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Background: Neurodegenerative diseases are increasingly recognized for their association with oxidative stress, which leads to progressive dysfunction and loss of neurons, manifesting in cognitive and motor impairments. This study aimed to elucidate the neuroprotective role of peroxiredoxin II (Prx II) in counteracting oxidative stress-induced mitochondrial damage, a key pathological feature of neurodegeneration. Methods: We investigated the impact of Prx II deficiency on endoplasmic reticulum stress and mitochondrial dysfunction using HT22 cell models with knocked down and overexpressed Prx II. We observed alcohol-treated HT22 cells using transmission electron microscopy and monitored changes in the length of mitochondria-associated endoplasmic reticulum membranes and their contact with endoplasmic reticulum mitochondria contact sites (EMCSs). Additionally, RNA sequencing and bioinformatic analysis were conducted to identify the role of Prx II in regulating mitochondrial transport and the formation of EMCSs. Results: Our results indicated that Prx II preserves mitochondrial integrity by facilitating the formation of EMCSs, which are essential for maintaining mitochondrial Ca2+ homeostasis and preventing mitochondria-dependent apoptosis. Further, we identified a novel regulatory axis involving Prx II, the transcription factor ATF3, and miR-181b-5p, which collectively modulate the expression of Armcx3, a protein implicated in mitochondrial transport. Our findings underscore the significance of Prx II in protecting neuronal cells from alcohol-induced oxidative damage and suggest that modulating the Prx II-ATF3-miR-181b-5p pathway may offer a promising therapeutic strategy against neurodegenerative diseases. Conclusions: This study not only expands our understanding of the cytoprotective mechanisms of Prx II but also offers necessary data for developing targeted interventions to bolster mitochondrial resilience in neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Background: To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance. Methods: In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Results: Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro. Conclusion: Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients. [ABSTRACT FROM AUTHOR]

Apoptosis of pancreatic β-cells is involved in the pathogenesis of type I and II diabetes. Peroxiredoxin I (Prx I) serves an important role in regulating cellular apoptosis; however, the role of Prx I in pancreatic β-cell apoptosis is not completely understood. In the present study, the role of peroxiredoxin 1 (Prx I) during streptozotocin (STZ)-induced apoptosis of pancreatic β-cells was investigated. The expression level of Prx I was decreased by STZ treatment in a time-dependent manner, and apoptosis of Prx I knockdown MIN6 cells was increased by STZ stimulation, compared with untransduced MIN6 cells. Furthermore, an intraperitoneal injection of STZ increased pancreatic islet damage in Prx I knockout mice, compared with wild-type and Prx II knockout mice. AKT and glycogen synthase kinase (GSK)-3β phosphorylation significantly decreased following Prx I knockdown in MIN6 cells. However, phosphorylated β-catenin and p65 levels significantly increased after STZ stimulation, compared with untransduced cells. The results of the present study indicate that deletion of Prx I mediated STZ-induced pancreatic β-cell death in vivo and in vitro by regulating the AKT/GSK-3β/β-catenin signaling pathway, as well as NF-κB signaling. These findings provide a theoretical basis for treatment of pancreatic damage. [ABSTRACT FROM AUTHOR]

Background: EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC. Methods: GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml. Results: GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model. Conclusion: Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC. [ABSTRACT FROM AUTHOR]

There are currently no clinically validated therapeutic targets for biliary tract cancer (BTC). Despite promising results in other cancers, compounds targeting the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, alone or in combination with Ras/Raf/MEK pathway inhibitors, have not been evaluated in BTC. Here, we examined the effects of a pan-PI3K inhibitor (BKM120) with or without a MEK inhibitor (MEK162), on eight human BTC cell lines carrying mutations in K-Ras and/or the PI3K catalytic subunit, PI3KCA. BKM120 inhibited the colony-forming ability and migration of BTC cells carrying wild-type (WT) PI3KCA and either mutant (MT) or WT K-Ras, but not of cells carrying mutations in both genes. In K-Ras-WT cells, BKM120 decreased the phosphorylation of Akt, its downstream effector kinase p70S6K, and the translational repressor 4E-BP1. Interestingly, BKM120 did not induce cell cycle arrest or suppress PI3K signaling via restoration of p-4E-BP1 in cells with PIK3CA and K-Ras double mutations. Notably, the resistance of dual K-Ras/PI3KCA-mutant cells to BKM120 was overcome by treatment with a combination of BKM120 and MEK162. Our findings thus support the clinical development of BKM120 monotherapy or BKM120/MEK162 combination therapy for the treatment of BTC. [ABSTRACT FROM AUTHOR]

Lipid droplets are unique lipid storage organelles in hepatocytes. Lipophagy is a key mechanism of selective degradation of lipid droplets through lysosomes. It plays a crucial role in the prevention of metabolic liver disease, including nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), and is a potential therapeutic target for treating these dysfunctions. In this review, we highlighted recent research and discussed advances in key proteins and molecular mechanisms related to lipophagy in liver disease. Reactive oxygen species (ROS) is an inevitable product of metabolism in alcohol-treated or high-fat-treated cells. Under this light, the potential role of ROS in autophagy in lipid droplet removal was initially explored to provide insights into the link between oxidative stress and metabolic liver disease. Subsequently, the current measures and drugs that treat NAFLD and AFLD through lipophagy regulation were summarized. The complexity of molecular mechanisms underlying lipophagy in hepatocytes and the need for further studies for their elucidation, as well as the status and limitations of current therapeutic measures and drugs, were also discussed. • Lipophagy, the selective degradation of lipid droplets through lysosomes, is a crucial mechanism in preventing metabolic liver diseases. • The role of reactive oxygen species (ROS) in autophagy and its connection to lipid droplet removal in liver disease is explored. • The discussion focuses on therapeutic approaches and drugs for lipophagy regulation in NAFLD and AFLD. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative diseases are a common group of neurological disorders characterized by progressive loss of neuronal structure and function leading to cognitive impairment. Recent studies have shown that neuronal pyroptosis mediated by the NLRP3 inflammasome plays a crucial role in the pathogenesis of neurodegenerative diseases. Objective and method: The NLRP3 inflammasome is a multiprotein complex that, when activated within cells, triggers an inflammatory response, ultimately leading to pyroptotic cell death of neurons. Pyroptosis is a typical pro-inflammatory programmed cell death process occurring downstream of NLRP3 inflammasome activation, characterized by the formation of pores on the cell membrane by the GSDMD protein, leading to cell lysis and the release of inflammatory factors. It has been found that NLRP3 inflammasome-mediated neuronal pyroptosis is closely associated with the development of various neurodegenerative diseases, such as Alzheimer's disease, traumatic brain injury, and Parkinson's disease. Therefore, inhibiting NLRP3 inflammasome activation and attenuating neuronal pyroptosis could potentially serve as novel strategies for the treatment of neurodegenerative diseases. Results: The aim of this review is to explore the role of NLRP3 activation-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases. Firstly, we extensively discuss the relationship between NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in various neurodegenerative diseases. Subsequently, we further explore the mechanisms driving NLRP3 activation and assembly, as well as the post-translational modifications regulating NLRP3 inflammasome activation. Conclusion: Understanding these mechanisms will contribute to a deeper understanding of the link between neuronal pyroptosis and neurodegenerative diseases, and hold significant implications for the treatment and prevention of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The gorgonian Echinogorgia sassapo reticulata contains two new bioactive polyhydroxylated steroids, sassapols A (1), B (2), and five related known compounds (3–7). Compound 6 has been encountered for the first time in natural sources. The structures of these new compounds were defined by spectroscopic analysis. All the compounds (1–7) isolated from E. sassapo reticulata were tested for anti-inflammatory activity. Compounds 1, 3, 5, and 7 inhibited both the generation of leukotriene C4 and the degranulation reaction in mouse bone marrow-derived mast cells. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen species (ROS), routinely produced in biological reactions, contribute to both normal aging and age-related decline in cognitive function. However, little is known regarding the involvement of specific antioxidants in the underlying mechanism(s). Here, we examined if peroxiredoxin II (Prx II) scavenges intracellular ROS that cause age-dependent mitochondrial decay in hippocampal CA1 pyramidal neurons and subsequent impairment of learning and memory. Age-dependent mitochondrial ROS generation and long-term potentiation (LTP) decline were more prominent in hippocampal neurons in Prx II−/− than in wild-type mice. Additionally, Prx II−/− mice failed to activate synaptic plasticity-related cellular signaling pathways involving CREB, CaMKII, and ERK, or to maintain functional integrity of their mitochondria. Dietary vitamin E alleviated Prx II deficiency-related deficits, including mitochondrial decay and CREB signaling, resulting in restoration of the abrupt cognitive decline in aged Prx II−/− mice. These results suggest that Prx II help maintain hippocampal synaptic plasticity against age-related oxidative damage. [Copyright &y& Elsevier]

Objectives: To investigate the effects of androgen administration at different periods of prepubertal life on penile size and potential fertility in hormonally normal rats. Methods: Eighty Sprague-Dawley rats were divided into 4 groups; group 1 received weekly injections of testosterone enanthate (8 mg/100 g) at 1-3 weeks group 2 at 3-5 weeks, group 3 at 1-5 weeks, and group 4 was control (n = 20 each). Animals were killed at age 60 days. Penile length, penile, testicular, and epididymal weight, testicular fertility index, serum follicular stimulating hormone, luteinizing hormone, and testosterone levels were measured and quantitative real time polymerase chain reaction of penile androgen receptor messenger ribonucleic acids was performed. Results: Penile length in the 3-5-week injection group was significantly longer than controls (41.18 vs 39.13 mm, P = .011), and it was smaller than controls in the 1-3 week injection group (37.24 vs 39.13 mm, P = .020). The penile wet weight showed a similar pattern to stretched penile length; however, statistical significance was not found. Testicular weight was significantly less in the testosterone injection group than controls (1.79, 2.16, 2.24, and 2.78 g in groups 1-4, respectively) as well as the epididymal weight (0.48, 0.42, 0.59, and 0.69 in groups 1-4, respectively). The mean tubular diameter and germ cell count were significantly reduced in the testosterone treated group. Total penile androgen receptor messenger ribonucleic acid level was significantly lower in group 3 as compared with controls. Conclusions: Testosterone administered during early prepubertal life resulted in smaller penis than controls, as well as having an adverse effect on testicular development which can jeopardize potential fertility. [Copyright &y& Elsevier]

The ductus arteriosus (DA), an essential vascular shunt for fetal circulation, begins to close immediately after birth. Although Ca2+ influx through several membrane Ca2+ channels is known to regulate vasoconstriction of the DA, the role of the T-type voltage-dependent Ca2+ channel (VDCC) in DA closure remains unclear. Here we found that the expression of α1G, a T-type isoform that is known to exhibit a tissue-restricted expression pattern in the rat neonatal DA, was significantly up-regulated in oxygenated rat DA tissues and smooth muscle cells (SMCs). Immunohistological analysis revealed that α1G was localized predominantly in the central core of neonatal DA at birth. DA SMC migration was significantly increased by α1G overexpression. Moreover, it was decreased by adding α1G-specific small interfering RNAs or using R(-)-efonidipine, a highly selective T-type VDCC blocker. Furthermore, an oxygenationmediated increase in an intracellular Ca2+ concentration of DA SMCs was significantly decreased by adding α1G-specific siRNAs or using R(-)-efonidipine. Although a prostaglandin E receptor EP4 agonist potently promoted intimal thickening of the DA explants, R(-)-efonidipine (10-6 M) significantly inhibited EP4-promoted intimal thickening by 40% using DA tissues at preterm in organ culture. Moreover, R(-)-efonidipine (10-6 M) significantly attenuated oxygenation-induced vasoconstriction by ∼27% using a vascular ring of fetal DA at term. Finally, R(-)-efonidipine significantly delayed the closure of in vivo DA in neonatal rats. These results indicate that T-type VDCC, especially α1G, which is predominantly expressed in neonatal DA, plays a unique role in DA closure, implying that T-type VDCC is an alternative therapeutic target to regulate the patency of DA. [ABSTRACT FROM AUTHOR]

Neuroinflammation is associated with many neurodegenerative diseases. Abnormal activation of microglial cells in the central nervous system (CNS) is a major characteristic of neuroinflammation. Nitric oxide (NO) free radicals are produced by activated microglia and prolonged presence of large quantities of NO in the CNS can lead to neuroinflammation and disease. Hispidin is a polyphenol derived from Phellinus linteus (a valuable medicinal mushroom) with strong antioxidant, anticancer and antidiabetic properties. A previous study demonstrated that hispidin significantly inhibited NO production via lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Therefore, the present study used MTT assay was used to detect the effect of hispdin on cell viability. Griess reagent analysis was used to measure NO production. Reverse transcription-semi quantitative PCR and western blotting were used to evaluate the effects of hispdin on iNOS mRNA and MAPK/ERK/JNK protein levels. Fluorescence microscopy and flow cytometry were used to detect the effects of hispdin on the production of ROS and phagocytosis of cells. The present results indicated that hispidin could significantly inhibit the increase of NO production and iNOS expression in BV-2 microglial cells stimulated by LPS. The inhibitory effect of hispidin on NO production was similar to that of S-methylisothiourea sulfate, an iNOS inhibitor. Signaling studies demonstrated that hispidin markedly suppresses LPS-induced mitogen activated protein kinases and JAK1/STAT3 activation, although not the NF-κB signaling pathway. The present observations in LPS-stimulated BV-2 microglial cells indicated that hispidin might serve as a therapeutic candidate for the treatment of NO-induced neuroinflammation and, potentially, as a novel iNOS inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: 2,3,7,8-Tedtrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic endocrine disruptors and has been reported to induce oxidative stress in the reproductive organs. However, the mechanism by which TCDD induces oxidative stress is unclear. The aim of this study is to examine the role of the general cytokine, TGF-β1, in TCDD-induced oxidative stress in the male reproductive system. To examine the effect of TCDD on antioxidant enzyme activity, we administered TCDD orally to C57BL/6 mice at 1μg/kg/day for 4 days. Using Smad2–siRNA, we examined the involvement of Smad and non-Smad pathways in TCDD-induced oxidative stress. We also measured the mRNA levels of typical antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and analyzed the activation of TGF-β1, and the downstream signals, Smad2, Smad4, transcription factors (c-Jun, ATF3), and three major MAPKs (JNK, ERK, p38). After TCDD treatment, the mRNA levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were significantly decreased. In addition, TGF-β1 activity increased and the receptor-activated protein, Smad2, was activated while Smad4 was not. The levels of major transcription factors, c-Jun and ATF3, and the regulator of these transcription factors, MAPK, were also increased by TCDD administration. The mRNA levels of the 3 antioxidant enzymes in the Smad2–siRNA and TCDD co-treated group were higher than that of the TCDD-only treated group but still decreased when compared to control. C-Jun and ATF3 levels were also increased in Smad2–siRNA and TCDD co-treated testes compared to control. However, the levels of c-Jun and ATF3 were lower than those in the group treated with TCDD only. Of the three MAPKs which showed increase in expression after TCDD treatment, p38 was the only one that showed a decrease with Smad2 inhibition, while both ERK and JNK expression were unaffected. In conclusion, we found that the activated TGF-β1-Smad pathway is involved in TCDD-induced oxidative stress. Furthermore, the effects of TCDD on the testes are caused by the coordinated action of both Smad and non-Smad pathways. [Copyright &y& Elsevier]

Abstract: The differential expression patterns of antioxidant enzymes observed in the brains of patients with neurodegenerative diseases suggest an important role for reactive oxygen species and antioxidant enzymes in neurodegeneration. The six mammalian peroxiredoxins (Prxs) comprise a novel family of anti-oxidative proteins that are widely distributed in most tissues, but few studies of Prx in brain tissue have been reported. The specific histology of the neural cell types in which Prxs are expressed is an important issue related to biological function and defense against oxidative stress in the brain. This study analyzed mouse brain neural cell types expressing Prx isoforms using single- or double-label immunohistochemical techniques. In neurons, immunoreactivity for Prx II–V was observed in the cytoplasm. In particular, Prx II was found in the habenular nuclei, and Prx III and V were found in the stratum lucidum of the hippocampus. Astrocytes and microglia were immunoreactive only for Prx VI and Prx I, respectively. Prx I and IV immunoreactivity was apparent in oligodendrocytes, where it was principally localized in the nuclei. The observed distribution of Prx isoforms in the mammalian brain may be indicative of their specific roles in their preferred neural cell types and subcellular locales. The results of this study will help in unraveling the physiological and pathophysiological roles of the different Prx isoforms in neural function. [Copyright &y& Elsevier]

Alterations in DNA damage response (DDR) pathways are hallmarks of cancer. Incorrect repair of DNA lesions often leads to genomic instability. Ataxia telangiectasia mutated (ATM), a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR. There is still a vast research opportunity for the development of ATM inhibitors as anticancer agents. Here, we focus on the recent findings of ATM signaling in DNA repair of cancer. Previous studies have identified several partners of ATM, some of which promote ATM signaling, while others have the opposite effect. ATM inhibitors, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390, have been evaluated for their antitumor effects. It has been revealed that ATM inhibition increases a cancer cell's sensitivity to radiotherapy. Moreover, the combination with PARP or ATR inhibitors has synergistic lethality in some cancers. Of note, among these ATM inhibitors, AZD0156 and AZD1390 achieve potent and highly selective ATM kinase inhibition and have an excellent ability to penetrate the blood-brain barrier. Currently, AZD0156 and AZD1390 are under investigation in phase I clinical trials. Taken together, targeting ATM may be a promising strategy for cancer treatment. Hence, further development of ATM inhibitors is urgently needed in cancer research. [ABSTRACT FROM AUTHOR]

Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC. [ABSTRACT FROM AUTHOR]

The roles of cyclin-dependent kinase 6 (CDK6) in various cancers, including small cell lung carcinoma (SCLC), remain unclear. Here, 111,54 multi-center samples were investigated to determine the expression, clinical significance, and underlying mechanisms of CDK6 in 34 cancers. The area under the curve (AUC), Cox regression analysis, and the Kaplan–Meier curves were used to explore the clinical value of CDK6 in cancers. Gene set enrichment analysis and correlation analysis were performed to detect potential CDK6 mechanisms. CDK6 expression was essential in 24 cancer cell types. Abnormal CDK6 expression was observed in 14 cancer types (e.g., downregulated in breast invasive carcinoma; p < 0.05). CDK6 allowed six cancers to be distinguished from their controls (AUC > 0.750). CDK6 expression was a prognosis marker for 13 cancers (e.g., adrenocortical carcinoma; p < 0.05). CDK6 was correlated with several immune-related signaling pathways and the infiltration levels of certain immune cells (e.g., CD8+ T cells; p < 0.05). Downregulated CDK6 mRNA and protein levels were observed in SCLC (p < 0.05, SMD = − 0.90). CDK6 allowed the identification of SCLC status (AUC = 0.91) and predicted a favorable prognosis for SCLC patients (p < 0.05). CDK6 may be a novel biomarker for the prediction and prognosis of several cancers, including SCLC. [ABSTRACT FROM AUTHOR]

Keratinocyte hyperproliferation is an essential link in skin cancer pathogenesis. Peroxiredoxin I (Prx I) is known to regulate cancer cell proliferation, differentiation, and apoptosis, but its role in skin cancer remains unclear. This study aimed to elucidate the role and mechanism of Prx I in skin cancer pathogenesis. Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were used to create a skin tumor model of the initiation/promotion stage of cancer. The role of Prx I in H 2 O 2 -induced keratinocyte apoptosis was also investigated. After DMBA/TPA treatment, Prx I deficiency was significantly associated with less skin tumors, lower Bcl-2 expression, and higher p-p38 and cleaved caspase-3 expressions in Prx I knockout tumors than in wild-type controls. H 2 O 2 stimulation caused more cellular apoptosis in Prx I knockdown HaCaT cells than in normal HaCaT cells. The signaling study revealed that Bcl-2, p-p38, and cleaved caspase-3 expressions were consistent with the results in the tumors. In conclusion, the deletion of Prx I triggered the DMBA/TPA-induced skin tumor formation in vivo and in vitro by regulating the reactive oxygen species (ROS)-p38 mitogen-activated protein kinase (MAPK) pathway. These findings provide a theoretical basis for treating skin cancer. • Peroxiredoxin I deficiency was associated with a smaller number of skin tumors. • Peroxiredoxin I deficiency was related to lower Bcl-2 and higher p-p38 and c-C3. • Peroxiredoxin I had no significant effect on the later stage of tumor development. • H 2 O 2 stimulation caused more cellular apoptosis in peroxiredoxin I-deficient mice. [ABSTRACT FROM AUTHOR]

Background: Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. Results: In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. Conclusions: Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. -6AE1Qxi5fhihA5_M9L54L Video Abstract [ABSTRACT FROM AUTHOR]

Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. 9w_3dtXFY6CUXRSJ-7gGif Video Abstract [ABSTRACT FROM AUTHOR]

The clinical progression of small-cell lung cancer (SCLC) remains pessimistic. The aim of the present study was to promote the understanding of the clinical significance and mechanism of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) in SCLC. Wilcoxon tests, standardized mean difference (SMD), and Kruskal–Wallis tests were utilized to compare OGT level differences among the experimental and control groups. The univariate Cox regression analysis, Kaplan–Meier curves, and receiver operating characteristic curves were applied to determine OGT's clinical relevance in cancers. The Spearman correlation analysis and enrichment analysis were utilized to explore the underlying mechanisms of OGT in cancers. For the first time in the field, we provide an overview of OGT in 32 cancers using a large number of samples (n = 21,196), determining distinct OGT expression in 25 cancers and its prognosis effects in 12 cancers. Furthermore, using 950 samples from multiple sources, upregulated OGT was found in both mRNA and protein levels in SCLC (SMD = 0.93, 95% CI [0.24, 1.63]). Higher OGT levels represented a more unfavorable disease-free interval for SCLC patients (p < 0.001). The research also identified OGT expression as a potential marker for SCLC prediction (sensitivity = 0.79, specificity = 0.86, and AUC = 0.88). The high expression of OGT in SCLC may result from the positive regulation of two transcription factors—DEK and XRN2. We primarily investigated the underlying mechanisms of OGT in SCLC. Herein, based on the analyses from pan-cancer to SCLC, OGT demonstrated conspicuous clinical significance. OGT may be an underlying biomarker for the treatment and identification of some cancers, including SCLC. [ABSTRACT FROM AUTHOR]

Background: Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. Methods and Findings: Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE-/- mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4+/-/ApoE-/- mice exhibited significantly less AAA formation than EP4+/+/ApoE-/- mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/- mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. Conclusion: An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the location of interstitial cells of Cajal-like cells and the ureteral aspect using histopathologic studies of obstructive and refluxing megaureters to reveal the different pathogenesis of megaureters in the human urinary tract. The underlying pathophysiology of obstructive megaureter and refluxing megaureter is poorly understood. Methods: The data from 14 patients with obstructive megaureter (7 boys and 7 girls), with a mean age of 12 months (range 2-84), and 9 patients with refluxing megaureter (7 boys and 2 girls), with a mean age of 11 months (range 4-24), were compared. We investigated the difference in the histopathologic aspects using Masson''s trichrome, terminal uridine deoxynucleotidyl transferase dUTP nick end labeling (for apoptosis), and human c-kit antibody (CD117 for interstitial cells of Cajal-like cells) between the obstructive and refluxing megaureters. Results: The proportion of smooth muscle was significantly lower in segments of refluxing megaureter (32.04% ± 4.96%) than in the segments of obstructive megaureter (52.48% ± 3.46%; P < .01). The number of apoptotic cells was significantly increased in the obstructive megaureter (mean 1661 ± 135.1 cells) compared with the refluxing megaureter (mean 375.2 ± 65.14 cells; P < .0001). The number of c-kit positive cells was significantly lower in the refluxing megaureter (mean 83.60 ± 48.84 cells) than in the obstructive megaureter (mean 463.6 ± 100.4 cells; P < .05). Conclusions: The differences in the histopathologic aspects can provide information on the possible pathophysiology of obstructive and refluxing megaureters. Ureteral peristalsis can be affected by the increased myocyte apoptosis in the obstructive megaureter and by the decreased number of interstitial cells of Cajal-like cells and smooth muscle content in refluxing megaureters. Additional research is warranted to elucidate the exact pathophysiology. [Copyright &y& Elsevier]

Abstract: We investigated the thermal stability of graphite oxides to heat treatment under ambient argon gas. Using X-ray diffraction, we observed the development of three phases in the annealed graphite oxides, instead of a mono-dispersed expanded interlayer distance as in the pristine graphite oxide. We found that the interlayer distances dropped off in a stepwise manner by approximately 0.1nm in relation to the annealing time. The three phases are related to the stepwise decrease in the interlayer distances which is attributed to the removal of water molecules, hydrogen atoms from hydroxyl groups, and hydroxyl groups in the annealed graphite oxide. These changes were confirmed using Fourier-transformed infrared spectroscopy, thermogravimetric analysis, and elemental analysis. [Copyright &y& Elsevier]

Abstract: Unoccupied electronic states of graphite oxides with different oxidation times have been investigated using X-ray absorption spectroscopy (XAS) in total electron yield (TEY) and total fluorescence yield (TFY) modes. The graphite oxides exhibit graphite-like sp2 states with additional electronic states originating from functional groups. The intensity of the π* state decreases as the atomic ratio O:C increases. The intensity ratio of carboxyl to π* states in XAS TEY mode corresponds to the area ratio of carboxyl to sp2 carbon in X-ray photoelectron spectroscopy. In addition, the two modes in XAS can identify electronic states of functional groups originating from surface or bulk regions. [Copyright &y& Elsevier]

Background: This study aimed to evaluate the association between soluble TGF‐β (sTGF‐β) and soluble PD‐L1 (sPDL1), the dynamics of sTGF‐β during treatment and its prognostic role in biliary tract cancer (BTC). Methods: The study population consisted of 90 BTC patients with first‐line chemotherapy (cohort 1) and 35 BTC patients with second‐ or third‐line chemotherapy (cohort 2). Plasma sTGF‐β and sPDL1 levels were measured using an enzyme‐linked immunosorbent assay. Results: In both groups, sTGF‐β was positive correlated with sPDL1 for baseline and change values after treatment. sTGF‐β was elevated at disease progression compared to baseline in cohort 1 (P <.001). Increased sTGF‐β after treatment revealed worse DFS and OS (P =.024, P =.028, respectively) in cohort 1 and significantly shorter OS (P =.020) in cohort 2. In multivariable analysis, this prognostic value of increased sTGF‐β for OS retained its significance in both cohorts (Hazard ratio (HR) = 1.8, 95% CI, 1.1‐3.0, P =.028, in cohort 1; HR = 4.7, 95% CI, 1.5‐14.6, P =.007, in cohort 2). Conclusions: In BTC, sTGF‐β was positively correlated with sPDL1 for baseline and changes after chemotherapy, and increased as tumour burden. sTGF‐β could be associated with survival; particularly, an elevated value after treatment suggests worse prognosis. [ABSTRACT FROM AUTHOR]

Objectives: Transforming growth factor‐beta (TGF‐β) is a multifunctional regulatory factor. Here we measured serum soluble TGF‐β (sTGF‐β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. Methods: We prospectively enrolled 60 patients treated with FOLFIRINOX as the first‐line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF‐β using an enzyme‐linked immunosorbent assay. Results: The patients' median overall survival (OS) and progression‐free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5‐12.1) and 6.5 (95% CI, 4.9‐8.1) months, respectively. Patients with low sTGF‐β at diagnosis (<31.2 ng/mL) had better OS and PFS than patients with high sTGF‐β, respectively, (OS, 13.7 vs 9.2 months; hazard ratio [HR], 2.602; P =.004; PFS, 9.0 vs 5.8 months; HR, 2.010; P =.034). At the time of disease progression, sTGF‐β was increased compared with that of diagnosis (mean, 26.4 vs 23.9 ng/mL). In particular, sTGF‐β was significantly increased at disease progression in patients with a partial response (mean, 25.7 vs 31.0 ng/mL; P =.049). Conclusions: Pretreatment sTGF‐β levels can serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF‐β during chemotherapy have prognostic value. [ABSTRACT FROM AUTHOR]

Derivatives of 1,4-naphthoquinone have excellent anti-cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti-cancer activity, two novel types of 1,4-naphthoquinone derivatives, 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ) were synthesized and their anti-tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway-associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L-02, normal lung IMR-90 and stomach GES-1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N-acetyl-L-cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c-Jun N-terminal kinase and downregulating extracellular signal-regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS-modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Hit, Lead & Candidate Discovery It is reported that 1,4‐naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2‐(naphthalene‐2‐thio)‐5,8‐dimethoxy‐1,4‐naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose‐dependent manner. NTDMNQ significantly induced mitochondrial‐related apoptosis in AGS cells and increased the accumulation of ROS. However, pre‐treatment with N‐acetyl‐L‐cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ‐induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c‐Jun N‐terminal kinase (JNK) and decreased the phosphorylation of extracellular signal‐regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen‐activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ‐induced gastric cancer cell apoptosis via ROS‐mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types. [ABSTRACT FROM AUTHOR]

Peroxiredoxin I (Prx I) plays a role in regulating macrophage proinflammatory cytokine production and gene expression and participates in immune regulation. However, the possible protective role of Prx I in endotoxin‑induced lethal shock is poorly understood. In the present study, western blot analysis, ELISA and haematoxylin and eosin staining were performed to examine the protein expression of cytoines and analyses the levels of cytokines in the serum and tissue to evaluate the tissue damage. The present study revealed that lipopolysaccharide (LPS)‑induced lethality in Prx‑/‑mice was is accelerated via the observed decreased serum IL‑10 levels. Results also demonstrated rapid immune cell infiltration and oxidative stress in the Prx ‑/‑mice liver after LPS injections. These phenomena increased liver apoptosis through increasing cleaved caspase‑3 protein expression in Prx I‑/‑ mice after LPS injections, resulting in high lethality after LPS challenges. These findings provide a new insight for understanding the function of Prx I against endotoxin‑induced injury. [ABSTRACT FROM AUTHOR]

High concentrations of glutamate may mediate neuronal cell apoptosis by increasing intracellular reactive oxygen species (ROS) levels. Peroxiredoxin V (Prx V), a member of the Prx family, serves crucial roles in protecting cells from oxidative stress. The present study investigated the regulatory effect of Prx V on glutamate‑induced effects on viability and apoptosis in HT22 cells. Western blotting was used for protein expression analysis and Annexin V/PI staining and flow cytometry for determination of apoptosis. The results demonstrated that glutamate may ROS‑dependently increase HT22 cell apoptosis and upregulate Prx V protein levels. Furthermore, knockdown of Prx V protein expression with a lentivirus significantly enhanced HT22 cell apoptosis mediated by glutamate, which was reversed by inhibition of ROS with N‑acetyl‑L‑cysteine. Inhibiting the extracellular signal‑regulated kinase (ERK) signaling pathway with PD98059, a specific inhibitor for ERK phosphorylation, markedly decreased glutamate‑induced HT22 cell apoptosis in Prx V knockdown cells, indicating the potential involvement of ERK signaling in glutamate‑induced HT22 cell apoptosis. In addition, an increase in nuclear apoptosis‑inducing factor was observed in Prx V knockdown HT22 cells following glutamate treatment, compared with mock cells, whereas no differences in B‑cell lymphoma‑2 and cleaved‑caspase‑3 protein expression levels were observed between mock and Prx V knockdown cells. The results of the present study indicated that Prx V may have potential as a therapeutic molecular target for glutamate‑induced neuronal cell death and provide novel insight into the role of Prx V in oxidative‑stress induced neuronal cell death. [ABSTRACT FROM AUTHOR]

1,4-Naphthoquinone and its derivatives have shown some efficacy as therapeutic compounds for cancer and inflammation, though their clinical application is limited by their side-effects. To reduce the toxicity of these compounds and optimize their effects, we synthesized two 1,4-naphthoquinone derivatives—2-butylsulfinyl- 1,4-naphthoquinone (BSNQ) and 2-octylsulfinyl-1,4-naphthoquinone (OSNQ)—and investigated their effects and underlying mechanisms in hepatocellular carcinoma cells. BSNQ and OSNQ decreased cell viability and significantly induced apoptosis, accompanied by the accumulation of reactive oxygen species (ROS). However, pretreatment with N -acetyl- l -cysteine, a specific ROS scavenger, blocked apoptosis. Western blot results indicated that BSNQ and OSNQ up-regulated the phosphorylation of p38 and JNK, and down-regulated the phosphorylation of ERK, Akt and STAT3, and that these effects were blocked by N-acetyl- l -cysteine. Furthermore, BSNQ and OSNQ suppressed tumor growth and modulated MAPK and STAT3 signaling in mouse xenografts without detectable effects on body weight or hematological parameters. These results indicate that BSNQ and OSNQ induce apoptosis in human hepatoma Hep3B cells via ROS-mediated p38/MAPK, Akt and STAT3 signaling pathways, suggesting that these 1,4-naphthoquinone derivatives may provide promising new anticancer agents to treat HCC. [ABSTRACT FROM AUTHOR]

Quinalizarin may be a potential chemical agent for cancer therapy, as it exerts anti-tumour effects against a variety of different types of cancer. However, the underlying regulatory mechanism and signalling pathways of quinalizarin in lung cancer cells remains unknown. The present study sought to investigate the effects of quinalizarin on proliferation, apoptosis and reactive oxygen species (ROS) generation in lung cancer. MTT assays were used to evaluate the effects of quinalizarin on the viability of lung cancer A549, NCI-H460 and NCI-H23 cells. Flow cytometry was employed to evaluate the effects of quinalizarin on the cell cycle, apoptosis and ROS generation in A549 cells. Western blotting was performed to detect cell cycle and apoptosis-associated protein expression levels in A549 cells. Quinalizarin inhibited A549, NCI-H460 and NCI-H23 cell proliferation and induced A549 cell cycle arrest at the G0/G1 phase. Quinalizarin induced apoptosis by upregulating the expression of B-cell lymphoma 2 (Bcl-2)-associated agonist of cell death, cleaved-caspase-3 and cleaved-poly (adenosine diphosphate-ribose) polymerase, and downregulating the expression of Bcl-2. Furthermore, quinalizarin activated mitogen-activated protein kinase (MAPK) and p53, and inhibited the protein kinase B and signal transducer and activator of transcription-3 (STAT3) signalling pathways. In addition, quinalizarin increased ROS generation. The ROS scavenger N-acetyl-L-cysteine restored quinalizarin-induced cell apoptosis, and inactivated the MAPK and STAT3 signalling pathways. The results of the present study demonstrated that quinalizarin induces G0/G1 phase cell cycle arrest and apoptosis via ROS mediated-MAPK and STAT3 signalling pathways. [ABSTRACT FROM AUTHOR]

Our research group showed that E-salignone inhibited the invasion of human breast cancer MDA-MB-231 cells induced by the chemokine epidermal growth factor (EGF). Due to the limited natural resources, we had to prepare sizable quantities of E-salignone for the antimetastasis investigation. E-Salignone was synthesized by methylation of the corresponding amine by reductive amination with paraformaldehyde in the presence of sodium triacetoxyhydroborate. The synthesized E-salignone exhibited significant inhibitory effects on the invasion of human MDA-MB-231 breast cancer cells and non-small cell lung cancer cells (A549) induced by the chemokine EGF with IC values of 0.36 μM and 5.77 μM, respectively. Since angiogenesis is required for tumor metastasis, anti-angiogenesis is consider a promising approach for tumor therapy. In our investigation of antimetastatic activity, E-salignone potently inhibited the migration of HUVEC and MDA-MB-231 in the wound healing assay. [ABSTRACT FROM AUTHOR]

Preclinical Research The preparation of novel E ‐ salignone derivatives and their biological evaluation as potential antimetastatic agents is described. The E ‐ salignone amide derivatives were prepared from epiandrosterone and androsterone, and characterized by analytical 1H NMR, 13C NMR, and mass spectrometry. The derivatives were evaluated for antimetastatic activity in MDA ‐ MB ‐ 231 cells by using a transwell assay. Comparing with the positive control, LY294002, compounds 19b, 19d, and 19e exhibited significant inhibitory effects on the EGF ‐ induced invasion of MB ‐ MDA ‐ 231 cells. Moreover, compound 19b also had antimigration effects in wound ‐ healing assay. Compound 19b may represent a novel antimetastatic agent for treating breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Multiwalled carbon nanotubes (MWCNTs) treated by microwave and heat treatment were used for hydrogen storage. Their storage capacity was measured using a quadruple quartz crystal microbalance in a moisture-free chamber at room temperature and at relatively low pressure (0.5MPa). Deuterium was also used to monitor the presence of moisture. The hydrogen storage capacity of the microwave-treated MWCNTs was increased to nearly 0.35wt% over 0.1wt% for the pristine sample and increased further to 0.4wt%, with improved stability after subsequent heat-treatment. The increase in the storage capacity by the microwave treatment was mostly attributed to the introduction of micropore surfaces, while the stability improvement after the subsequent heat treatment was related to the removal of functional groups. We also propose a measurement method that eliminates the moisture effect by measuring the storage capacity with hydrogen and deuterium gas. [Copyright &y& Elsevier]

Abstract: We have investigated the effect of Au-ion treatment on the work function and the electronic structure change of reduced graphite oxides (RGOs). Au-ions were reduced spontaneously by extracting electrons (i) from sp2 carbons of RGO at low concentration and (ii) from some oxygen-related functional groups at high concentration. This implies that the work function was modulated by the amount of charges transferred to Au-ions. The sheet resistance of the RGO film was improved with Au-ion treatment. This was explained in terms of electron donation to Au-ions that eventually led to a p-type doping in RGO film. [Copyright &y& Elsevier]

The aim of the present study was to verify the pro-apoptotic anticancer potential of several 5,8-dimethoxy-1,4-phthoquinone (DMNQ) derivatives in Ras-mediated tumorigenesis. MTT assays were used to detect cellular viability and flow cytometry was performed to assess intracellular reactive oxygen species (ROS) levels and apoptosis. The expression levels of proteins were detected via western blotting. Among the 12 newly synthesized DMNQ derivatives, 2-benzylthio-5,8-dimethoxynaphthalene-1,4-dione (BZNQ; component #1) significantly reduced cell viability both in mouse NIH3T3 embryonic fibroblasts cells (NC) and H-RasG12V transfected mouse NIH3T3 embryonic fibroblasts cells (NR). Moreover, BZNQ resulted in increased cytotoxic sensitivity in Ras-mutant transfected cells. Furthermore, the reactive oxygen species (ROS) levels in H-RasG12V transfected HepG2 liver cancer cells (HR) were significantly higher compared with the levels in HepG2 liver cancer cells (HC) following BZNQ treatment, which further resulted in increased cellular apoptosis. Eliminating cellular ROS using an ROS scavenger N-acetyl-L-cysteine markedly reversed BZNQ-induced cellular ROS accumulation and cell apoptosis in HC and HR cells. Western blotting results revealed that BZNQ significantly downregulated H-Ras protein expression and inhibited the Ras-mediated downstream signaling pathways such as protein kinase B, extracellular signal-related kinase and glycogen synthase kinase phosphorylation and β-catenin protein expression. These results indicated that the novel DMNQ derivative BZNQ may be a therapeutic drug for Ras-mediated liver tumorigenesis. The results of the current study suggest that BZNQ exerts its effect by downregulating H-Ras protein expression and Ras-mediated signaling pathways. [ABSTRACT FROM AUTHOR]

The cover image is based on the Research Article The compound 2‐(naphthalene‐2‐thio)‐5,8‐dimethoxy‐1,4‐naphthoquinone induces apoptosis via reactive oxygen species‐regulated mitogen‐activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells, by Jia‐Ru Wang et al., DOI: 10.1002/ddr.21442. [ABSTRACT FROM AUTHOR]