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Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, -7, -9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and -7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and -7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and -7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the last decades, 4-nitrophenol is regarded as one of highly toxic organic pollutants in industrial wastewater, which attracts great concern to earth sustainability. Herein, atomically dispersed ternary FeCoNb active sites were incorporated into nitrogen-doped honeycomb-like mesoporous carbon (termed FeCoNb/NHC) by a two-step pyrolysis strategy, whose morphology, structure and size were characterized by a set of techniques. Further, the catalytic activity and reusability of the as-prepared FeCoNb/NHC were rigorously examined by using 4-NP catalytic hydrogenation as a proof-of-concept model. The influence of the secondary pyrolysis temperature on the catalytic performance was investigated, combined by illuminating the catalytic mechanism. The resultant catalyst exhibited significantly enhanced catalytic features with a normalized rate constant (k app ) of 1.2 × 10 4 min -1 g -1 and superior stability, surpassing the home-made catalysts in the control groups and earlier research. This study provides some constructive insights for preparation of high-efficiency and cost-effectiveness single-atom nanocatalysts in organic pollutants environmental remediation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Facile synthesis of high-efficiency and stable bifunctional electrocatalyst is essential for producing clean hydrogen in energy storage systems. Herein, low Rh-doped flower-like Ni 3 S 2 /Co 3 S 4 heterostructures were facilely prepared on porous nickel foam (labeled Rh-Ni 3 S 2 /Co 3 S 4 /NF) by a hydrothermal method. The correlation of the precursors types with the morphological structures and catalytic properties were rigorously investigated for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in the control groups. The low Rh doping within the catalyst played important role in boosting the catalytic characteristics. The resulting catalyst showed the smaller overpotentials of 197 and 78 mV to drive a current density of 10 mA cm -2 for the OER and HER in alkaline electrolyte, respectively. And the potential only required 1.71 V to drive a current density of 100 mA cm -2 in a water splitting device. It reflects excellent overall water splitting of the home-made Rh-Ni 3 S 2 /Co 3 S 4 /NF. This strategy shed some constructive light for preparing transition metal sulfide-based electrocatalysts in water splitting devices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Primary sinonasal mucosal melanoma is a rare aggressive malignancy. In this video, a case of a 68-year-old female who presented with diplopia for 2 weeks is described. The present video reports the endoscopic endonasal surgical excision of a primary sinonasal mucosal melanoma. The video contains patient's medical history, preoperative radiological evaluations and step-by-step description of surgical steps of the procedure with the utilization of computer-assisted navigation system., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The prevention of postoperative recurrence after endoscopic sinus surgery (ESS) relies on targeting specific pathological mechanisms according to individuals' immunological profiles. However, essential biomarkers and biological characteristics of difficult-to-treat chronic rhinosinusitis (CRS) patients are not well-defined. The aim of this study was to explore the immunologic profiles of subgroups of CRS patients and determine the specific cytokines responsible for recalcitrant or recurrent CRS with nasal polyposis (rCRSwNP). We used 30 cytokine antibody arrays to determine the key cytokines related to recurrent polypogenesis. Enzyme-linked immunosorbent assay (ELISA) experiments were conducted to assess the levels of these key cytokines in 78 patients. Polymorphonuclear leukocytes (PMNs) isolated from nasal polyps were challenged with specific cytokines to examine the levels of enhanced interleukin (IL)-8 production. Finally, we used immunohistochemistry (IHC) staining to check for the presence and distribution of the biomarkers within nasal polyps. A cytokine antibody array revealed that IL-8, IL-13, IL-15, and IL-20 were significantly higher in the recalcitrant CRSwNP group. Subsequent ELISA screening showed a stepwise increase in tissue IL-8 levels in the CHR, CRSsNP, and CRSwNP groups. PMNs isolated from nine CRSwNP cases all demonstrated enhanced IL-8 production after IL-15 treatment. IHC staining was labeled concurrent IL-8 and IL-15 expression in areas of prominent neutrophil infiltration. Our results suggest that IL-15 within the sinonasal mucosa plays a crucial role in promoting IL-8 secretion by infiltrating PMNs in recalcitrant nasal polyps. In addition, we propose a novel therapeutic strategy targeting the anti-IL-15/IL-8 axis to treat CRS with nasal polyposis.

Supplementation of oral Ca via blanket administration of an oral Ca bolus at 0 and 24 h after calving has shown limited success in increasing production and minimizing adverse health events. Recent evidence that reductions in blood Ca at 4 d in milk (DIM) are more closely associated with negative outcomes than hypocalcemia at 0 to 24 h postpartum might explain this lack of Ca bolus efficacy. Therefore, our primary objective was to explore the effect of delayed oral Ca bolus supplementation on milk production, with secondary objectives of exploring the effects on disease incidence and postpartum blood Ca dynamics. We conducted a randomized controlled trial on multiparous Holstein cows (n = 998) from 4 herds in New York. At calving, cows were randomly assigned to 1 of 3 treatment groups: (1) control, no supplemental Ca at or around parturition (CON; n = 343); (2) conventional bolus, an oral Ca bolus containing 43 g of Ca at calving and 24 h later (BOL-C; n = 330); or (3) delayed bolus, an oral Ca bolus containing 43 g of Ca at 48 and 72 h after calving (BOL-D; n = 325). We created generalized linear mixed models to analyze differences in milk yield for the first 10 wk of lactation and serum total Ca (tCa) at 1 and 4 DIM between treatment groups; multivariable Poisson regression models were used to analyze adverse event outcomes (metritis, displaced abomasum, herd removal, or a combination of one or more of the 3) in the first 30 DIM. Milk yield increased by week and was not affected by treatment. However, a treatment by parity group interaction for milk yield showed that BOL-D cows in the third parity produced more milk than third-parity BOL-C or CON cows (BOL-D = 52.0 kg/d, 95% confidence interval [50.6, 53.4] kg/d, BOL-C = 47.9 [46.3, 49.5] kg/d, CON = 49.8 [48.2, 51.2] kg/d). The incidence of adverse health events was similar between treatments (BOL-D = 3.7%, BOL-C = 3.7%, CON = 3.6%). Serum tCa was lower at 1 than 4 DIM, and we detected no difference in tCa between treatment groups. Our findings suggest that delaying oral Ca bolus supplementation has limited influence on blood Ca concentrations but may be beneficial to cohorts of cows as a targeted prophylactic supplement to support milk production., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N -Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Highly photoactive 3D nanoflower-like FeIn 2 S 4 /CdS heterostructures were synthesized by hydrothermal treatment and low-temperature cation exchange. The FeIn 2 S 4 /CdS displayed 14.5 times signal amplification in contrast to FeIn 2 S 4 alone. It was applied as a photoactive substrate to construct a label-free photoelectrochemical (PEC) aptasensor for ultrasensitive determination of kanamycin (KAN). Under the optimal conditions, the constructed PEC aptasensor displayed a wide linear range (5.0 × 10 -4  ~ 5.0 × 10 1  ng mL -1 ) and a low detection limit (S/N = 3) of 40.01 fg mL -1 . This study provides some constructive insights for preparation of advanced photoactive materials and exhibits great potential for quantitative determination of antibiotics in foods and environmental samples., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Chlorpyrifos (CPF) is one of the most abundant and widely used organophosphate pesticides for agricultural, industrial, and household purposes in the world. Epidemiological studies have reported that CPF can induce neurotoxic impairments in mammalian, which is linked to an important risk factor for development of neurodegenerative diseases (NDs). However, limited information is available on CPF-induced neurotoxicity, with the underlying exact mechanism remains unclear. In this study, CPF exposure (10-400 μM) significantly reduced Neuro-2a cell viability and induced apoptotic events, including the increase in caspase-3 activity, apoptotic cell population, and cleavage of caspase-3/-7 and PARP. Exposure of Neuro-2a cells to CPF also triggered CHOP activation. Transfection with CHOP-specific siRNA markedly suppressed the expression of CHOP, and attenuated cytotoxicity and apoptotic events in CPF-exposed Neuro-2a cells. Furthermore, CPF exposure obviously evoked the phosphorylation of Akt as well as ROS generation in a time-dependent manner. Pretreatment with LY294002 (an Akt inhibitor) effectively attenuated the CPF-induced Akt phosphorylation, CHOP activation, and apoptotic events, but not that ROS production. Of note, buffering the ROS generation with antioxidant N-acetylcysteine effectively prevented the CPF-induced ROS generation, CHOP activation, and apoptotic events, but not that the Akt phosphorylation. Collectively, these findings indicate that CPF exposure exerts neuronal cytotoxicity via the independent pathways of ROS generation and Akt activation downstream-regulated CHOP-triggered apoptosis, ultimately leading to neuronal cell death., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85-90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC is higher in the tongue than any other anatomic area of the oral cavity. Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The results showed that docetaxel (10-300 nM) induced cytotoxicity and caspase-3 activity in SAS cells. Moreover, docetaxel (100 nM) promoted the expression of apoptosis-related signaling molecules, including the cleavages of caspase-3, caspase-7, and poly (ADP-ribose) polymerase (PARP). In mitochondria, docetaxel (100 nM) decreased the mitochondrial membrane potential (MMP) and Bcl-2 mRNA and protein expression and increased cytosolic cytochrome c protein expression and Bax mRNA and protein expression. In terms of mitogen-activated protein kinase (MAPK) and adenosine monophosphate-activated protein kinase (AMPK) signaling, docetaxel increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK), and p-AMPKα protein expression but not p-p38 protein expression. Moreover, the increase in caspase-3/-7 activity and Bax protein expression and decreased Bcl-2 protein expression and MMP depolarization observed in docetaxel-treated SAS cells could be reversed by treatment with either SP600125 (a JNK inhibitor), PD98059 (an MEK1/2 (mitogen-activated protein kinase kinase 1/2) inhibitor), or compound c (an AMPK inhibitor). The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth.

Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01-0.5 mM) exhibited greater cytotoxicity than ketamine (0.1-3 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2α, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1/2, and p38 signaling and increased intracellular calcium concentrations ([Ca 2+ ] i ). Pretreatment of cells with both PD98059 (an ERK1/2 inhibitor) and BAPTA/AM (a cell-permeable Ca 2+ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca 2+ ] i in NK-exposed cells could be obviously inhibited by BAPTA/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca 2+ ] i -regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca 2+ ] i /ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis.

Objective. To investigate and identify factors that enhance and restrict Doctor of Pharmacy student engagement in mandatory and voluntary community-engaged learning activities. Methods. A phenomenological study exploring the motivations and barriers faced by pharmacy students in a mandatory community-engaged learning course and voluntary community-engaged learning activities (eg, community outreach) was conducted using semi-structured interviews. Fifteen students were randomly selected to participate in the interviews. Student responses were analyzed using qualitative thematic analysis. Results. Primary factors motivating student engagement in mandatory community-engaged learning included having structured learning activities for students and incorporating reflective learning. Motivating factors for students participating in voluntary community-engaged learning included personal interest in the topic, convenient location and time of activity, opportunity for career development, and the chance to advocate for the pharmacy profession. Overlapping motivations for both mandatory and voluntary community-engaged learning included developing a better understanding of and broader perspective on the diverse populations in the community and having a positive impact. Common barriers identified included having limited information about student responsibilities, being given a limited student role, and feeling unconfident or unprepared. Conclusion. Students perceived benefits from both mandatory and voluntary participation in community-engaged learning activities. However, opportunities exist for identifying and managing barriers to enhancing student engagement in community-engaged learning within a pharmacy program. Additionally, learning tools such as critical reflection can be used to further enhance student engagement with community-engaged learning activities., (© 2022 American Association of Colleges of Pharmacy.)

Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic ( Bax , Bak , p53 )/antiapoptotic ( Bcl-2 ) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N -acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death.

Tongue squamous cell carcinoma (SCC) is a most common type of oral cancer. Due to its highly invasive nature and poor survival rate, the development of effective pharmacological therapeutic agents is urgently required. Quercetin (3,3',4',5,7-pentahydroxyflavone) is a polyphenolic flavonoid found in plants and is an active component of Chinese herbal medicine. The present study investigated the pharmacological effects and possible mechanisms of quercetin on apoptosis of the tongue SCC-derived SAS cell line. Following treatment with quercetin, cell viability was assessed via the MTT assay. Apoptotic and necrotic cells, mitochondrial transmembrane potential and caspase-3/7 activity were analyzed via flow cytometric analyses. A caspase-3 activity assay kit was used to detect the expression of caspase-3 activity. Western blot analysis was performed to examine the expression levels of proteins associated with the MAPKs, AMPKα, GSK3-α/β and caspase-related signaling pathways. The results revealed that quercetin induced morphological alterations and decreased the viability of SAS cells. Quercetin also increased apoptosis-related Annexin V-FITC fluorescence and caspase-3 activity, and induced mitochondria-dependent apoptotic signals, including a decrease in mitochondrial transmembrane potential and Bcl-2 protein expression, and an increase in cytosolic cytochrome c , Bax, Bak, cleaved caspase-3, cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase protein expression. Furthermore, quercetin significantly increased the protein expression levels of phosphorylated (p)-ERK, p-JNK1/2 and p-GSK3-α/β, but not p-p38 or p-AMPKα in SAS cells. Pretreatment with the pharmacological JNK inhibitor SP600125 effectively reduced the quercetin-induced apoptosis-related signals, as well as p-ERK1/2 and p-GSK3-α/β protein expression. Both ERK1/2 and GSK3-α/β inhibitors, PD98059 and LiCl, respectively, could significantly prevent the quercetin-induced phosphorylation of ERK1/2 and GSK3-α/β, but not JNK activation. Taken together, these results suggested that quercetin may induce tongue SCC cell apoptosis via the JNK-activation-regulated ERK1/2 and GSK3-α/β-mediated mitochondria-dependent apoptotic signaling pathway., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Huang et al.)

Construction of high-efficiency, low cost and stable non-noble metal catalyst on air cathode is of great importance for design and assembly of rechargeable Zn-air battery. Eriochrome black T (EBT) has phenolic hydroxyl and -N=Ν- groups, which provides multiple coordination sites for metal ions. Herein, Co 9 S 8 nanoclusters implanted in Co/Mn-S,N multi-doped porous carbon (Co 9 S 8 @Co/Mn-S,N-PC) are fabricated with the mixture (i.e. EBT, metal precursors and dicyandiamide) by a coordination regulated pyrolysis strategy. Specifically, EBT effectively chelates with the Co and Mn ions, resulting in multiple incorporation and fine modulation of the carbon electronic structures. Meanwhile, its sulfonic acid groups are reduced at such high temperature, accompanied by simultaneously embedding S element in the carbon, ultimately in situ forming Co 9 S 8 nanoclusters. The Co 9 S 8 @Co/Mn-S,N-PC performs as an effective bifunctional oxygen catalyst, displaying a positive half-wave potential of 0.85 V and a large limiting current density of 5.89 mA cm -2 for oxygen reduction reaction (ORR) in alkaline media, coupled with a small overpotential of 320 mV at 10 mA cm -2 towards oxygen evolution reaction (OER), outperforming commercial Pt/C and RuO 2 catalysts, respectively. Furthermore, the assembled rechargeable Zn-air battery with Co 9 S 8 @Co/Mn-S,N-PC exhibits the much better charge/discharge performance and long-term durability (210 h, 630 cycles). This research opens an instructive avenue to develop high-efficient and stable bifunctional oxygen electrocatalysts in energy transformation and storage devices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Water environmental pollution caused by spent batteries is a nonignorable environmental issue. In this study, the early life stage of zebrafish was employed to assess the environmental risk of spent batteries after exposure to 0, 1%, 2%, 5% and 10% spent battery extract for 120 h. Our results clearly indicated that spent battery extract can significantly decrease the survival rate, hatching rate and body length and increase heart rate. Moreover, spent battery extract exposure-induced zebrafish larvae generate oxidative stress and inhibit the mRNA transcriptional levels of heat shock protein (HSP70) and metallothionein (MT) genes. These results showed that the spent batteries not only affected the survival and development performance of zebrafish at an early life stage but also caused oxidative stress and interfered with the detoxification of zebrafish. This study provided novel insight into spent battery induced toxicity in the early life stage of fish., (Copyright © 2021. Published by Elsevier Ltd.)

Arsenic (As) in the aquatic environment is a considerable environmental issue, previous studies have reported the toxic effects of low concentrations (≤ 150 μg/L) of As on fish. However, limited information is available regarding the impact of low levels of As on apoptosis. To evaluate this, zebrafish embryos were exposed to different concentrations (0, 25, 50, 75, and 150 μg/L) of As (arsenite [AsIII] and arsenate [AsV]) for 120 h. Our results indicated that low concentrations of AsIII exposure significantly inhibited the survival of zebrafish larvae, and significantly increased the transcription of Caspase-9 and Caspase-3, the ratio of Bax/Bcl-2 transcription, and protein levels of Caspase-3. In contrast, AsV decreased the ratios of Bax/Bcl-2 transcription and protein levels, as well as protein levels of Caspase-3. Our data demonstrated that AsIII and AsV exert different toxic effects, AsIII induced apoptosis via the mitochondrial pathway and the extrinsic pathway, while AsV induced apoptosis only via the mitochondrial pathway., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the fact that accumulation of microglia, the resident macrophages of the central nervous system (CNS) are the main feature of glioblastoma, the role of microglia in the progression of glioma is still arguable. Based on the correlation of inflammation with tumor progression, in this study, we attempt to determine if peripheral inflammation aggravates glioma expansion and the activation of microglia associated with the tumor. Experimental animals were administered intraperitoneally by inflammagen lipopolysaccharide (LPS) for 7 days (LPS priming) before intracerebral implantation of glioma cells. Moreover, a reduced level of tumor necrosis factor receptor type 2 (TNFR2) that is restricted to immune cells, neurons, and microglia has been found in patients with glioblastoma through the clinic analysis of monocyte receptor expression. Thus, in addition to wildtype (WT) mice, heterogeneous TNFR2 gene deficiency ( TNFR2 +/- ) mice and homogeneous TNFR2 gene knockout ( TNFR2 -/- ) mice were used in this study. The results show that peripheral challenge by LPS, Iba1 + - or CD11b + -microglia increase in numbers in the cortex and hippocampus of TNFR2 -/- mice, when compared to WT or TNFR2 +/- mice. We further conducted the intracerebral implantation of rodent glioma cells into the animals and found that the volumes of tumors formed by rat C6 glioma cells or mouse GL261 glioma cells were significantly larger in the cortex of TNFR2 -/- mice when compared to that measured in LPS-primed WT or LPS-primed TNFR2 +/- mice. Ki67 + -cells were exclusively clustered in the tumor of LPS-primed TNFR2 -/- mice. Microglia were also extensively accumulated in the tumor formed in LPS-primed TNFR2 -/- mice. Accordingly, our findings demonstrate that aggravation of microglia activation by peripheral inflammatory challenge and a loss of TNFR2 function might lead to the promotion of glioma growth.

Inorganic arsenic (As 3+ ), a well-known worldwide industrial and environmental pollutant, has been linked to neurodegenerative disorders (NDs). Autophagy plays an important role in controlling neuronal cell survival/death. However, limited information is available regarding the toxicological mechanism at the interplay between autophagy and As 3+ -induced neurotoxicity. The present study found that As 3+ exposure induced a concomitant activation of apoptosis and autophagy in Neuro-2a cells, which was accompanied with the increase of phosphatidylserine exposure on outer membrane leaflets and apoptotic cell population, and the activation of caspase-3, -7, and PARP as well as the elevation of protein expressions of LC3-II, Atg-5, and Beclin-1, and the accumulation of autophagosome. Pretreatment of cells with autophagy inhibitor 3-MA, but not that of Z-VAD-FMK (a pan-caspase inhibitor), effectively prevented the As 3+ -induced autophagic and apoptotic responses, indicating that As 3+ -triggered autophagy was contributing to neuronal cell apoptosis. Furthermore, As 3+ exposure evoked the dephosphorylation of Akt. Pretreatment with SC79, an Akt activator, could significantly attenuated As 3+ -induced Akt inactivation as well as autophagic and apoptotic events. Expectedly, inhibition of Akt signaling with LY294002 obviously enhanced As 3+ -triggered autophagy and apoptosis. Exposure to As 3+ also dramatically increased the phosphorylation level of AMPKα. Pretreatment of AMPK inhibitor (Compound C) could markedly abrogate the As 3+ -induced phosphorylated AMPKα expression, and autophagy and apoptosis activation. Taken together, these results indicated that As 3+ exerted its cytotoxicity in neuronal cells via the Akt inactivation/AMPK activation downstream-regulated autophagy-dependent apoptosis pathways, which ultimately lead to cell death. Our findings suggest that the regulation of Akt/AMPK signals may be a promising intervention to against As 3+ -induced neurotoxicity and NDs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Replacing precious metal catalysts with low-price and abundant catalysts is one of urgent goals for green and sustainable energy development. It is imperative yet challenging to search low-cost, high-efficiency, and long-durability electrocatalysts for oxygen reduction reaction (ORR) in energy conversion devices. Herein, three-dimensional low-cost Co 3 Fe 7 nanoparticles/nitrogen, manganese-codoped porous carbon (Co 3 Fe 7 /N, Mn-PC) was synthesized with the mixture of dicyandiamide, cobalt (II) tetramethoxyphenylporphyrin (Co(II)TMOPP), hemin, and manganese acetate by one-step pyrolysis and then acid etching. The resultant Co 3 Fe 7 /N, Mn-PC exhibited excellent durability and prominent ORR activity with more positive onset potential (E onset , 0.98 V) and half-wave potential (E 1/2 , 0.87 V) in 0.1 M KOH electrolyte, coupled with strong methanol resistance. The pyrolysis temperature and optimal balance of graphite with pyridine-nitrogen are of significance for the ORR performance. The prepared Co 3 Fe 7 /N, Mn-PC displayed excellent ORR performance over commercial Pt/C in the identical environment. It was ascribed to the uniform 3D architecture, Mn- and N-doping effects by finely adjusting the electronic structures, coupled with the synergistic catalytic effects of multi-compositions and multi-active sites. This work provides some constructive guidelines for preparation of low-cost and high-efficiency ORR electrocatalysts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is recognized as a harmful pollutant in the worldwide. Growing studies have reported that BPA can cause adverse effects and diseases in human, and link to a potential risk factor for development of neurodegenerative diseases (NDs). 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which generated in the mammalian liver after BPA exposure, is a major active metabolite of BPA. MBP has been suggested to exert greater toxicity than BPA. However, the molecular mechanism of MBP on the neuronal cytotoxicity remains unclear. In this study, MBP exposure significantly reduced Neuro-2a cell viability and induced apoptotic events that MBP (5-15 μM) exhibited greater neuronal cytotoxicity than BPA (50-100 μM). The mitochondria-dependent apoptotic signals including the decrease in mitochondrial membrane potential (MMP) and the increase in cytosolic apoptosis-induced factor (AIF), cytochrome c release, and Bax protein expression were involved in MBP (10 μM)-induced Neuro-2a cell death. Exposure of Neuro-2a cells to MBP (10 μM) also triggered endoplasmic reticulum (ER) stress through the induction of several key molecules including glucose-regulated protein (GRP)78, C/EBP homologous protein (CHOP), X-box binding protein (XBP)-1, protein kinase R-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme(IRE)-1, activation transcription factor(AFT)4 and ATF6, and caspase-12. Pretreatment with 4-PBA (an ER stress inhibitor) and specific siRNAs for GRP78, CHOP, and XBP-1 significantly suppressed the expression of these ER stress-related proteins and the activation of caspase-12/-3/-7 in MBP-exposed Neuro-2a cells. Furthermore, MBP (10 μM) exposure dramatically increased the activation of extracellular regulated protein (ERK)1/2 and decreased Akt phosphorylation. Pretreatment with PD98059 (an ERK1/2 inhibitor) and transfection with the overexpression of activation of Akt1 (myr-Akt1) effectively suppressed MBP-induced apoptotic and ER stress-related signals. Collectively, these results demonstrate that MBP exposure exerts neuronal cytotoxicity via the interplay of ERK activation and Akt inactivation-regulated mitochondria-dependent and ER stress-triggered apoptotic pathway, which ultimately leads to neuronal cell death., (Copyright © 2021 Elsevier B.V. All rights reserved.)

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.

Objective: Repeated surgical interventions are usually required to control recurrent respiratory papillomatosis (RRP), but at considerable risk of worsened postoperative voice quality. Potassium titanyl phosphate (KTP) laser has been reported to effectively manage RRP; however, voice quality after repeated procedures has not been investigated., Methods: This study recruited 16 patients with RRP treated using KTP laser between 2013 and 2019. KTP laser procedures were performed under general anesthesia via direct suspension laryngoscope or under local anesthesia via flexible endoscope, depending on the need for pathological proof, patient tolerance, and lesion size and location. Disease control was investigated by videolaryngostroboscopy. Voice outcome was evaluated using a 10-item voice handicap index (VHI-10), acoustic and perceptual analyzes., Results: We reviewed the medical records of 11 male and 5 female patients with RRP (age range: 23-73 years). Five patients received KTP laser once, six patients received it 2 to 5 times, and five patients received 6 to 15 procedures. Median VHI-10 decreased from 28.3 to 12.0 points after the initial procedure and were maintained at 10.1 to 11.0 points following subsequent procedures ( P  < .01, generalized estimating equation). Acoustic and perceptual analysis of voice quality also revealed significant improvements ( P  < .01), which remained stable even after 6 to 10 KTP laser procedures. Minor adverse events included slight fibrotic change of vocal folds and glottic web, but these did not significantly alter postoperative voice quality., Conclusion: This longitudinal follow-up study revealed that serial KTP laser procedures can effectively control RRP while preserving phonatory function and maintaining adequate voice quality., Level of Evidence: 4.

Developing efficient and stable electrocatalysts with three-dimensional (3D) hierarchical nanostructures is extremely important in practical applications of direct alcohol fuel cells. Herein, 3D hierarchical thorn-like multi-metallic PtPdNiCu alloyed nanotripods (PtPdNiCu TNTPs) were efficiently fabricated by a one-pot aqueous method, in which Pluronic F127 performed as the structure-director and dispersing agent. The as-prepared PtPdNiCu TNTPs exhibited distinct electrocatalytic activity for methanol oxidation reaction (MOR) with a mass activity (MA) of 1.465 A mg -1 Pd , which is superior to commercial Pt/C (0.925 A mg -1 Pd ) in 1.0 M KOH solution, along with the greater MA (1.019 A mg -1 Pd ) for ethanol oxidation reaction (EOR) than Pt/C (0.712 A mg -1 Pd ). This work would provide an impetus for rationally constructing multimetal nanomaterials to commercial implementation of advanced alcohol fuel cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Silicon dioxide nanoparticles (SiO 2 NPs) are widely applied in industry, chemical, and cosmetics. SiO 2 NPs is known to induce pulmonary toxicity. In this study, we investigated the molecular mechanisms of SiO 2 NPs on pulmonary toxicity using a lung alveolar epithelial cell (L2) model. SiO 2 NPs, which primary particle size was 12 nm, caused the accumulation of intracellular Si, the decrease in cell viability, and the decrease in mRNAs expression of surfactant, including surfactant protein (SP)-A, SP-B, SP-C, and SP-D. SiO 2 NPs induced the L2 cell apoptosis. The increases in annexin V fluorescence, caspase-3 activity, and protein expression of cleaved-poly (ADP-ribose) polymerase (PARP), cleaved-caspase-9, and cleaved-caspase-7 were observed. The SiO 2 NPs induced caspase-3 activity was reversed by pretreatment of caspase-3 inhibitor Z-DEVD-FMK. SiO 2 NPs exposure increased reactive oxygen species (ROS) production, decreased mitochondrial transmembrane potential, and decreased protein and mRNA expression of Bcl-2 in L2 cells. SiO 2 NPs increased protein expression of cytosolic cytochrome c and Bax, and mRNAs expression of Bid, Bak, and Bax. SiO 2 NPs could induce the endoplasmic reticulum (ER) stress-related signals, including the increase in CHOP, XBP-1, and phospho-eIF2α protein expressions, and the decrease in pro-caspase-12 protein expression. SiO 2 NPs increased phosphoinositide 3-kinase (PI3K) activity and AKT phosphorylation. Both ROS inhibitor N-acetyl-l-cysteine (NAC) and PI3K inhibitor LY294002 reversed SiO 2 NPs-induced signals described above. However, the LY294002 could not inhibit SiO 2 NPs-induced ROS generation. These findings demonstrated first time that SiO 2 NPs induced L2 cell apoptosis through ROS-regulated PI3K/AKT signaling and its downstream mitochondria- and ER stress-dependent signaling pathways.

Hexavalent chromium (Cr(VI)), a well-known toxic industrial and environmental pollutant, has been shown to cause serious toxic and health effects. However, limited information is available on Cr(VI)-induced neurotoxic potential, with the underlying toxicological mechanisms remain mostly unclear. The present study demonstrated that the mitochondria-dependent apoptosis pathway was involved in Cr(VI)-induced SH-SY5Y cell (the human neuroblastoma cell line) death, which was accompanied by the appearance of cell shrinkage, increased mitochondrial membrane potential (MMP) depolarization and cytochrome c release, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Cr(VI) treatment also increased the generation of intracellular reactive oxygen species (ROS). Pretreatment of SH-SY5Y cells with antioxidant N-acetylcysteine (NAC) effectively attenuated ROS production and reversed these Cr(VI)-induced cytotoxicity and apoptotic responses. Furthermore, exposure to Cr(VI) significantly increased the phosphorylation levels of Akt, extracellular regulated kinase (ERK)1/2, and AMP-activated protein kinase (AMPK)α. NAC and the pharmacological inhibitor of Akt (LY294002), ERK1/2 (PD980590), and AMPKα (Compound C) markedly abrogated the Cr(VI)-induced activation of Akt, ERK1/2, and AMPKα signal, respectively, with the concomitant inhibition of mitochondrial dysfunction and caspase activation. Additionally, all these inhibitors suppressed Cr(VI)-induced phosphorylation of Akt, ERK1/2, and AMPKα and of each other. Collectively, these results suggest that Cr(VI) exerts its cytotoxicity on neuronal cells by inducing mitochondria-dependent apoptosis through the interdependent activation of Akt, ERK1/2, and AMPKα, which are mainly mediated by ROS generation., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Human exposure to silica nanoparticles (SiNPs) has been widely applied as vehicles for drug delivery and cellular manipulations in nanoneuromedicine. SiNPs may cause adverse effects in the brain, but potential mechanisms underlying SiNPs-induced neurotoxicity are remained unclear. Here, we examined cytotoxic effects and the cellular mechanisms of SiNPs-induced neuronal cell death. In this study, the results showed that SiNPs significantly decreased cell viability and induced apoptosis in Neuro-2a cells as evidenced by the increase caspase-3 activity and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). In addition, endoplasmic reticulum (ER) stress was triggered as indicated by several key molecules including glucose-regulated protein (GRP)78 and 94, C/EBP homologous protein (CHOP), activation transcription factor (ATF)-4, and caspase-12. Pretreatment of Neuro-2a cells with specific pharmacological inhibitor of ER stress (4-phenylbutyric acid (4-PBA)) effectively alleviated the SiNPs-induced ER stress and apoptotic related signals. Furthermore, 2',7'-Dichlorofluorescein fluorescence as an indicator of reactive oxygen species (ROS) formation after exposure of Neuro-2a cells to SiNPs significantly increased ROS levels. Antioxidant N-acetylcyseine (NAC) effectively reversed SiNPs-induced cellular responses. Taken together, these results suggest that SiNPs exposure exerts its neurotoxicity in cultured neuronal cells by inducing apoptosis via a ROS generation-activated downstream ER stress signaling pathway., (Copyright © 2019. Published by Elsevier Ltd.)

Advanced Pt-based ternary nanocatalysts display dramatically enhanced utilization efficiency of Pt alternative to mono- and bi-counterparts, owing to the synergistic effects of the tri-metals. Herein, multicomponent uniform 3D PtCoRh highly branched nanoassemblies (HBNAs) were prepared by glycine-assisted one-pot solvothermal method in oleylamine (OAm). The effects of the precursor types, reaction time and amount of glycine were critically investigated in this synthesis. The as-prepared PtCoRh HBNAs displayed outstanding electrocatalytic activity and improved stability towards ethanol oxidation reaction (EOR) and methanol oxidation reaction (MOR) in 1 M KOH electrolyte, whose mass/specific activities were 1.75 A mg -1 /4.03 mA cm -2 and 0.98 A mg -1 /2.34 mA cm -2 , respectively, which were remarkably higher than commercial Pt/C (0.85 A mg -1 /4.03 mA cm -2 and 0.47 A mg -1 /0.89 mA cm -2 ). This study provides some novel guidelines to fabricate advanced multimetallic electrocatalysts for practical applications in direct alcohol fuel cells (DAFCs)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Specifications about the size and stiffness of healthy salivary glands with ultrasound (US) are not available for Asian people. Using a Toshiba Apolio 500 US platform, we determined the size (including anterior-posterior median length, median paramandibular depth dimension, and cranio-caudal height) and hardness of 100 healthy submandibular and parotid glands in volunteers without a history of disease affecting the salivary glands or post-radiation, and compared the dimensions to those of 36 parotid glands and 37 submandibular glands in post-irradiated patients. The dimensions of the parotid and submandibular glands were significantly correlated with body weight. However, the dimension of the parotid glands was not significantly correlated with that of patients with prior radiation; the shear wave velocity (SWV) significantly increased (1.99 m/s versus 2.43 m/s, p-value < 0.01). The dimension of the submandibular glands was significantly correlated with prior radiation, where the SWV also significantly increased (2.32 m/s versus 2.50 m/s, p-values < 0.01). We find that US is a useful tool for assessment of the reference dimensions and hardness of major salivary glands that may be altered by irradiation.

Objective: The carotid intimal-medial thickness (CIMT) is a strong predictor of future cardiovascular events. We assessed the mean CIMT and evaluated associated factors in head and neck cancer (HNC) patients., Materials and Methods: Between January 2016 and March 2018, 70 volunteers underwent automatic ultrasound measurement of the common carotid artery CIMT. A mean CIMT ≥ 1.0 mm was regarded as an elevated risk for cardiovascular disease (CVD). We aimed to investigate the risk factors for an increased mean CIMT., Results: We recruited 20 HNC survivors and 50 noncancer control individuals. Multiple linear regression analysis showed that old age (β = 0.006, 95% confidence interval, CI 0.004-0.008), increased weight (β = 0.003, 95% CI 0.001-0.005), hypertension (β = 0.10, 95% CI 0.03-0.17), and prior irradiation (β = 0.13, 95% CI 0.08-0.19) were positively correlated with the mean CIMT. From logistic regression analysis, it was shown that patients who underwent radiotherapy (OR 13.5, 95% CI 1.48-122.8) and who had higher bodyweight (OR 1.09, 95% CI 1.01-1.18) had a significantly higher risk of developing CVD., Conclusion: Measurement of the mean CIMT using ultrasound could be useful for assessing CVD risk in HNC survivors after neck irradiation.

Rational design of highly efficient and durable electrocatalysts for hydrogen evolution reaction (HER) is of prime importance for renewable and sustainable energy. Herein, PtNi nanodentrites (PtNi NDs) were facilely synthesized in oleylamine (OAm) by a one-pot solvothermal method, using melamine and cetyltrimethylammonium chloride (CTAC) as co-structure-directing agents. The obtained catalyst showed superior catalytic activity and enhanced durability for HER relative to commercial Pt/C, home-made PtNi 3 nanocrystals (NCs) and Pt 3 Ni NCs both in alkaline and acidic media. The enhanced HER activities are attributed to bimetallic synergies and interface structures in PtNi NDs. This work provides an effective strategy to prepare highly efficient and durable electrocatalysts for HER., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor subtype. Despite that metastasis of GBM beyond the central nervous system (CNS) is rare, its malignancy is attributed to the highly infiltration trait, leading to the difficulty of complete surgical excision. Matrix gla protein (MGP) is a vitamin K-dependent small secretory protein, and functions as a calcification inhibitor. The involvement of MGP function in glioma cell dynamics remains to be clarified. The study showed that a low proliferative rat C6 glioma cell line named as C6-2 exhibited faster migratory and invasive capability compared to that observed in a high tumorigenic rat C6 glioma cell line (called as C6-1). Interestingly, C6-2 cells expressed higher levels of MGP molecules than C6-1 cells did. Lentivirus-mediated short hairpin RNA (shRNA) against MGP gene expression (MGP-KD) in C6-2 cells or lentivirus-mediated overexpression of MGP transcripts in C6-1 cells resulted in the morphological alteration of the two cell lines. Moreover, MGP-KD caused a decline in cell migration and invasion ability of C6-2 cells. In contrast, increased expression of MGP in C6-1 cells promoted their cell migration and invasion. The observations were further verified by the results from the implantation of C6-1 and C6-2 cells into ex vivo brain slice and in vivo rat brain. Thus, our results demonstrate that the manipulation of MGP expression in C6 glioma cells can mediate glioma cell migratory activity. Moreover, our findings indicate the possibility that high proliferative glioma cells expressing a high level of MGP may exist and contribute to tumor infiltration and recurrence.

Herein, reduced graphene oxide supported porous PtAg alloy nanoflowers (PtAg NFs/rGO) were synthesized by a simple one-pot aqueous method using pyridinium-based dicationic ionic liquid (1,4-bis(pyridinium)butane dibromide, Bpb-2Br) as the new structure-director and stabilizing agent. The products were characterized by a series of techniques. The obtained nanocomposite had more positive onset potential (1.03 V) for oxygen reduction reaction (ORR) in alkaline electrolyte than those of commercial Pt/C (50 wt%, 0.96 V) and home-made Pt nanoparticles (NPs)/rGO (Pt NPs/rGO, 0.97 V), showing the enhanced catalytic performance for hydrogen evolution reaction (HER) with the positive onset potential (-26 mV) and a small Tafel slope (31 mV dec -1 ) relative to Pt/C (-18 mV, 31 mV dec -1 ) and Pt NPs/rGO (-42 mV, 36 mV dec -1 ) in 0.5 M H 2 SO 4 ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

B-cell CLL/lymphoma 11B (Bcl11b) - a C2H2 zinc finger transcriptional factor - is known to regulate neuronal differentiation and function in the development of the central nervous system (CNS). Although its expression is reduced during oligodendrocyte (OLG) differentiation, its biological role in OLGs remains unknown. In this study, we found that the downregulation of Bcl11b gene expression in glial progenitor cells (GPCs) by lentivirus-mediated gene knockdown (KD) causes a reduction in cell proliferation with inhibited expression of stemness-related genes, while increasing the expression of cell cyclin regulator p21. In contrast, OLG specific transcription factors (Olig1) and OLG cell markers, including myelin proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), were upregulated in Bcl11b-KD GPCs. Chromatin immunoprecipitation (ChIP) analysis indicated that Bcl11b bound to the promoters of Olig1 and PLP, suggesting that Bcl11b could act as a repressor for Olig1 and PLP, similar to its action on p21. An increase in the number of GC + - or PLP + - OLGs derived from Bcl11b-KD GPCs or OLG precursor cells was also observed. Moreover, myelin basic protein (MBP) expression in OLGs derived from Bcl11b-KD GPCs was enhanced in hippocampal neuron co-cultures and in cerebellar brain-slice cultures. The in vivo study using a lysolecithin-induced demyelinating animal model also indicated that larger amounts of MBP + -OLGs and PLP + -OLGs derived from implanted Bcl11b-KD GPCs were present at the lesioned site of the white matter than in the scramble group. Taken together, our results provide insight into the functional role of Bcl11b in the negative regulation of GPC differentiation through the repression of OLG differentiation-associated genes.

Although hyaluronan (HA)-based biomaterials have been proposed to promote mucociliary differentiation of nasal epithelial cells (NECs), the mechanism by which HA affects the growth and differentiation of NECs has not been thoroughly explored. This study investigates the effect and mechanism of HA on the differentiation of NECs. The experiment cultures human NECs in four conditions, namely controls, transforming growth factor (TGF)-β1, TGF-β1 + HA and HA groups. In the TGF group, the NECs become irregular shape without formation of tight junction and mucociliary differentiation of NECs is inhibited. Epithelial-mesenchymal transition (EMT) of NECs also occurs in the TGF group. However, with addition of HA in TGF groups, NECs reveal the mucociliary phenotypes of epithelial cells with tight junction expression. Incubation of TGF-β1 in an NEC culture leads to an increase in phosphorylated type 1 TGF-β receptors (p-TβRI). This increase is attenuated when NECs are cultured in the presence of HA. Similar expressions are observed in phosphorylated smad2/smad3. Additionally, HA-dependent inhibition of TGF-β1 signalling is inhibited by co-incubation with a blocking antibody to CD44. Experimental results indicate that HA can antagonize TGF-β1 effect on EMT and mucociliary differentiation of NECs by down-regulation of TβR I, which is via CD44.

In this work, well-defined bimetallic AuPd alloyed nanocrystals (AuPd NCs) were facilely synthesized by a straightforward and controllable one-step wet-chemical strategy, using a biomolecule (L-hydroxyproline, L-Hyp) as the green stabilizer and the structure-directing agent. Their morphology, size, composition, crystal structures and growth mechanism were investigated by a series of techniques. The synthesized architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic activity, enhanced durability and stability towards ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR) in alkaline electrolytes in comparison with commercial Pd black catalyst., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Although endoscopic sinus surgery is the mainstay surgical treatment for chronic rhinosinusitis, over 15% of patients require a repeat operation wherein postoperative adhesion formation is one of the main causes of failure. Several recently proposed chitosan-based biomaterials promote mucosal healing, reduce postoperative adhesion formation and restore mucociliary function of sinonasal mucosa. However, the effects of chitosan on cellular morphology, re-epithelization, and mucociliary differentiation of nasal epithelial cells (NECs) during the wound healing process have not been thoroughly investigated. The present study investigates the direct effects of chitosan on cellular growth, cellular migration, mucociliary differentiation and aquaporin (AQP) formation of NECs to elucidate the role of chitosan in sinonasal applications. Wound healing assay reveals that proliferation and migration of NECs are inhibited by incubation of chitosan. The NECs become irregular in shape without formation of tight junction and mucociliary differentiation of NECs is inhibited during a culture period with incubation of chitosan. However, AQP3 and AQP5 formation in NECs is significantly higher in chitosan groups than in control groups. Further, expressions of transforming growth factor (TGF)-β1, Smad2, and Smad3 are significantly higher in the chitosan groups compared with controls. The results of the comparison indicate that chitosan inhibits proliferation, migration and mucociliary differentiation of NECs through increasing production of TGF-β1. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In this paper, growth hormone releasing peptide-6 (GHRP-6) is a bioactive polypeptide and acts as the reducing agent and capping ligand for synthesis of bright green fluorescent gold nanoclusters (GHRP-6-Au NCs) by a simple and environmental-friendly aqueous method, with the assistance of NaBr as the fluorescent sensitizer. The obtained GHRP-6-Au NCs had high fluorescent quantum yield (10.7%), and the fluorescence was strongly quenched by the existence of trace Fe 3+ . Thus, a new and highly sensitive sensor for the assay of Fe 3+ was constructed based on the analyte-induced fluorescent quenching mechanism. The sensor had a low detection limit of 1.4µM (S/N=3) and a wide linear range of 2-1000µM. Besides, GHRP-6-Au NCs exhibited low cytotoxicity and high biocompatibility for cell imaging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Herein, a simple one-pot aqueous method was developed for the fabrication of uniform hollow bimetallic AgPt alloyed nanocrystals (H-AgPt NCs) by using 5-aminoorotic acid (5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid) as a growth-directing agent, without any seed, organic solvent or template involved. The prepared H-AgPt NCs displayed enhanced electrocatalytic activity for hydrogen evolution reaction (HER) with a more positive onset overpotential (η onset ) of -28mV and a smaller Tafel slope of 40mVdec -1 relative to commercial Pt black (-34mV, 50mVdec -1 ) and Pt/C (20wt.%, -33mV, 33mVdec -1 ) in 0.5M H 2 SO 4 . Meanwhile, the obtained catalyst exhibited improved catalytic features toward oxygen reduction reaction (ORR) with a positive η onset (0.916V) and enhanced kinetic current density (243.23mAmg -1 Pt ) in 0.1M HClO 4 at 0.850V compared with Pt black (0.876V, 25.85mAmg -1 Pt )., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Herein, we develop a simple one-pot aqueous method to prepare AuPd alloy nanocrystals on reduced graphene oxide (AuPd NCs/rGO), by using 1-acetyl-4-(p-hydroxyphenyl) piperazine (AHPP) as the reductant, stabilizing agent and structure-director, without any other additives (e.g., seed, surfactant or polymer). The product is mainly characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction and thermogravimetric analysis. The obtained AuPd NCs/rGO displays enlarged electrochemically active surface area and superior catalytic performances toward oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER) relative to Pt/C, Pd/C, Pd/rGO and Au/rGO catalysts, showing promising applications in energy storage and conversion., (Copyright © 2017 Elsevier Inc. All rights reserved.)

CD200, a type I transmembrane glycoprotein, can interact with its receptor CD200R, which plays an inhibitory role in the activation of microglia-the resident macrophages of the central nervous system. In this study, the rat C6 glioma cell line (C6-1) that was previously characterized with high in vivo tumorigenicity was found to generate CD200 mRNA abundantly. However, CD200 expression was barely detected in another C6 glioma cell clone (C6-2) that was previously found to display low tumorigenic behavior. The results from CD200 immunohistochemistry on human glioma tissue array also showed that tumor cells in Grade I-II astrocytoma expressed a lower level of CD200 immunoreactivity than those detected in Grade III-IV glioblastoma multiforme. C6-1 transfectants with stable downregulation of CD200 gene expression using lentivirus knockdown approach were generated (C6-KD). Microglia and iNOS + cells were increased when microglia were co-cultured with C6-KD cells. The colony formation of C6-KD was also augmented when those cells were co-cultured with microglia. Yet, increased colony formation of C6-KD transfectants in the co-culture with microglia was effectively suppressed by interleukin (IL)-4 and IL-10. The in vivo results indicated that the tumor formation of C6-1 cells in rat brain was promoted after CD200 gene knockdown. Moreover, CD11b + activated microglia and iNOS + microglia were highly accumulated in the tumor site formed by C6-KD. In conclusion, our findings demonstrate that the downregulation of CD200 expression in CD200-rich glioma cells could foster the formation of an activated microglia-associated tumor microenvironment, leading to glioma progression. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

B cell CLL/lymphoma 11B (Bcl11b), a C2H2 zinc finger transcription factor, not only serves as a critical regulator in development but also plays the controversial role in T cell acute lymphoblastic leukemia (T-ALL). We previously found that the enriched expression of Bcl11b was detected in high tumorigenic C6 glioma cells. However, the role of Bcl11b in glioma malignancy and its mechanisms remains to be uncovered. In this study, using the lentivirus-mediated knockdown (KD) approach, we found that Bcl11b KD in tumorigenic C6 cells reduced the cell proliferation, colony formation, and migratory ability. The results were further verified using two human malignant glioma cell lines, U87 and U251 cells. A cyclin-dependent kinase inhibitor p21, a known Bcl11b target, was significantly upregulated in tumorigenic C6, U87, and U251 cells after Bcl11b KD. Cellular senescence was observed by examination of the β-galactosidase activity in U87 and U251 cells with Bcl11b KD. Reduced expression of stemness gene Sox-2 and its downstream effector Bmi-1 was also observed in U87 and U251 cells with Bcl11b KD. These results suggest that the ablation of Bcl11b gene expression induced glioma cell senescence. Propidium iodide (PI) staining combined with flow cytometry analysis also showed that Bcl11b KD led to the cell cycle arrest of U87 and U251 cells at the G0/G1 or at the S phase, indicating that Bcl11b is required for glioma cell cycle progression. Together, this is the first study to show that the inhibition of Bcl11b suppresses glioma cell growth by regulating the expression of the cell cycle regulator p21 and stemness-associated genes (Sox-2/Bmi-1).

Background: This study presents the first report in the same patients on the time efficiency of surface registration as well as the navigational accuracy using optic and electromagnetic tracking systems., Methods: Thirty patients with bilateral chronic paranasal pansinusitis underwent endoscopic sinus surgery. After surface registration, the surgeries were performed on one side using optic navigation guidance and on the other side using electromagnetic navigation guidance. The intraoperative measurements performed included the time taken for the surface registration and surgical procedure on each side, as well as the navigation errors at the different locations., Results: The time for surface registration was significantly longer in the optic navigation group than the electromagnetic group. A comparison of the navigation errors along the 3 axes showed that the deviation in the medial-lateral direction was significantly less than that in the anterior-posterior and cranial-caudal directions in the optic navigation group as well as the electromagnetic group., Conclusions: The procedure for surface registration in both optic and electromagnetic guidance is efficient and convenient. The accuracy of both navigation systems is comparable and within acceptable ranges for clinical use. In addition, the best accuracy was measured in the medial-lateral direction compared with the other two axes.

The gray values accuracy of dental cone-beam computed tomography (CBCT) is affected by dental metal prostheses. The distortion of dental CBCT gray values could lead to inaccuracies of orthodontic and implant treatment. The aim of this study was to quantify the effect of scanning parameters and dental metal prostheses on the accuracy of dental cone-beam computed tomography (CBCT) gray values using the Taguchi method. Eight dental model casts of an upper jaw including prostheses, and a ninth prosthesis-free dental model cast, were scanned by two dental CBCT devices. The mean gray value of the selected circular regions of interest (ROIs) were measured using dental CBCT images of eight dental model casts and were compared with those measured from CBCT images of the prosthesis-free dental model cast. For each image set, four consecutive slices of gingiva were selected. The seven factors (CBCTs, occlusal plane canting, implant connection, prosthesis position, coping material, coping thickness, and types of dental restoration) were used to evaluate scanning parameter and dental prostheses effects. Statistical methods of signal to noise ratio (S/N) and analysis of variance (ANOVA) with 95% confidence were applied to quantify the effects of scanning parameters and dental prostheses on dental CBCT gray values accuracy. For ROIs surrounding dental prostheses, the accuracy of CBCT gray values were affected primarily by implant connection (42%), followed by type of restoration (29%), prostheses position (19%), coping material (4%), and coping thickness (4%). For a single crown prosthesis (without support of implants) placed in dental model casts, gray value differences for ROIs 1-9 were below 12% and gray value differences for ROIs 13-18 away from pros-theses were below 10%. We found the gray value differences set to be between 7% and 8% for regions next to a single implant-supported titanium prosthesis, and between 46% and 59% for regions between double implant-supported, nickel-chromium alloys (Ni-Cr) prostheses. Quantification of the effect of prostheses and scanning parameters on dental CBCT gray values was assessed.

Background: Prevention of adhesion formation and restoration of mucociliary mucosa are major determinants of the success of endoscopic sinus surgery (ESS). Vitamin A (VA) can promote mucociliary differentiation of respiratory epithelium. However, whether topical VA can promote sinonasal wound healing or reduce adhesion formation after ESS in humans remains unexplored., Objective: To investigate the effect of topical VA on sinonasal wound healing and adhesion formation after ESS., Methods: This is a within-subject control study. Patients with chronic rhinosinusitis were included. Each patient underwent ESS, and topical VA was applied over the sinonasal wound. Postoperative outcomes were assessed by using the Lund-Kennedy score, and the antrostomy size was measured. In vitro wound healing assay of fibroblasts with or without VA was evaluated. Restoration of ciliated epithelium was examined by using scanning electron microscopy., Results: Thirty patients were enrolled. The mean (standard deviation {SD}) scores for scarring/adhesion in the VA-treated side at 3 and 12 months after surgery (0.20 ± 0.40 and 0.23 ± 0.42, respectively) were significantly lower than those in the controls (0.47 ± 0.50 and 0.53 ± 0.62, respectively). The mean (SD) antrostomy size in the VA treated side at 1, 3, and 12 months after surgery (0.85 ± 0.30 cm(2), 0.7 ± 0.30 cm(2), and 0.70 ± 0.27 cm(2), respectively) were significantly larger than those in the controls (0.79 ± 0.26 cm(2), 0.60 ± 0.25 cm(2), and 0.57 ± 0.24 cm(2), respectively). Wound healing assay revealed that VA significantly inhibited the proliferation and migration of fibroblasts. Scanning electron microscopy showed mature ciliated cells in the VA-treated side., Conclusion: Topical VA is a promising agent for sinonasal wound healing after ESS because it can promote mucociliary reepithelization, reduce adhesion, and prevent antrostomy stenosis.

Colchicine, an anti-microtubule and antimitotic drug, is a common therapeutically agent for gout, which is thought to have potential anti-tumor effects. Owing to concerns of colchicines poisoning, the development of derivatives with low dose efficacy and less side effects is of obvious interest. In this study, we characterized the inhibitory effects of a colchicine derivative named AD1 on the cell proliferation of human malignant glioblastoma (MG) cell lines, U87MG and U373MG. We found that 50 % of U87MG and U373MG cells were reduced in the cultures after exposure to AD1 for 24 h at 10 and 50 nM, respectively. Moreover, α-tubulin immunostaining indicated that AD1 induced the disruption of the microtubule polymerization in glioma cells with apoptotic features including membrane budding/blebbing or fragmented nuclei. Increased levels of reactive oxygen species (ROS) were also detected in AD1-treated U87MG and U373MG cells compared to that observed in the control culture. Moreover, examination of microtubule-associated protein 1A/1B-light chain 3 (LC3I)/LC3II conversion and acridine orange staining for autophagic vesicles, combined with flow cytometry, showed that treatment with AD1 induced the autophagic pathway in U87MG and U373MG cells. Furthermore, we found that the intermittent intravenous administration of AD1 suppressed glioma growth in rat brain receiving intracerebral injection with rat C6 glioma cells. Taken together, our findings reveal that treatment with AD1 at nanomolar scales can reduce glioma cell viability effectively, with the occurrence of a rise in ROS and cellular autophagy. In conjunction with the observations from in vivo study, the colchicine derivative AD1 has chemotherapeutic potential to suppress glioma progression.

Chloroacetic acid (CA), a chlorinated analog of acetic acid and an environmental toxin that is more toxic than acetic, dichloroacetic, or trichloroacetic acids, is widely used in chemical industries. Furthermore, CA has been found to be the major disinfection by-products (DBPs) of drinking water. CA has been reported to be highly corrosive and to induce severe tissue injuries (including nervous system) that lead to death in mammals. However, the effects and underlying mechanisms of CA-induced neurotoxicity remain unknown. In the present study, we found that CA (0.5-2.0 mM) significantly increased LDH release, decreased the number of viable cells (cytotoxicity) and induced apoptotic events (including: increases in the numbers of apoptotic cells, the membrane externalization of phosphatidylserine (PS), and caspase-3/-7 activity) in Neuro-2a cells. CA (1.5 mM; the approximate to LD50) also triggered ER stress, which was identified by monitoring several key molecules that are involved in the unfolded protein responses (including the increase in the expressions of p-PERK, p-IRE-1, p-eIF2α, ATF-4, ATF-6, CHOP, XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78- and GRP 94-specific si-RNA effectively abrogated CA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in CA-exposed cells. Taken together, these results suggest that the higher concentration of CA exerts its cytotoxic effects in neuronal cells by triggering apoptosis via a ROS-induced ER stress signaling pathway., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Bladder cancer is a common malignancy worldwide. However, there is still no effective therapy for bladder cancer. In this study, we investigated the cytotoxic effects of cantharidin [a natural toxin produced (pure compound) from Chinese blister beetles (Mylabrisphalerata or Mylabriscichorii) and Spanish flies (Cantharis vesicatoria)] in human bladder cancer cell lines (including: T24 and RT4 cells). Treatment of human bladder cancer cells with cantharidin significantly decreased cell viability. The increase in the expressions of caspase-3 activity and cleaved form of caspase-9/-7/-3 were also increased in cantharidin-treated T24 cells. Furthermore, cantharidin increased the levels of phospho-eIF2α and Grp78 and decreased the protein expression of procaspase-12, which was accompanied by the increase in calpain activity in T24 cells. Cantharidin was capable of increasing the intracellular Ca (2+) and the phosphorylation of protein kinase C (PKC) in T24 cells. The addition of BAPTA/AM (a Ca (2+) chelator) and RO320432 (a selective cell-permeable PKC inhibitor) effectively reversed the increase in caspase-3 and calpain activity, the phosphorylation levels of PKC and eIF2α and Grp78 protein expression, and the decrease in procaspase-12 expression induced by cantharidin. Importantly, cantharidin significantly decreased the tumor volume (a dramatic 71% reduction after 21 days of treatment) in nude mice xenografted with T24 cells. Taken together, these results indicate cantharidin induced human bladder cancer cell apoptosis through a calcium/PKC-regulated ER stress pathway. These findings suggest that cantharidin may be a novel and potential anticancer agent targeting on bladder cancer cells.