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Background: Syringin (Syr), a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, possesses various biological properties, including anticancer activities. However, the cytotoxicity effects of Syr on breast cancer have not yet been elucidated., Purpose: In this study, we evaluated the anticancer potential of Syr on breast carcinoma and the mechanism involved., Study Design/methods: Non-tumorigenic (M10), tumorigenic (MCF7) and metastatic (MDA-MB-231) breast cancer cell lines as well as xenograft model were treated with Syr. Proliferation and cell cycle distribution were evaluated using the MTT, the colony formation assay and flow cytometry. The expression levels of cytotoxicity-related proteins were detected by Western blot., Results: Here, we found that colony formation inhibition, cell cycle arrest in the G2/M phase, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3/9 activation were observed in MCF7 and MDA-MB-231 cells treated with Syr. Moreover, pretreatment with a pan-caspase inhibitor (Z-DEVD-FMK) inhibited Syr-induced apoptosis. In addition, treatment with Syr also increased the production of reactive oxygen species (ROS). However, the antioxidant N-acetyl-cysteine (NAC) reversed the ROS levels and rescued the apoptotic changes. Meanwhile, Syr inhibited the growth of breast cancer xenograft models and dramatically decreased tumor volume without any obvious body weight loss in vivo., Conclusion: Our findings suggest that Syr induces oxidative stress to suppress the proliferation of breast cancer and thus might be an effective therapeutic agent to treat breast cancer., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Aims: Mitochondrial succinate dehydrogenase (SDH) is an essential complex of the electron transport chain and tricarboxylic acid cycle. Mutations in the human SDH subunit D frequently lead to paraganglioma (PGL), but the mechanistic consequences of the majority of SDHD polymorphisms have yet to be unraveled. In addition to the originally discovered yeast SDHD subunit Sdh4, a conserved homolog, Shh4, has recently been identified in budding yeast. To assess the pathogenic significance of SDHD mutations in PGL patients, we performed functional studies in yeast., Results: SDHD protein expression was reduced in SDHD-related carotid body tumor tissues. A BLAST search of SDHD to the yeast protein database revealed a novel protein, Shh4, that may have a function similar to human SDHD and yeast Sdh4. The missense SDHD mutations identified in PGL patients were created in Sdh4 and Shh4, and, surprisingly, a severe respiratory incompetence and reduced expression of the mutant protein was observed in the sdh4Δ strain expressing shh4. Although shh4Δ cells showed no respiratory-deficient phenotypes, deletion of SHH4 in sdh4Δ cells further abolished mitochondrial function. Remarkably, sdh4Δ shh4Δ strains exhibited increased reactive oxygen species (ROS) production, nuclear DNA instability, mtDNA mutability, and decreased chronological lifespan., Innovation and Conclusion: SDHD mutations are associated with protein and nuclear and mitochondrial genomic instability and increase ROS production in our yeast model. These findings reinforce our understanding of the mechanisms underlying PGL tumorigenesis and point to the yeast Shh4 as a good model to investigate the possible pathogenic relevance of SDHD in PGL polymorphisms.

In this study, we investigated the antitumor activity of a novel coumarin derivative, 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC), on colorectal carcinoma. DMAC treatment resulted in substantial proapoptotic activity against colon cancer HCT116 and LoVo cells. Induction of apoptotic characteristics, including cellular shrinkage, chromatin condensation, and Annexin V detection, was observed following DMAC treatment. Mechanistically, we observed that DMAC elicited induction of proteolytic cascade activation including cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) expression and loss of the antiapoptotic proteins, Mcl-1 and Bcl-XL, accompanied by an increase in expression of the proapoptotic protein, Bak. In addition, suppressing c-Jun N-terminal protein kinase (JNK), but not extracellular-regulated protein kinase (ERK) or p38, substantially diminished DMAC-induced cell death and caspase-3 and PARP cleavage. However, pretreatment with antioxidants, including N-acetyl-l-cysteine (NAC) and diphenylene iodonium (DPI), failed to protect against DMAC-elicited apoptosis. Pretreatment with the JNK inhibitor, SP600125, suppressed DMAC-induced JNK phosphorylation, which was accompanied by a reversal of Bcl-XL expression. Moreover, combining DMAC treatment with the conventional anticancer drugs, 5-FU and CPT-11, considerably enhanced their therapeutic efficacies. Structural-activity relationship analyses further revealed that an alkylation substitution at position 6 of the coumarin ring was critical for inducing apoptosis, and the phenyl group at position 4 might have enhanced its bioactivity. Our data showed that DMAC can be used as part of a promising strategy to enhance therapeutic efficacies, and could be used to develop an approach for structure-based drug design for cancer treatment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Arecoline is the major alkaloid of areca nut (AN) and known to induce reactive oxygen species (ROS) production and apoptosis. The metabolic sensor AMP-activated protein kinase (AMPK), activated by ROS, also regulates apoptosis. This study used several types of cells as the experimental model to analyze the roles of ROS and AMPK in arecoline-induced apoptosis. We found that arecoline dose-dependently increased intracellular ROS level, and two antioxidants, N-acetyl-L-cysteine (NAC) and glutathione, attenuated arecoline-induced apoptotic cell death. Interestingly, arecoline dose- and time-dependently inhibited rather than stimulated AMPK-Thr(172) phosphorylation, and both NAC and glutathione relieved this inhibition. The AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), also restored the phosphorylation level of AMPK-Thr(172) and attenuated apoptotic cell death under arecoline insult. In contrast, the AMPK inhibitor, compound C, and RNA interference of AMPK expression increased the cytotoxicity of arecoline. Collectively, these results suggest that arecoline may inhibit AMPK through intracellular ROS, responsible for the execution of apoptosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Areca nut (AN) is an addictive carcinogen used by about 200-600 million people worldwide. Some AN components are shown to induce apoptosis; however, we previously demonstrated that AN extract (ANE) and the 30-100kDa fraction of ANE (ANE 30-100K) induced autophagy-like responses, such as swollen cell morphology, empty cytoplasm, acidic vesicles, and LC3-II accumulation, in an oral cancer cell line, OECM-1. To further assess the responses of other cell types to ANE 30-100K, we used both normal and malignant cells as the targets of ANE 30-100K and found that normal oral fibroblasts (CMT415), peripheral blood lymphocytes (PBLs), Jurkat leukemia T cells, and esophageal carcinoma cells (CE81T/VGH) exhibited similar responses after ANE 30-100K challenge. ANE 30-100K drastically increased acidic vesicle-containing PBLs isolated from two independent donors (from 0.1% to 92.1% and 2.9% to 64.2%). Furthermore, both ANE- and ANE 30-100K-induced LC3-II accumulation in CMT415 and CE81T/VGH was further increased in the presence of the lysosomal protease inhibitors (pepstatin A, E64d, and leupeptin). On the other hand, ANE 30-100K also increased the level of intracellular reactive oxygen species (ROS), and the ROS scavengers, N-acetylcysteine (NAC) and Tiron, inhibited ANE 30-100K-induced cell death and LC3-II accumulation. Collectively, these results suggest the existence of an autophagy-inducing AN ingredient (AIAI) in ANE 30-100K, which renders ANE as an autophagic flux inducer through ROS in both normal and malignant cells., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The genotoxic potential of podophyllin (PD) was investigated in this study. PD increased bacterial revertants and abnormal chromosomal structures in a concentration-dependent manner, both with and without metabolic activating enzymes, and increased the incidence of micronuclei in imprinted control region mouse reticulocytes. Results from three studied constituents of PD, such as podophyllotoxin, kampferol, and quercetin, suggested that the mutagenic effect of PD was not due to the presence of podophyllotoxin, kampferol, and quercetin and might be related to other components and the formation of reactive oxygen species. The detailed mutagenic mechanisms need further investigation, and the medicinal use of PD needs to be cautioned against.

Cancer therapies based on energy conversion, such as photothermal therapy (PTT, light-to-thermal energy conversion) and photodynamic therapy (PDT, light-to-chemical energy conversion) have attracted extensive attention in preclinical research. However, the PTT-related hyperthermia damage to surrounding tissues and shallow penetration of PDT-applied light prevent further advanced clinical practices. Here, we developed a thermoelectric therapy (TET) based on thermoelectric materials constructed p-n heterojunction (SrTiO3/Cu2Se nanoplates) on the principle of light-thermal-electricity-chemical energy conversion. Upon irradiation and natural cooling-induced the temperature gradient (35–45 oC), a self-build-in electric field was constructed and thereby facilitated charges separation in bulk SrTiO3 and Cu2Se. Importantly, the contact between SrTiO3 (n type) and Cu2Se (p type) constructed another interfacial electric field, further guiding the separated charges to re-locate onto the surfaces of SrTiO3 and Cu2Se. The formation of two electric fields minimized probability of charges recombination. Of note, high-performance superoxide radicals and hydroxyl radicals’ generation from O2 and H2O under catalyzation by separated electrons and holes, led to intracellular ROS burst and cancer cells apoptosis without apparent damage to surrounding tissues. Construction of bulk and interfacial electric fields in heterojunction for improving charges separation and transfer is also expected to provide a robust strategy for diverse applications.

Artesunate (ART) has great value in the field of tumor therapy. Interestingly, in this study, we found that ART could obviously induce ferroptosis in hepatocellular carcinoma (HCC) cells, but its low water solubility and bioavailability limited its application potential. Hence, we synthesized ART-loaded mesoporous silica nanoparticles (MSNs) conjugated with folic acid (FA) (MSN-ART-FA) with tumor-targeting performance and assessed their characteristics. We evaluated the ability of MSN-ART and MSN-ART-FA to induce ferroptosis of hepatoma cells via testing levels of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA) and glutathione (GSH), observation of mitochondrial morphology, as well as the expression of key proteins in ferroptosis. The results showed that prepared MSN-ART and MSN-ART-FA could remarkedly improve the bioavailability of ART to enhance ferroptosis, thereby inhibiting cell proliferation, migration and invasion in vitro. Besides, MSN-ART-FA group displayed slower tumor growth and smaller tumor volumes than MSN-ART group in HepG2 xenograft mouse model. It provided a potential therapeutic option for HCC and expanded the horizon for the clinical treatment of other cancers. [ABSTRACT FROM AUTHOR]

• Green Mn2O3 was used to active PDS for removing E3 from real wastewaters. • Effects of substrates of wastewaters on the removal of E3 by Mn 2 O 3 /PDS system. • Combined DFT, LC-MS analyses and ECOSAR to understand the reaction mechanisms. • The degradation pathway and toxicity of intermediates were predicted. While green synthesized Mn 2 O 3 has been used to activate peroxydisulfate (PDS) to degrade estrogens, effective application in real wastewater is less common due to variation in environmental matrices in wastewater. Here, green synthesized Mn 2 O 3 was used as a Fenton-like catalyst to activate PDS for estriol (E3) degradation in wastewater. The results show that the high concentration of K+ and humic acid in wastewater could inhibit the activation process of the Mn 2 O 3 /PDS system, resulting in low removal efficiency of E3 in wastewater. However, when the concentration of PDS was increased to 15 mM, the removal efficiency of E3 in medical wastewater can reach 100 %, because the high PDS concentration increases the main reactive oxygen species singlet oxygen (1O 2) in medical wastewater. XRD and SEM-EDS analysis indicate that the crystal structure of Mn 2 O 3 is stable, with a consistent rice grain-like morphology before and after reaction. XPS results show no obvious changes in the percentages of Mn(II), Mn(III) and Mn(IV) before and after reaction, indicating that Mn 2 O 3 has good stability when degrading E3 in medical wastewater. Based on density functional theory (DFT) calculations, liquid chromatography-mass spectrometry (LC-MS), and ecological structure–activity relationship (ECOSAR) modeling data analysis, the reactive oxygen species produced by the Mn 2 O 3 /PDS system mainly attack the benzene ring structure of E3, where the toxicity of its intermediate products declines significantly after breaking the benzene ring structure. Overall, this work provides greater understanding of the E3 degradation pathway and the toxicity of its degradation products. [ABSTRACT FROM AUTHOR]

Aims and objectives: To investigate the distribution and risk factors associated with undiagnosed obstructive sleep apnoea among hypertensive patients. Background: Obstructive sleep Apnoea has been deemed a cardinal risk factor affecting cardiovascular event, and the condition is still frequently overlooked clinically. The lack of advanced diagnosis often causes hypertensive patients with obstructive sleep apnoea to miss opportunities for preventing chronic diseases. Design: A cross‐sectional design. Methods: A total of 215 hypertensive participants were recruited from the cardiovascular outpatients of medical centre in northern and middle Taiwan. The Chinese version of Pittsburgh Sleep Quality Index, the Chinese version of the Epworth Sleep Scale and a portable sleep monitoring device were used for data collection. Logistic regression analysis was conducted to identify the factors affecting hypertensive patients with obstructive sleep apnoea, and a multinomial logistic regression analysis was used to examine the major influence factors for each obstructive sleep apnoea severity level. Results: 81.9% of the hypertensive participants were found having obstructive sleep apnoea. Concerning to the obstructive sleep apnoea severity, 50.0% of participants had mild obstructive sleep apnoea. After controlling the confounding variables, the supine position (odds ratio, 1.04; 95% CI, 1.01–1.07), SO2 (odds ratio, 0.58; 95% CI, 0.38–0.89) and oxygen desaturation index (odds ratio, 2.70; 95% CI, 1.18–6.18) were significantly associated with obstructive sleep apnoea. Furthermore, severe obstructive sleep apnoea was significantly correlated with gender (odds ratio, 0.04; 95% CI, 0.00–0.66), excessive daytime sleepiness (odds ratio, 20.27; 95% CI, 1.58–26.97) and oxygen desaturation index (odds ratio, 4.05; 95% CI, 1.86–8.81). Conclusions: Nearly 82% of the hypertensive participants were found having undiagnosed obstructive sleep apnoea, and 80% of them were mild or moderate severity. Oxygen desaturation index, SO2 and the supine position were found to be major predictors for obstructive sleep apnoea. Remarkably, oxygen desaturation index was the most significant predictor for mild, moderate and severe obstructive sleep apnoea. Relevance to clinical practice: Healthcare providers should enhance their sensitivities to hypertensive patients at a high risk for obstructive sleep apnoea by actively assessing common obstructive sleep apnoea symptoms and providing strategies to alleviate obstructive sleep apnoea symptoms. [ABSTRACT FROM AUTHOR]

Hypoxia-induced pulmonary vasoconstriction (HPV) is attributed to an increase in intracellular Ca2+ concentration ([Ca2+]i) in pulmonary artery smooth muscle cells (PASMCs). We have reported that phospholipase C-γ1 (PLCγ1) plays a significant role in the hypoxia-induced increase in [Ca2+]i in PASMCs and attendant HPV. In this study, we intended to determine molecular mechanisms for hypoxic Ca2+ and contractile responses in PASMCs. Our data reveal that hypoxic vasoconstriction occurs in pulmonary arteries, but not in mesenteric arteries. Hypoxia caused a large increase in [Ca2+]i in PASMCs, which is diminished by the PLC inhibitor U73122 and not by its inactive analog U73433. Hypoxia augments PLCγ1-dependent inositol 1,4,5-trisphosphate (IP3) generation. Exogenous ROS, hydrogen peroxide (H2O2), increases PLCγ1 phosphorylation at tyrosine-783 and IP3 production. IP3 receptor-1 (IP3R1) knock-down remarkably diminishes hypoxia- or H2O2-induced increase in [Ca2+]i. Hypoxia or H2O2 increases the activity of IP3Rs, which is significantly reduced in protein kinase C-ε (PKCε) knockout PASMCs. A higher PLCγ1 expression, activity, and basal [Ca2+]i are found in PASMCs, but not in mesenteric artery smooth muscle cells from mice exposed to chronic hypoxia (CH) for 21 days. CH enhances H2O2- and ATP-induced increase in [Ca2+]i in PASMCs and PLC-dependent, norepinephrine-evoked pulmonary vasoconstriction. In conclusion, acute hypoxia uniquely causes ROS-dependent PLCγ1 activation, IP3 production, PKCε activation, IP3R1 opening, Ca2+ release, and contraction in mouse PASMCs; CH enhances PASM PLCγ1 expression, activity, and function, playing an essential role in pulmonary hypertension in mice. [ABSTRACT FROM AUTHOR]

• Carbonized manganese oxides derived from biomass were developed. • Manganese oxides were used as catalyst for the activation of PDS. • The catalytic ability were in the order Mn2O3＞Mn3O4＞MnO. • Mechanism for activated PDS was proposed. A green tea extract was used as a natural reducing agent to prepare three different manganese oxides (Mn 3 O 4 , Mn 2 O 3 and MnO) which after carbonization in different atmospheres, were evaluated for their ability to degrade estriol (E3). Catalytic ability of the three manganese oxides varied in the order Mn 2 O 3 > Mn 3 O 4 > MnO; corresponding to E3 degradation efficiencies of 100, 100 and 92.5 % after 180 min. After calcination, no new functional groups were observed on the surface of three manganese oxides, except the corresponding spectra. The morphology of the manganese oxides was primarily olive-shaped, with numerous small cubic particles stacked at the nanoscale, with a uniform distribution of elements. Free radicals and Mn ion leaching was observed from the prepared manganese oxides where leaching of manganese ions was related to the intensity of singlet oxygen. Advanced material characterization showed while green synthesis resulted in materials being doped with a small amounts of elements such as C and S, the broad crystal structure of the three materials was still the main factor affecting the removal efficiency of E3; with Mn(III) playing a major role in the catalytic peroxydisulfate (PDS) process. [ABSTRACT FROM AUTHOR]

Oral cancer is one of the leading causes of cancer-related deaths worldwide. Chemotherapy is widely used in the treatment of oral cancer, but its clinical efficacy is limited by drug resistance. Hence, novel compounds capable of overcoming drug-resistance are urgently needed. Plumbagin (PG), a natural compound isolated from Plumbago zeylanica L, has been used to treat various cancers. In this study, we investigated the anticancer effects of PG on drug-resistant oral cancer (CR-SAS) cells, as well as the underlying mechanism. MTT assays were used to evaluate the effect of PG on the viability of CR-SAS cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined using flow cytometry. Protein expression levels were detected by western blotting. The results show that PG reduces the viability and causes the apoptosis of CR-SAS cells. PG is able to induce intracellular and mitochondrial ROS generation that leads to mitochondrial dysfunction. Furthermore, endoplasmic reticulum (ER) stress was triggered in PG-treated CR-SAS cells. The inhibition of ROS using N-acetylcysteine (NAC) abrogated the PG-induced ER stress and apoptosis, as well as the reduction in cell viability. Meanwhile, similar results were observed both in zebrafish and in murine models of drug-resistant oral cancer. Our results indicate that PG induces the apoptosis of CR-SAS cells via the ROS-mediated ER stress pathway and mitochondrial dysfunction. It will be interesting to develop the natural compound PG for the treatment of drug-resistant oral cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

• Green synthesis of Mn 3 O 4 NPs was as a new Fenton catalyst. • The removal efficiency was 97.5% for E3 and 96.4% for EE2. • Various radicals were observed in the catalytic system. • A new mechanism was proposed. Manganese tetroxide (Mn 3 O 4) nanomaterials were prepared by green tea extract and applied to catalyze sodium peroxydisulfate (PDS) for the simultaneous degradation of estriol/17a-ethinylestradiol (E3/EE2) with removal efficiencies of 97.5 and 96.4% for E3 and EE2, respectively. XPS also showed that before and after the reaction the divalent manganese content decreased from 50.2 to 34.8%, indicating divalent manganese plays a major role in the catalytic process. EPR quenching and electrochemical studies showed that while initially singlet oxygen (1O 2), sulfate (SO 4 •-), superoxide (O 2 •-) and hydroxyl (•OH) radicals were all generated in the system, thereafter, the oxidation of E3/EE2 mainly depended on 1O 2 and O 2 •-, where O 2 •- intermediates participated in the generation of 1O 2 in the Fenton-like process. LC-MS analysis showed that degradation products of E3/EE2 were mainly produced via hydroxyl and sulfate degradation pathways. Finally, a mechanism of Fenton-like oxidation of E3/EE2 was proposed. [ABSTRACT FROM AUTHOR]

Oxidative stress-mediated cellular injury has been considered as a major cause of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. The scavenging of reactive oxygen species (ROS) mediated by antioxidants may be a potential strategy for retarding the diseases’ progression. Costunolide (CS) is a well-known sesquiterpene lactone, used as a popular herbal remedy, which possesses anti-inflammatory and antioxidant activity. This study aimed to investigate the protective role of CS against the cytotoxicity induced by hydrogen peroxide (H2O2) and to elucidate potential protective mechanisms in PC12 cells. The results showed that the treatment of PC12 cells with CS prior to H2O2 exposure effectively increased the cell viability. Furthermore, it decreased the intracellular ROS, stabilized the mitochondria membrane potential (MMP), and reduced apoptosis-related protein such as caspase 3. In addition, CS treatment attenuated the cell injury by H2O2 through the inhibition of phosphorylation of p38 and the extracellular signal-regulated kinase (ERK). These results demonstrated that CS is promising as a potential therapeutic candidate for neurodegenerative diseases resulting from oxidative damage and further research on this topic should be encouraged. [ABSTRACT FROM AUTHOR]

Abstract: The rhizome of Menispermum dauricum DC (Menispermaceae) is one of the most commonly used traditional Chinese medicines officially listed in Chinese Pharmacopeia. In present study, we purified a water-soluble polysaccharide (WMDP) from this plant and investigated its physicochemical properties. WMDP was a homogeneous polysaccharide, with an average molecular weight of approximately 3.5×104 Da, as determined by high-performance gel-permeation chromatography (HPGPC). Gas chromatography (GC) analysis identified that WMDP was composed of Glc, Gal, Xyl, Rha, Ara and Man in the ratio of 2.45:2.13:1.05:1.29:1.63:1.45. The interreaction between Gongo Red and WMDP in NaOH solutions resulted in the shift of maximum absorption, indicating WMDP had a triple-helix conformation. We also investigated the antitumor activities and mechanisms of WMDP in human ovarian carcinoma SKOV3 cells. The experimental evidence showed that WMDP significantly inhibited cell proliferation and DNA synthesis in SKOV3 cells in a concentration-dependent manner, due to a significant increase in the number of apoptotic cells. Furthermore, treatment with WMDP caused a rapid loss of intracellular glutathione (GSH) content and stimulation of reactive oxygen species (ROS). In addition, nuclear factor-kappa B (NF-κB) in SKOV3 cells received WMDP treatment was inactivated. Taken together, induction of apoptosis on SKOV3 cells by WMDP was mainly associated with ROS production, GSH depletion and NF-κB inactivation. [Copyright &y& Elsevier]

An increase in intracellular calcium concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) induces hypoxic cellular responses in the lungs; however, the underlying molecular mechanisms remain incompletely understood. We report, for the first time, that acute hypoxia significantly enhances phospholipase C (PLC) activity in mouse resistance pulmonary arteries (PAs), but not in mesenteric arteries. Western blot analysis and immunofluorescence staining reveal the expression of PLC-γ1 protein in PAs and PASMCs, respectively. The activity of PLC-γ1 is also augmented in PASMCs following hypoxia. Lentiviral shRNA-mediated gene knockdown of mitochondrial complex III Rieske iron-sulfur protein (RISP) to inhibit reactive oxygen species (ROS) production prevents hypoxia from increasing PLC-γ1 activity in PASMCs. Myxothiazol, a mitochondrial complex III inhibitor, reduces the hypoxic response as well. The PLC inhibitor U73122, but not its inactive analog U73433, attenuates the hypoxic vasoconstriction in PAs and hypoxic increase in [Ca2+]i in PASMCs. PLC-γ1 knockdown suppresses its protein expression and the hypoxic increase in [Ca2+]i. Hypoxia remarkably increases inositol 1,4,5-trisphosphate (IP3) production, which is blocked by U73122. The IP3 receptor (IP3R) antagonist 2-aminoethoxydiphenyl borate (2-APB) or xestospongin- C inhibits the hypoxic increase in [Ca2+]i. PLC-γ1 knockdown or U73122 reduces H2O2-induced increase in [Ca2+]i in PASMCs and contraction in PAs. 2-APB and xestospongin-C produce similar inhibitory effects. In conclusion, our findings provide novel evidence that hypoxia activates PLC-γ1 by increasing RISP-dependent mitochondrial ROS production in the complex III, which causes IP3 production, IP3R opening, and Ca2+ release, playing an important role in hypoxic Ca2+ and contractile responses in PASMCs. [ABSTRACT FROM AUTHOR]

Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics. [ABSTRACT FROM AUTHOR]

Ciprofloxacin (CIP) as an anti-inflammatory drug is frequently detected in various water resources. Recently, Sulfate Radical-based advanced oxidation processes with manganese oxides have been recognized as a highly effective method for CIP degradation. Herein, ε-MnO 2 was obtained through a convenient drying process. After different atmospheric treatments, MnO and Mn 2 O 3 were fabricated for subsequent degradation experiments. The results show that MnO exhibits better catalytic activity than Mn 2 O 3 , with high removal efficiency of almost 84.3% for CIP. Quenching test and electron paramagnetic resonance spectra confirm that 1O 2 is the dominant species during reaction, while ·OH and SO 4 ·- play a supporting role. A related discussion about the role of valence states of Mn and oxygen vacancies is presented, which can provide a theoretical basis for further development of Mn/peroxymonosulfate system. • A convenient drying process was used to fabricate nanosized ε-MnO 2. • H 2 -calcined MnO can effectively degrade ciprofloxacin at a wide pH range. • The influence of oxygen vacancies and chemical states were investigated. • 1O 2 is the dominant reactive oxygen species in Fenton-like reaction. [ABSTRACT FROM AUTHOR]

[Display omitted] • New (η6- p -cymene) ruthenium(II) benzimidazole complex have been synthesized. • X-ray studies of the complex reveal a classical pseudo octahedral three-legged piano stool structure. • Synthesized compounds showed good in vitro cytotoxicity in HA22T cell lines. • The mitochondrial superoxide generation in HA22T cells was studied using MitoSOX™ Red staining. A new half-sandwich benzimidazole-based Ru(II) complex of the type of [(η6- p -cymene)RuCl(κ2- C,N - 6)] (7) has been successfully synthesized from the reaction of neutral precursor [Ru(p -cymene)Cl 2 ] 2 and corresponding ligand (6). The ligand and complex were fully characterized by various spectroscopic techniques, such as 1H NMR, 13C NMR, IR, mass spectrometry, and elemental analysis. The structure of the ruthenium complex was determined by a single crystal X-ray diffraction analysis, which demonstrates a typical pseudo-octahedral geometry. Furthermore, the MTS ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)2H-tetrazolium]) assay has measured the cytotoxicity of ligand (6) and complex (7) against the human hepatoma (HA22T), HepG2, breast cancer cell-MCF-7, and non-small cell lung cancer cell-A549 cell lines. Compounds 6 and 7 showed a better inhibitory effect on the viability of all the cell lines against cisplatin. The mitochondrial reactive oxygen species (ROS) accumulation was determined by using a mitochondrial superoxide indicator (MitoSOX) red fluorescent probe. The inhibition of cell viability was associated with increased mitochondrial ROS. Additionally, the cell morphological studies also indicated effective anticancer potentials even at low concentrations. It suggests that the p- cymene Ru(II) complex is a promising cancer therapeutic candidate worthy of further investigation. [ABSTRACT FROM AUTHOR]

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e 6 , a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives 3a , 3b , 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n -hexyloxy chain in chlorin e 6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a , 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives, especially 3c and 8 , might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT. Image 1 • The 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives were synthesized. • In vitro photodynamic activity and mechanism of target compounds were investigated. • In vivo antitumor potency and pharmacokinetic of target compounds were evaluated. • In vitro and in vivo PDT antitumor efficacy of 3a , 3c , 8 were better than Talaporfin. • In vitro and in vivo PDT antitumor efficacy of 3c and 8 were superior to 3a. [ABSTRACT FROM AUTHOR]