized in HepG2 (PSMA-) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMAâº) cells than in HepG2 (PSMA-) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase.