The importance of nicotinamide adenine dinucleotide (NAD+) in human physiology is well recognized. As the NAD+ concentration in human skin, blood, liver, muscle, and brain are thought to decrease with age, finding ways to increase NAD+ status could possibly influence the aging process and associated metabolic sequelae. Nicotinamide mononucleotide (NMN) is a precursor for NAD+ biosynthesis, and in vitro/in vivo studies have demonstrated that NMN supplementation increases NAD+ concentration and could mitigate aging-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammatory responses. The promotion of NMN as an antiaging health supplement has gained popularity due to such findings; however, since most studies evaluating the effects of NMN have been conducted in cell or animal models, a concern remains regarding the safety and physiological effects of NMN supplementation in the human population. Nonetheless, a dozen human clinical trials with NMN supplementation are currently underway. This review summarizes the current progress of these trials and NMN/NAD+ biology to clarify the potential effects of NMN supplementation and to shed light on future study directions.

Purpose:The uncoordinated-51 like kinase 1 (ULK1) is an important serine/threonine protein kinase involved in autophagy, especially for the initiation stage. Previous studies have shown that ULK1 could be used as a prognostic marker in predicting poor progression-free survival and a therapeutic target for hepatocellular carcinoma (HCC) when treated with sorafenib; however, its role during hepatocarcinogenesis remains to be elucidated.Methods:CCK8 and colony formation assay were used to detect cell growth ability. Western blotting was performed to determine expression level of protein. Data from public database were downloaded to analyze expression of ULK1 at mRNA level and predict survival time. RNA-seq was conducted to reveal disturbed gene profile orchestrated by ULK1 depletion. A diethylnitrosamine (DEN)-induced HCC mice model was used to uncover the role of ULK1 in hepatocarcinogenesis.Results:ULK1 was up-regulated in liver cancer tissues and cell lines, and knockdown of ULK1 promoted apoptosis and suppressed proliferation of liver cancer cells. In in vivo experiments, Ulk1 depletion attenuated starvation-induced autophagy in mice liver, reduced diethylnitrosamine (DEN)-induced hepatic tumor number and size, and prevented tumor progression. Further, RNA-seq analysis revealed a close relationship between Ulk1 and immunity with significant changes in gene sets enriched in the interleukin and interferon pathways.Conclusion:ULK1 deficiency prevented hepatocarcinogenesis and inhibited hepatic tumor growth, and might be a molecular target for the prevention and treatment of HCC.

Background: Given the increasing exposure of humans to environmental chemicals and the limitations of con-ventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. Objectives: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets.Methods: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts.Results: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 x10- 5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts.Conclusion: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

Nickel-zinc (Ni-Zn) batteries have received extensive attention in the field of energy storage. However, the unsatisfactory durability greatly impedes their wider commercial application. Herein, a novel and efficient zinc induced phase reconstruction method was reported to boost the electrochemical stability of cobalt-nickel double hydroxide (CoNi-DH) cathode materials for developing high-stability and high-rate Ni-Zn batteries. The inherent mechanism for this phase reconstruction method to achieve the improvement of electrochemical stability was systematically investigated and clarified in this work by combining theoretical calculations and experimental tests. The research results confirmed that the zinc-induced phase reconstruction can produce a new phase of Zn2Co3(OH)(10)center dot 2H(2)O in the mixed-phase of CoNi-DH without sacrificing its hierarchical micro-nano structure. This Zn2Co3(OH)(10)center dot 2H(2)O phase has a much smaller shrinkage of the lattice spacing of host layers during the redox reaction relative to the pure Co(OH)(2) phase, thereby it can inhibit structural damage during the charge-discharge cycle. In addition, the retained hierarchical micro-nano structure can ensure good capacity output. Therefore, the as-fabricated mixed hydroxide electrode and Ni-Zn battery achieve remarkable improvement in the cycling life and exhibit superior rate performance. Moreover, the resultant mixed hydroxide electrode displays good application in the flexible quasi-solid-state Ni-Zn battery.

AbstractBackgroundOral squamous cell carcinoma (OSCC) is one of malignant tumors in oral and maxillofacial region with high fatality. Huanglianjiedu Decoction (HLJDD) is a well-known traditional Chinese medicinal prescription, which consists ofCoptis chinensis Franch,Scutellaria baicalensis Georgi,Phellodendron amurense RuprandGardenia jasminoides J.Ellis. Some clinical studies showed HLJDD had good effectiveness on OSCC, but the mechanism is unclear.MethodsIn this study, potential components of HLJDD and putative targets were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combining with potential targets of OSCC searched from Therapeutic Target Database (TTD) and Online Mendelian Inheritance in Man (OMIM), we drew protein–protein interaction (PPI) network by Cytoscape v3.2.0 software. After topological analysis we got core targets and further did Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then we did the in vitro experiments to verify the major biological processes (cell cycle, apoptosis and proliferation) and signaling pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), protein kinase B (AKT)) on OSCC cell lines, SCC-25 and CAL-27.ResultsThe potential component targets number ofCoptis chinensis Franch,Scutellaria baicalensis Georgi,Phellodendron amurense RuprandGardenia jasminoides J.Elliswere 39, 93, 81and 88, respectively. Then we got 52 core targets which enriched in cell cycle, apoptosis, proliferation, MAPK activation etc. and obtained TOP30 pathways. On SCC-25 and CAL-27, HLJDD suppressed cell proliferation, induced late apoptosis and inhibited cell invasion and migration which were consistent with the results from network pharmacology analysis. Additionally, in cell cycle, we confirmed HLJDD inhibited G1 phase and arrested in S phase to reduce cell proliferation on SCC-25. In signaling pathways, HLJDD inhibited the phosphorylation of extracellular regulatory protein kinase 1/2 (ERK1/2) and NF-κB p65 (S468) on SCC-25 and CAL-27.ConclusionsHLJDD played a potential therapeutic role on OSCC via inhibiting p-ERK1/2 and p-NF-κB p65 (S468).Graphical abstract

The plasticizer di(2-ethylhexyl) phthalate (DEHP) and its hydrolysate mono(2-ethylhexyl) phthalate (MEHP) are major toxicants from plastics, but their association with hormone-dependent cancers has been controversial. We treated the human ovarian cancer cell lines SKOV3 and A2780 with low concentrations of DEHP/MEHP, and found that although no significant effect on cell proliferation was observed, ovarian cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) were promoted by submicromolar MEHP but not DEHP. Next, ovarian cancer patient data from The Cancer Genome Atlas (TCGA) were obtained and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) supported enrichment and Kaplan-Meier survival analyses, which identified PI3K/Akt pathway as a pivotal signaling pathway in ovarian cancer. We found that 500 nM MEHP treatment significantly increased PIK3CA expression, which could be reversed by the knockdown of peroxisome proliferator-activated receptor alpha (PPARα). Silencing PIK3CA significantly suppressed the MEHP-induced migration, invasion and EMT. In addition, we validated that MEHP treatment promoted phosphorylation of Akt and degradation of IκB-α, thereby activating NF-κB and enhancing NF-κB nuclear translocation. In nude mice, MEHP exposure significantly promoted the metastasis of ovarian cancer xenografts, which could be suppressed by the treatment of PPARα inhibitor GW6471. Our findings showed that low-dose MEHP promoted ovarian cancer progression through activating PI3K/Akt/NF-κB pathway, in a PPARα-dependent manner.

The relatively low specific capacitance of flexible carbons hinders their practical application for fabricating high-performance flexible supercapacitors. In this work, a surface engineering method is proposed to boost the supercapacitive performance of the flexible carbon. In this method, a flexible carbon was fabricated from carbon felt via co-activation with potassium argininate and potassium hydroxide (KOH) as activators, and the resulting material is abbreviated as AKCF. Unlike traditional KOH activation processes, the addition of potassium argininate can produce a micro-graphitized carbon layer to be the outer layer of AKCF fibers for achieving better electronic transfer. Due to the improved conductivity and lower charge transfer resistance endowed by a thin micro-graphitized carbon layer, the capacitance of the AKCF-0.1 (0.1 M arginine was used) electrode obtained by the co-activation process is elevated to a 1.8-fold higher value of 403 C.g(-1) (2583 mC.cmz) relative to the AKCF-0 (0 M arginine was used) electrode prepared by KOH activation alone (222 C.g(-1) or 1369 mC.cmz). Moreover, this AKCF-0.1 electrode also displays satisfactory rate capability (66% capacitance retention after a 20-fold current increase) and highly stable cycling performance (no capacitance decline after 20,000 cycles). In addition, the asymmetric supercapacitors constructed with this AKCF-0.1 electrode as the flexible negative electrode expresses high energy densities of 68.4 Wh.kg(-1) and 0.139 mWh.cm(-2) in aqueous and gel electrolytes, respectively. (C) 2021 Elsevier Inc. All rights reserved.

The electrochemical oxygen evolution reaction (OER) by efficient catalysts is a crucial step for the conversion of renewable energy into hydrogen fuel, in which surface/near-surface engineering has been recognized as an effective strategy for enhancing the intrinsic activities of the OER electrocatalysts. Herein, a facile quenching approach is demonstrated that can simultaneously enable the required surface metal doping and vacancy generation in reconfiguring the desired surface of the NiCo2 O4 catalyst, giving rise to greatly enhanced OER activities in both alkaline freshwater and seawater electrolytes. As a result, the quenched-engineered NiCo2 O4 nanowire electrode achieves a current density of 10 mA cm-2 at a low overpotential of 258 mV in 1 m KOH electrolyte, showing the remarkable catalytic performance towards OER. More impressively, the same electrode also displays extraordinary activity in an alkaline seawater environment and only needs 293 mV to reach 10 mA cm-2 . Density functional theory (DFT) calculations reveal the strong electronic synergies among the metal cations in the quench-derived catalyst, where the metal doping regulates the electronic structure, thereby yielding near-optimal adsorption energies for OER intermediates and giving rise to superior activity. This study provides a new quenching method to obtain high-performance transition metal oxide catalysts for freshwater/seawater electrocatalysis.

A simple one-step combustion reaction between 2-methylimidazole (C4H6N2) and sodium nitrate (NaNO3) is employed to convert bamboo powder to produce an N, O co-doped porous carbon (BC-CNa) for usage as a zincion hybrid supercapacitor (ZnHS) cathode material. The as-prepared BC-CNa owns proper N, O co-doping, diverse carbon defects, and high specific surface area and pore volume. Owing to the combined effect of these features, the ZnHS fabricated with this BC-CNa as the cathode material exhibits much higher specific capacities and energy densities than the ZnHSs based on pristine bamboo-derived carbon (BC), bamboo plus C4H6N2 derived carbon (BC-C), and bamboo plus NaNO3 derived carbon (BC-Na). The maximum specific capacity and energy density of BC-CNa based ZnHS can reach 51.4 mA h g(-1) and 48.3 Wh kg(-1), respectively. And this ZnHS also exhibits superb cycle stability with 96 % capacity retention after 90,000 cycles.

The unsatisfactory cycle life of nickel-based cathodes hinders the widespread commercial usage of nickel-zinc (Ni-Zn) batteries. The most frequently used methods to improve the cycle life of Ni-based cathodes are usually complicated and/or involve using organic solvents and high energy consumption. A facile process based on the hydrolysis-induced exchange of the cobalt-based metal-organic framework (Co-MOF) was developed to prepare aluminum (Al)-doped cobalt-nickel double hydroxides (Al-CoNiDH) on a carbon cloth (CC). The entire synthesis process is highly efficient, energy-saving, and has a low negative impact on the environment. Compared to undoped cobalt-nickel double hydroxide (Al-CoNiDH-0%), the as-prepared Al-CoNiDH as the electrode material displays a remarkably improved cycling stability because the Al-doping successfully depresses the transition in the crystal phase and microstructure during the long cycling. Benefiting from the improved performance of the optimal Al-CoNiDH electrode (AlCoNiDH-5% electrode), the as-constructed aqueous Ni-Zn battery with Al-CoNiDH-5% as the cathode (AlCoNiDH-5%//Zn) displays more than 14% improvement in the cycle life relative to the Al-CoNiDH-0%//Zn battery. Moreover, this Al-CoNiDH-5%//Zn battery achieves a high specific capacity (264 mAh g(-1)), good rate capability (72.4% retention at a 30-fold higher current), high electrochemical energy conversion efficiency, superior fast-charging ability, and strong capability of reversible switching between fast charging and slow charging. Furthermore, the as-assembled quasi-solid-state Al-CoNiDH-5%//Zn battery exhibits a decent electrochemical performance and satisfactory flexibility. (C) 2020 Elsevier Inc. All rights reserved.

Low-cost, high-performance, and long-life cathode materials are highly desired for zinc ion hybrid supercapacitors (ZHSs). Here, an N, O co-doped two-dimensional (2D) carbon nanosheet material is successfully fabricated via a one-step combustion conversion of wood for the excellent usage as the cathode material in zincion hybrid supercapacitors. This novel combustion conversion synthesis with Zn(NO3)(2)center dot 6H(2)O as oxidizer and urea as fuel can easily achieve the carbonization, pore-forming, and heteroatom doping within a one-step process. More interestingly, the resulting N, O co-doped porous carbon owns relatively uniform 2D sheet structure and very high specific surface area (1248 m(2) g(-1)), which can not only provide short electric/ionic transfer path plus optimized wettability and conductivity for high power output, but also offer abundant interfacial active sites as well as improved ion adsorption capacity for high energy storage. Benefiting from these advantages, the ZHS based on this N, O co-doped 2D carbon nanosheets exhibits a superior specific capacity of 111.0 mAh g(-1) at 0.1 A g(-1), high rate capability of 57.6% capacity retention at a 30-fold higher current, and attractive energy density of 109.5 Wh kg(-1) at 225 W kg(-1). More gratifyingly, it displays ultralong cycling life with 92.7% capacity reservation after 50,000 charge and discharge cycles. Moreover, a quasi-solid ZHS with N, O co-doped 2D carbon nanosheets coated on the carbon cloth as the cathode also displays satisfactory specific capacity (34.6 mAh g(-1)), impressive energy density (27.7 Wh kg(-1)), and nice flexibility.

Objective: To explore the association between sleep duration, sleep quality and the prevalence of hypertension in the elderly aged 65 years and above. Methods: This study was conducted among the elderly in communities in Yiwu, China from April to July, 2019, and participants were recruited through physical examination in the hospital. Face-to-face interview was performed to obtain basic information. Sleep duration and sleep quality were evaluated by Pittsburgh Sleep Quality Index (PSQI). Associations between sleep duration, sleep quality and hypertension were evaluated by multivariate logistic regression analysis. Results: A total of 3 169 elderly persons, aged ≥65 years old, were included in the study. The overall prevalence of hypertension was 50.8%. The elderly with very poor sleep quality and short sleep duration accounted for 22.4% and 28.5%, respectively. After adjusting for demographic characteristics, socioeconomic status, lifestyle and health status, the OR of hypertension for the elderly with very poor sleep quality was 1.42 (95%CI: 1.12-1.80) compared with those with very good sleep quality. Compared with the elderly with sleep duration of 6-7 h a night, the OR of hypertension for those with sleep duration <6 h was 1.37 (95%CI: 1.15-1.65). As the sleep quality decreased, the risk for hypertension increased. An U-shaped association was found between sleep duration and risk of hypertension. Subgroup analyses showed that this association existed in both men and women, but only significant in the elderly aged <75 years. Conclusion: Poor sleep quality and short sleep duration were associated with risk for hypertension in the elderly.

Aspartame (ASP) and sucralose (SUC) are non-nutritive sweeteners which are widely consumed worldwide. They are considered safe for human consumption, but their effects on certain physiological aspects, such as the lifespan or health status, of the organism have not yet been studied in depth and only limited data are available in the literature. The objectives of this study were to evaluate the effects of ASP and SUC on the lifespan and health indexes using Caenorhabditis elegans (C. elegans) as a model system. Interestingly, it was shown that at the concentrations tested, ASP (0.03-3 mg mL-1) showed an increasing trend of the mean lifespan of C. elegans, with a significant increase of 27.6% compared to the control at 3 mg mL-1. Similarly, SUC (ranging from 0.03 to 10 mg mL-1) also significantly increased the mean lifespan by 20.3% and 22.3% at 0.03 and 0.3 mg mL-1, respectively. However, 10 mg mL-1 SUC had a negative effect on the lifespan, though it did not reach a statistically significant level. In addition, ASP and SUC decreased lipofuscin accumulation and transiently improved motility, indicating improved health status. Nonetheless, they had different effects on food intake and intestinal fat deposition (IFD) at different intervals of time. Taken together, our findings revealed that ASP and SUC can prolong the lifespan and improve the health status of C. elegans.

Rational design of micro-nano morphology and suitable crystalline structure are highly desired for metal hydroxides to achieve overall high-performance in the advanced electrodes for flexible supercapacitors. Herein, a novel wisteria flower-like microstructure of cobalt-nickel double hydroxide (CoNi-DH) is successfully constructed on carbon cloth (CC) using an in-situ hydrolysis-induced exchange process between hydroxide ions and organic ligands of the Co-MOF in four different kinds of solutions containing Ni2+. The as-prepared wisteria flower-like microstructure grown on CC shows vertically aligned arrays with high specific area and abundant active sites, which not only guarantee the CoNi-DH active materials to be thoroughly exposed in the electrolyte, resulting in highly effective pseudocapacitive energy storage, but also are beneficial to rapid and reversible redox kinetics and thus give rise to high-rate capability. In addition, compared to Ni(NO3)2, NiCl2, and Ni(CH3COO)2 solutions, the Ni2SO4 solution is found to facilitate the formation of the most regular morphology and the largest interlayer spacing on (003) plane of the layered nickel hydroxide phase in the resultant CoNi-DH. As a result, the optimal CoNi-DH-S@CC (CoNi-DH prepared in Ni2SO4) serves as an advanced electrode to show high-rate capability (only 13% Cs decay after a 15-fold current elevation) and a superior specific capacity (Cs) of 929.4 C g-1, which remarkably exceeds those of CoNi-DH-N (823.1 C g-1, in Ni(NO3)2), CoNi-DH-Cl (798.4 C g-1, in NiCl2), CoNi-DH-C (803.8 C g-1, in Ni(CH3COO)2), and other similar metal hydroxides. Moreover, with this CoNi-DH-S electrode as the positive electrode, the as-prepared asymmetric supercapacitor (ASC) delivers an impressive capacity of 204.8 C g-1, a superior energy density of 42.5 Wh kg-1, and satisfactory cycle life (81.5% reservation after 7500 cycles). As a proof-of-concept application, a quasi-solid-state ASC is further successfully fabricated based on the CoNi-DH-S electrode to exhibit encouraging application potential.

Aging is the primary driver of various diseases, including common neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Currently there is no cure for AD and PD, and the development of novel drug candidates is demanding. Spermidine is a small anti-aging molecule with elimination of damaged mitochondria via the process of mitophagy identified as a molecular mechanism of action. Here, we show that spermidine inhibits memory loss in AD worms and improves behavioral performance, e.g., locomotor capacity, in a PD worm model, both via the PINK1-PDR1-dependent mitophagy pathway. Additionally, spermidine delays accelerated aging and improves healthspan in the DNA repair-deficient premature aging Werner syndrome (WS) worm model. While possible intertwined interactions between mitophagy/autophagy induction and DNA repair by spermidine are to be determined, our data support further translation of spermidine as a possible therapeutic intervention for such diseases.

Tongue squamous cell carcinoma (TSCC) accounts for a large proportion of cases of head and neck cancer. Transient receptor potential melastatin 2 (TRPM2) is a non‑selective cation channel sensitive to oxidative stress. High TRPM2 expression has been reported in various types of cancer, including neuroblastoma, glioblastoma, non‑small cell lung cancer and breast cancer. However, whether expression levels of TRPM2 are associated with aggressive clinical features in TSCC remains unclear. A total of 26 clinical sample tissues with TSCC were collected in the present study. The expression levels of the TRPM2 channel were determined by immunohistochemistry, western blot, and qPCR analysis. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured to reveal oxidative stress levels in TSCC tissues with different degrees of differentiation. The protein expression levels of caspase‑8, Bcl‑xL, Bax, caspase‑9, cleaved caspase‑9, caspase‑3, cleaved caspase‑3, poly [ADP‑ribose] polymerase (PARP) and cleaved PARP were detected by western blot analysis. Analysis of the tissue specimens from 26 patients with TSCC showed that TRPM2 was not upregulated in all specimens. Notably, the expression levels of TRPM2 were associated with the histological grading of different tissues. The specimens with low TRPM2 expression were significantly associated with moderate or poor differentiation (P=0.003), and exhibited increased lipid peroxidation level and decreased SOD activity. Furthermore, the altered expression of pro‑ and anti‑apoptotic proteins indicated a significant upregulation of apoptosis in TSCC tissues with low TRPM2 expression. These results suggested that low TRPM2 expression in TSCC may inhibit the ability of cells to adapt to or resist the oxidative stress, resulting in increased susceptibility to apoptosis. Therefore, the oxidative stress‑sensitive TRPM2 channel may serve as a potent biomarker, and the present study provides insights into the underlying mechanisms of tumor cell differentiation.

Synthesis of hollow colloidal particles with a well-defined structure in a single step is challenging and highly desired for numerous applications. We propose a simple and productive approach to synthesize hierarchical nickel hydroxidenitrate hollow colloidal particles (NiHNHCP) with tunable structure and property via a one-pot manner for the application in supercapacitor. In this approach, the formation of the NiHN shells and the dissolution of the melamine-formaldehyde (MF) template particles occur simultaneously and successively under a solvothermal condition with time. It is found that the nickel precursors can protonate the solvent, declining the pH and further causing the dissolution of the MF particles. Meanwhile, the nickel precursors transform into NiHN nanosheets that self-assemble into hierarchical shells exclusively at the surface of the MF particles. With the reactions proceeding, the NiHNHCP are yielded ultimately. These NiHNHCP are characterized with superior electrochemical performance, making them practically useful in the application of supercapacitor.

BACKGROUND:Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation. RESULTS:Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice. CONCLUSION:The ROS/PARP/TRPM2 signaling is critical in SiNPs-induced pulmonary inflammation, providing novel mechanistic insights into NPs-induced lung injury. Our study identifies TRPM2 channel as a new target for the development of preventive and therapeutic strategies to mitigate nanomaterials-induced lung inflammation.

The melamine and cyanuric acid (CA) complex has been suggested to cause the toxic effects observed in melamine-contaminated food or milk. However, the cytotoxic and genotoxic effects of co-exposure to melamine and CA are not fully clear. Therefore, the cytotoxic effects of melamine and CA were first examined by co‐exposure in human kidney 293 cells using the MTT assay. During a 24-h period for the three concentrations tested (0.5, 1, and 5 mg/mL), neither melamine nor CA alone showed significant toxic effects on 293 cells at 0.5 mg/mL, while higher concentrations led to decreased in cell viability. However, co-exposure to several combinations of melamine and CA [100:1, 10:1, 1:10, and 1:100 (v:v), at a final concentration of 0.5 mg/mL] did cause cytotoxicity with higher levels of CA leading to higher cytotoxicity. By contrast, while neither melamine nor CA alone induced phosphorylated-H2AX (γH2AX) foci formation, melamine and CA at a 100:1 ratio induced γH2AX foci 24 h post-treatment. The alkaline comet assay also revealed the presence of DNA damage following melamine and CA co-exposure. In vivo assay also revealed the presence of melamine-CA complex in the kidney. These data indicated that the cytotoxic and genotoxic effects of melamine and CA co-exposure differ from those of melamine or CA alone.

Cisplatin is a first-line chemotherapeutic agent for the treatment of many types of cancer, but the emergence of chemoresistance hinders its application. Thus, a better understanding of cisplatin-induced DNA damage response (DDR) would help to overcome this problem. Previously, we have identified a panel of microRNAs with altered expression after cisplatin treatment in HeLa cells. In the current study, we focused on one of them, miR-191, and investigated its function in cisplatin-induced DDR. We found that overexpression of miR-191 sensitized HeLa cells to the cytotoxic effects of cisplatin, resulted in decreased viable cells. However, overexpression of miR-191 did not cause changes in apoptotic cell ratio but rather induced significant G2/M arrest in HeLa cell treated with cisplatin. Additionally, enhanced cisplatin-induced DNA damage was observed. Through bioinformatic analysis and verified by dual-luciferase assay, it was demonstrated that the chromosome condensation 2 regulator (RCC2) gene is a target for miR-191 regulation. Furthermore, the downregulation of RCC2 by siRNA mimics the effects of miR-191, in which greater DNA damage was observed upon cisplatin treatment. Taken together, our study indicates that miR-191 may be an important player in cisplatin-induced DDR, and it elicits its function, at least partially, through the regulation of RCC2.