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  • Cantharidin suppresses gastric cancer cell migration/invasion by inhibiting the PI3K/Akt signaling pathway via CCAT1
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-13
    Mengyun Song; Xianfei Wang; Yajun Luo; Zilin Liu; Wang Tan; Pengcheng Ye; Zhiming Fu; Fei Lu; Wanping Xiang; Linghan Tang; Lin Yao; Yuqiang Nie; Jiangwei Xiao

    Cantharidin (CTD) is a traditional Chinese medicine that shows an anticancer effects in multiple types of cancer cells. However, the mechanism of CTD anti-cancer function in gastric cancer (GC) is still unclear. The aim of the present study was to investigate the underlying mechanism that CTD inhibits proliferation and migration through suppression of the PI3K/Akt signaling. CTD induced GC cell apoptosis and inhibited metastasis measured by CCK8 assays as well as wound healing assays and transwell assays. Mechanistic investigations suggested that CTD modulated the PI3K/Akt signaling via western-blot and quantitative q-PCR. In addition, we identified and confirmed CCAT1 as a novel direct target of CTD inhibited PI3K/AKt signaling expression. In conclusion, our results provide new point into the critical role of CTD in suppressing PI3K/Akt signaling via down-regulation of CCAT1, resulting in suppression GC cell growth and migration/invasion.

    更新日期:2020-01-13
  • Trigonelline protects hippocampal neurons from oxygen-glucose deprivation-induced injury through activating the PI3K/Akt pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-11
    Zhengguo Qiu; Kefeng Wang; Chao Jiang; Yuqiang Su; Xiaoying Fan; Jing Li; Sha Xue; Li Yao

    Trigonelline is a plant alkaloid that has generated interest for its neuroprotective roles in brain pathology. However, the protective effect of trigonelline on cerebral ischemia/reperfusion (I/R) injury and the potential mechanism have not been fully evaluated. Our results showed that trigonelline pretreatment ameliorated oxygen-glucose deprivation/reperfusion (OGD/R)-induced hippocampal neurons injury. The OGD/R-caused reactive oxygen species (ROS) generation and decreased concentrations of superoxide dismutases (SOD) and glutathione peroxidase (GPx) were markedly attenuated by trigonelline. In addition, the increased levels of TNF-α, IL-6 and IL-1β in OGD/R-induced hippocampal neurons were significantly decreased by trigonelline pretreatment. Trigonelline also suppressed caspase-3 activity and bax expression, and induced bcl-2 expression in OGD/R-induced hippocampal neurons. Furthermore, trigonelline induced the activation of PI3K/Akt pathway in hippocampal neurons exposed to OGD/R condition. Inhibition of PI3K/Akt signaling reversed the protective effects of trigonelline on OGD/R-induced hippocampal neurons injury. Taken together, these findings indicated that trigonelline protected hippocampal neurons from OGD/R-induced injury, which was mediated by the activation of PI3K/Akt signaling pathway.

    更新日期:2020-01-13
  • 更新日期:2020-01-13
  • Fasudil enhanced differentiation of BMSCs in vivo and vitro, involvement of P38 signaling pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-11
    Meihui Chen; Dan Luo; Jiheng Zhan; Yu Hou; Shudong Chen; Xing Li; Dingkun Lin

    Bone mesenchymal stem cells (BMSCs) are a well-known donor graft source due to their potential for self-renewal and differentiation into multi-lineage cell types, including osteoblasts that are critical for fracture healing. Fasudil (FAS), a Rho kinase inhibitor, has been proven to induce the differentiation of bone marrow stem cells (BMSCs) into neuron-like cells. However, its role in the osteogenesis of BMSCs remain uncertain. Herein, we for the first time studied the effects of FAS on osteogenic differentiation in a mouse fracture model and further explored the involved mechanisms in mouse BMSCs. The results showed that FAS stimulated bone formation in the fracture mouse model. Additionally, at 30 μM, FAS significantly promotes alkaline phosphatase activity, mineralization, and the expression of osteogenic markers COL-1, RUNX2 and OCN in murine BMSCs. Blocking of P38 by SB202190 significantly reversed the effects of FAS, in vitro, suggesting that P38, but not ERK or JNK activation is required for FAS-induced osteogenesis. Collectively, our results indicate that FAS may be a promising agent for promoting fracture healing.

    更新日期:2020-01-13
  • Cytoprotective effects of berry anthocyanins against induced oxidative stress and inflammation in primary human diabetic aortic endothelial cells
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-11
    Anahita Aboonabi; Indu Singh; Roselyn Rose' Meyer

    Type 2 diabetes is associated with oxidative stress and low-grade inflammation resulting in endothelial dysfunction (ED). This study determined to explore the protective effects of berry-derived anthocyanins (AC) with potent antioxidant and anti-inflammatory activities in human diabetic endothelial cells upon oxidative and inflammatory stressors. Cultured healthy human aortic endothelial cells (HAEC) and diabetic human aortic endothelial cells (D-HAEC) exposed to oxidative stress by hydrogen peroxide (H2O2, 75 μM) and lipopolysaccharide (LPS, 1 μg/mL) as an inflammatory inducer before treatment with AC (50 μl/ml). The results from cytotoxicity assays showed that AC had no significant effects in cell viability (P-value < 0.0001), and exposure to H2O2 75 μM had a less toxic effect (P-value < 0.05). Although, AC significantly decreased H2O2-induced cytotoxicity and oxidative stress in both HAEC and D-HAEC cell lines (P-value < 0.0001), no positive impact of AC was found on the GSSG/GSH ratios (P-value < 0.05). Exposure to the LPS increased the production of IL-6 in both HAEC and D-HAEC cell lines (P-value < 0.0001), whereas AC treatment reduced LPS‐induced IL‐6 production in both cell lines with a more robust impact on D-HAEC (P-value < 0.0001). While LPS increased inflammasome assembling and caspase-1 activation, AC treatment inhibited caspase-1 activation in D-HAEC (P ≤ 0.05). This study indicated that berry anthocyanins reduced oxidative stress and inflammation via the inhibition of the NF-ƙB signaling pathway, which contributes to mitigating the diabetes-induced up-regulation of NF-ƙB.

    更新日期:2020-01-13
  • Apigenin attenuates pulmonary hypertension by inducing mitochondria-dependent apoptosis of PASMCs via inhibiting the hypoxia inducible factor 1α–KV1.5 channel pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-10
    Yuanzhou He; Xiaoyu Fang; Jing Shi; Xiaochen Li; Min Xie; Xiansheng Liu

    Pulmonary hypertension (PH) is distal pulmonary arterial remodelling and is mainly due to the abnormal proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Apigenin, a natural dietary flavonoid, is a promising PH preventive agent that inhibits PASMC proliferation and induces apoptosis. In this study, we investigated the biological effects of apigenin on PH. PH was induced in male Sprague-Dawley rats by chronic hypoxia exposure. Administration of apigenin prevented the development of PH, hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodelling and prevented the progression of established PH in this model. Moreover, treatment with apigenin induced mitochondria-dependent apoptosis. To explore the underlying mechanisms, the mitochondrial membrane potential (Δψm) and the mitochondria-dependent apoptosis factors cytochrome C, BAX, Bcl-2, cleaved caspase 3, and cleaved caspase 9 were analysed. These results confirmed that apigenin induces mitochondria-dependent apoptosis in hypoxic PASMCs to protect against PH. In addition, treatment with apigenin reversed hypoxia-induced inhibition of KV1.5 expression both in vivo and in vitro. The KV1.5 inhibitor diphenyl phosphine oxide-1 (DPO-1) abrogated apigenin-induced mitochondria-dependent apoptosis in hypoxic PASMCs, suggesting that KV1.5 is implicated in apigenin-induced mitochondria-dependent apoptosis. Furthermore, functional studies revealed that apigenin activated mitochondria-dependent apoptosis by modulation of hypoxia-induced factor 1α (HIF-1α) signalling. Together, our study shows that apigenin attenuates PH via inhibiting the HIF-1α-KV1.5 channel pathway to induce PASMC mitochondria-dependent apoptosis.

    更新日期:2020-01-11
  • Nicotine-induced autophagy via AMPK/mTOR pathway exerts protective effect in colitis mouse model
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-10
    Qian Gao; Pinduan Bi; Ding Luo; Ying Guan; Wanli Zeng; Haiying Xiang; Qili Mi; Guangyu Yang; Xuemei Li; Bin Yang

    Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.

    更新日期:2020-01-11
  • Effect of m-trifluoromethyl-diphenyl diselenide on acute and subchronic animal models of inflammatory pain: Behavioral, biochemical and molecular insights
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-09
    Paulo Cesar Oliveira Araujo; Marcel Henrique Marcondes Sari; Natália Silva Jardim; Juliano Ten Kathen Jung; César Augusto Brüning
    更新日期:2020-01-09
  • Eugenol restricts Cancer Stem Cell population by degradation of β-catenin via N-terminal Ser37 phosphorylation-an in vivo and in vitro experimental evaluation
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-08
    Pritha Choudhury; Atish Barua; Anup Roy; Rudradip Pattanayak; Maitree Bhattacharyya; Prosenjit Saha
    更新日期:2020-01-09
  • Comparison of long-term versus short-term effects of okadaic acid on the apoptotic status of human HepaRG cells
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2020-01-08
    Jessica Dietrich; Magdalena Schindler; Alfonso Lampen; Albert Braeuning; Stefanie Hessel-Pras

    The biotoxin okadaic acid (OA) is a lipophilic secondary metabolite of marine microalgae. Therefore, OA accumulates in the fatty tissue of various shellfish and may thus enter the food chain. The ingestion of OA via contaminated marine species can lead to the diarrhetic shellfish poisoning syndrome characterized by the occurrence of a series of acute gastrointestinal symptoms in humans. In addition, genotoxicity and tumor-promoting properties of OA might constitute a long-term threat to human health. In order to deepen our understanding of the molecular effects of OA, we compared long-term (14 d) and short-term (24 h and 48 h) apoptotic effects of the compound on human HepaRG hepatocarcinoma cells. Cells were treated either with single doses for 24 and 48 h, respectively, or seven times over a period of 14 d, so that the cumulated quantities of OA in the long-term approach were equal to the single doses upon short-term treatment. Both short-term treatment scenarios led to the induction of apoptosis. Specific caspase activation assays and transcriptional analysis of mRNAs encoding proteins involved in the regulation of apoptosis suggest that OA-induced apoptosis occurs presumably by activation of the intrinsic apoptotic pathway. In contrast, effects were much less pronounced in case of long-term treatment. This is possibly linked to cellular protective mechanisms against low amounts of toxins, e.g. transporter-mediated efflux. In conclusion, our results show a clear concentration- and time-dependency of OA-mediated apoptotic effects in HepaRG cells and contribute to the elucidation of molecular effects of OA.

    更新日期:2020-01-08
  • PDGFBB-modified stem cells from apical papilla and thermosensitive hydrogel scaffolds induced bone regeneration
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-23
    Jiajia Deng; Jie Pan; Xinxin Han; Liming Yu; Jing Chen; Weihua Zhang; Luying Zhu; Wei Huang; Shangfeng Liu; Zhengwei You; Yuehua Liu

    Bone defects caused by cancer surgery or trauma have a strong negative impact on human health. Treatment with cell and material-based complexes provides an alternative strategy for the regeneration of damaged bone tissue. The good physical properties and suitable biodegradability of a thermosensitive hydrogel has been shown to act as a valuable scaffold. Platelet derived growth factor BB (PDGFBB) is mainly secreted by platelets and promotes the migration and angiogenesis of mesenchymal stem cells (MSCs). Although PDGFBB is known to indirectly enhance bone repair in vivo, the effects of PDGFBB on stem cells from apical papilla (SCAPs) require further investigation. In our study, the proliferation of cells was investigated by the cell counting kit-8 and live/dead staining methods. The results indicated that PDGFBB promoted the proliferation of SCAPs. Real-time polymerase chain reaction and Western blot experiments were used to detect osteogenic genes and proteins. Moreover, calvarial defects were created in Sprague-Dawley rats and different complexes implanted. The results shown by micro-CT and hematoxylin and eosin analysis demonstrated that the hydrogel combined with lentiviral supernatant-green fluorescent protein-PDGFBB significantly improved new bone formation and mineralization compared with the other three groups. In summary, our research showed that a thermosensitive hydrogel can be used as a scaffold for 3D cell culture, and PDGFBB gene-modified SCAPs can improve bone formation in calvarial defects.

    更新日期:2019-12-23
  • Ganoderic acid DM induces autophagic apoptosis in non-small cell lung cancer cells by inhibiting the PI3K/Akt/mTOR activity
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-23
    Junbo Xia; Lujun Dai; Liusheng Wang; Jing Zhu

    The incidence and mortality of lung cancer are the highest among cancer-related deaths. However, the long-term use of currently available cytotoxic drugs can increase genetic alterations in cancer cells and cause drug-resistance, which significantly limits their usage. Since current systemic treatment options are limited, effective chemotherapeutic agents are urgently needed for non-small cell lung cancer (NSCLC) treatment. In this study, we demonstrated that ganoderic acid DM (GA-DM) could increase apoptosis in A549 and NCI–H460 NSCLC cells. GA-DM treatment decreased the protein expression levels of Bcl-2 and increased the expression levels of Bax, cleaved caspase-3 and cleaved PRAP. Furthermore, GA-DM could promote autophagic flux, and the cytotoxic effect against cancer cells of GA-DM was significantly inhibited by targeted suppression of autophagy, suggesting that autophagy contributed to GA-DM-induced cell death in NSCLC. Moreover, GA-DM clearly induced autophagy by inactivating the PI3K/Akt/mTOR pathway. When overexpression of Akt reactivated Akt/mTOR pathway in A549 or NCI–H460 cells, the increase of autophagy related marker LC3B-II and apoptosis related protein cleaved PARP and cleaved caspase 3 and the ration of apoptotic cells by GA-DM was reversed, suggesting that GA-DM promoted autophagy and apoptosis by inhibiting Akt/mTOR pathway-mediated autophagy induction. In conclusion, our study indicated that GA-DM can induce autophagic apoptosis in NSCLC by inhibiting Akt/mTOR activity. (209 words).

    更新日期:2019-12-23
  • GSPE alleviates renal fibrosis by inhibiting the activation of C3/ HMGB1/ TGF-β1 pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-23
    Kun Wang; Haotian Wei; Juan Zhan; Xinjun Liang; Chunxiu Zhang; Yanyan Liu; Gang Xu
    更新日期:2019-12-23
  • Iron-based nanoparticles and their potential toxicity: Focus on oxidative stress and apoptosis
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-21
    Jovana Paunovic; Danijela Vucevic; Tatjana Radosavljevic; Stefan Mandić-Rajčević; Igor Pantic

    Recently, there have been several studies indicating that iron-based nanomaterials may exhibit certain toxic properties. Compared to conventional iron and iron oxides, iron nanoparticles (FeNPs) have some unique physical and chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently, most of the recent research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and functions. Some studies suggested that, in certain cell types, FeNPs may increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. In this short review, we focus on the recent research on potential cytotoxicity of iron-based nanomaterials, and the potential implications of this new knowledge in medicine, chemistry and biology.

    更新日期:2019-12-21
  • Agonism of GPR120 prevents ox-LDL-induced attachment of monocytes to endothelial cells
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-21
    Tiechao Jiang; Dongli Jiang; Dong You; Lirong Zhang; Long Liu; Qini Zhao

    Oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation plays an important role in the development of cardiovascular diseases. G protein-coupled receptors (GPCR) are gaining traction as potential treatment targets due to their roles in mediating a wide range of physiological processes. GPR120 is a recently identified omega-3 fatty acid receptor. We hypothesized that agonism of GPR120 might attenuate ox-LDL-induced endothelial dysfunction. In the present study, we tested the effects of two GPR120 agonists—GW9508 and TUG-891—in mitigating endothelial insult induced by ox-LDL in human aortic endothelial cells (HAECs). Real-time PCR, western blot, and ELISA analyses were used in our experiments. Our findings demonstrate that GPR120 is downregulated by exposure to ox-LDL, suggesting a role for GPR120 in mediating ox-LDL insult. Furthermore, we found that agonism of GPR120 could suppress oxidative stress and inflammation by inhibiting the production of reactive oxygen species and the expression of proinflammatory cytokines. Importantly, we show that agonism of GPR120 prevents the attachment of monocytes to endothelial cells by suppressing the expression of VCAM-1 and E-selectin. Finally, we show that agonism of GPR120 exerts a remarkable atheroprotective effect by elevating the expression level of Krüppel-like factor 2 (KLF2). Together, our results demonstrate a potential role for specific agonism of GPR120 in the prevention of endothelial damages induced by ox-LDL.

    更新日期:2019-12-21
  • Osthole induces cell cycle arrest and apoptosis in head and neck squamous cell carcinoma by suppressing the PI3K/AKT signaling pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-20
    Jing Yang; Xin-jiang Zhu; Ming-Zhu Jin; Zhi-Wei Cao; Yao-Yao Ren; Zhao-Wei Gu

    Background Head and neck squamous cell carcinoma (HNSCC) is one of the most common lethal tumors with a high recurrence rate and low survival rate. Therefore, an urgent need exists for novel and effective treatment strategies for HNSCC patients. Methods Osthole, a natural ingredient extracted from Cnidium monnieri (L.) ‘Cusson’, has multiple pharmacological effects including antineoplastic activity. Regrettably, the antineoplastic effect of osthole in HNSCC cells remains undefined. We utilize in vitro assays to assess the anti-proliferative effects of osthole in HNSCC cells and tumorigenesis assays using FaDu cells in murine HNSCC models to assess in vivo function. Moreover, the possible molecular mechanisms of Osthole on HNSCC cells was also investigated. Results Our findings show that the anti-proliferation effect of osthole might function through induction of cell cycle arrest (G2/M phase) and apoptosis in HNSCC. Osthole could also down-regulating the protein level of cell cycle and apoptosis related proteins, such as Bcl-2, PARP1, Survivin, CyclinB1 and Cdc2, while up-regulating expression of Cleaved Caspase3/9, Cleaved PARP1 and Bax. Similarly, osthole suppressed the in vivo growth of FaDu cells in a subcutaneous tumor model. In terms of mechanism, our data show that osthole can suppress the PI3K/AKT pathway. Conclusions In the current study, our in vitro and in vivo assay showed the suppressive effect of Osthole on HNSCC cells through induce cell cycle arrest (G2/M phase) and apoptosis. Moreover, the action mechanisms of Osthole on proliferation related signaling pathways was disclosed. Our present study suggests that osthole might be used as an effective therapeutic agent for patients with HNSCC.

    更新日期:2019-12-20
  • Effects of inflammation on irinotecan pharmacokinetics and development of a best-fit PK model
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-20
    Pavan Kumar Chityala; Lei Wu; Diana S-L Chow; Romi Ghose

    Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.p.-injected with either saline or lipopolysaccharide (LPS) to induce inflammation. After 16 h, irinotecan was administered orally. Blood was collected from the tail vein of mice from 0 to 24 h after dosing. Concentrations of irinotecan, SN-38 and SN-38G were analyzed using LC-MS/MS. The AUC, Cmax, and tmax were derived using WinNonlin® 5.2. A PK model was developed using Phoenix NLME® to describe the PK of irinotecan and SN-38 during inflammation. Results indicated a significant increase in the blood concentrations of irinotecan and SN-38 in mice during inflammation. The AUC of irinotecan and SN-38 in LPS group were 2.6 and 2-folds, respectively, of those in control saline-treated mice. The Cmax of irinotecan and SN-38 in LPS treated mice were 2.4 and 2.3-folds of those in saline-treated mice. The PK model was successfully developed and validated. The best-fit plots of individual PK analysis showed a good correlation between observed and predicted concentrations of irinotecan and SN-38. Together, this study reveals that SN-38 concentrations are elevated during inflammation, which may increase the GI toxicity and diarrhea in patients who receive irinotecan; and the developed PK model can quantitatively describe the PK of irinotecan and SN-38 during inflammation.

    更新日期:2019-12-20
  • Anti-cancer effects of Polyphyllin I: An update in 5 years
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-20
    Ye Tian; Guan-Yu Gong; Liang-Liang Ma; Zhuo-Qun Wang; Dan Song; Mei-Yun Fang

    Chong-lou, the rhizome of Paris polyphylla, has been used in herbal regimes to treat parotitis, mastitis and certain malignant tumors for thousands of years in traditional medicine. Polyphyllin I (PPI) is the main bioactive component in Paris polyphylla. Recent studies of PPI in various types of cancers have shown that PPI may exert a broad spectrum of anti-tumor effects, including inducing cell cycle arrest, inducing cell apoptosis, inducing autophagy, anti-angiogenesis, sensitizing tumors to chemotherapy, and participating in the modulation of inflammatory and immune response. Along with the growing research interest in PPI as well as accumulation of experimental evidences, this review periodically summarized the recent advances in regard to PPI's anti-tumor propensities in various cancers and the underlying mechanisms for future prospective research.

    更新日期:2019-12-20
  • Functional role of ferroptosis on cancers, activation and deactivation by various therapeutic candidates-an update
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-19
    B. Mahalakshmi; Hai-Liang Huang; Shin-Da Lee; Bharath Kumar Velmurugan
    更新日期:2019-12-19
  • The influence of carboxylesterase 1 polymorphism and cannabidiol on the hepatic metabolism of heroin
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-16
    Yuli Qian; Tara K. Gilliland; John S. Markowitz

    Heroin (diamorphine) is a highly addictive opioid drug synthesized from morphine. The use of heroin and incidence of heroin associated overdose death has increased sharply in the US. Heroin is primarily metabolized via deacetylation (hydrolysis) forming the active metabolites 6-monoacetylmorphine (6-MAM) and morphine. A diminution in heroin hydrolysis is likely to cause higher drug effects and toxicities. In this study, we sought to determine the contribution of the major hepatic hydrolase carboxylesterase 1 (CES1) to heroin metabolism in the liver as well as the potential influence of one of its known genetic variants, G143E (rs71647871). Furthermore, given the potential therapeutic application of cannabidiol (CBD) for heroin addiction and the frequent co-abuse of cannabis and heroin, we also assessed the effects of CBD on heroin metabolism. In vitro systems containing human liver, wild-type CES1, and G143E CES1 S9 fractions were utilized in the assessment. The contribution of CES1 to the hydrolysis of heroin to 6-MAM was determined as 3.66%, and CES1 was unable to further catalyze 6-MAM under our assay conditions. The G143E variant showed a 3.2-fold lower intrinsic clearance of heroin as compared to the WT. CBD inhibited heroin and 6-MAM hydrolysis in a reversible manner, with IC50s of 14.7 and 12.1 μM, respectively. Our study results suggested only minor involvement of CES1 in heroin hydrolysis in the liver. Therefore, the G143E variant is unlikely to cause significant impact despite a much lower hydrolytic activity. CBD exhibited potent in vitro inhibition toward both heroin and 6-MAM hydrolysis, which may be of potential clinical relevance.

    更新日期:2019-12-17
  • Isoniazid promotes the anti-inflammatory response in zebrafish associated with regulation of the PPARγ/NF-κB/AP-1 pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-16
    Yun Zhang; Chao Wang; Zhi-li Jia; Rui-jiao Ma; Xue-fang Wang; Wei-yun Chen; Ke-chun Liu
    更新日期:2019-12-17
  • Acetylation of cedrelone increases its cytotoxic activity and reverts the malignant phenotype of breast cancer cells in 3D culture
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-16
    Amanda Blanque Becceneri; Angelina Maria Fuzer; Cecília Patrícia Popolin; Cristiane de Melo Cazal; Vanessa de Cássia Domingues; João Batista Fernandes; Paulo Cezar Vieira; Marcia Regina Cominetti
    更新日期:2019-12-17
  • 更新日期:2019-12-17
  • Sodium acetate protects against nicotine-induced excess hepatic lipid in male rats by suppressing xanthine oxidase activity
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-16
    E.O. Dangana; T.E. Omolekulo; E.D. Areola; K.S. Olaniyi; A.O. Soladoye; L.A. Olatunji

    Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-alcoholic fatty liver disease. Short chain fatty acids (SCFAs) elicit beneficial metabolic alterations in IR and related syndromes. In the present study, we evaluated the preventive effects of a SCFA, acetate, on nicotine-induced dysmetabolism and fatty liver. Twenty-four male Wistar rats (n = 6/group): vehicle-treatment (p.o.), nicotine-treated (1.0 mg/kg; p.o.), sodium acetate-treated (200 mg/kg; p.o.) and nicotine + sodium acetate-treated groups. The treatments lasted for 8 weeks. IR was estimated by oral glucose tolerance test and homeostatic model assessment of IR. Plasma and hepatic free fatty acid, triglyceride (TG), glutathione peroxidase, adenosine deaminase (ADA), XO and uric acid (UA) were measured. Nicotine exposure resulted in reduced body weight, liver weight, visceral adiposity, glycogen content and glycogen synthase activity. Conversely, exposure to nicotine increased fasting plasma glucose, lactate, IR, plasma and hepatic TG, free fatty acid, TG/HDL-cholesterol ratio, lipid peroxidation, liver function enzymes, plasma and hepatic UA, XO and ADA activities. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defense was not affected by nicotine. Concomitant treatment with acetate ameliorated nicotine-induced effects. Taken together, these results indicate that nicotine exposure leads to excess deposition of lipid in the liver by enhancing XO activity. The results also imply that acetate confers hepatoprotection and is accompanied by decreased XO activity.

    更新日期:2019-12-17
  • Modification of stem cell states by alcohol and acetaldehyde
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-14
    Ryan N. Serio; Lorraine J. Gudas

    Ethanol (EtOH) is a recreationally ingested compound that is both teratogenic and carcinogenic in humans. Because of its abundant consumption worldwide and the vital role of stem cells in the formation of birth defects and cancers, delineating the effects of EtOH on stem cell function is currently an active and urgent pursuit of scientific investigation to explicate some of the mechanisms contributing to EtOH toxicity. Stem cells represent a primordial, undifferentiated phase of development; thus encroachment on normal physiologic processes of differentiation into terminal lineages by EtOH can greatly alter the function of progenitors and terminally differentiated cells, leading to pathological consequences that manifest as fetal alcohol spectrum disorders and cancers. In this review we explore the disruptive role of EtOH in differentiation of stem cells. Our primary objective is to elucidate the mechanisms by which EtOH alters differentiation-related gene expression and lineage specifications, thus modifying stem cells to promote pathological outcomes. We additionally review the effects of a reactive metabolite of EtOH, acetaldehyde (AcH), in causing both differentiation defects in stem cells as well as genomic damage that incites cellular aging and carcinogenesis.

    更新日期:2019-12-17
  • Parameritannin A-2 from Urceola huaitingii enhances doxorubicin-induced mitochondria-dependent apoptosis by inhibiting the PI3K/Akt, ERK1/2 and p38 pathways in gastric cancer cells
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-13
    Lu Liang; Aftab Amin; Wing-Yan Cheung; Rui Xu; Rujian Yu; Jinshan Tang; Xinsheng Yao; Chun Liang

    Parameritannin A-2 (PA-2) is a natural product extracted from the stems of the plant Urceola huaitingii. Our previous studies have shown that PA-2 exhibits significant synergistic anticancer effects with doxorubicin (DOX) in HGC27 gastric cancer cell lines. Here we report that our isobolographic analysis confirms the synergistic cytotoxic effects of PA-2 and DOX in HGC27 cells. Flow cytometry and immunoblotting indicate that PA-2 enhances DOX-mediated apoptosis. Importantly, PA-2 enhances the intracellular accumulation of DOX in HGC27 cells. The combination of DOX and PA-2 remarkably increases the release of cytochrome C and the activation of caspase-3 and caspase-9, compared with DOX treatment alone. Moreover, PA-2 attenuates the DOX-induced activation of Akt, ERK1/2 and p38 signaling pathways, providing a molecular mechanism for the synergistic effects of DOX and PA-2 in the induction of apoptosis. In conclusion, our studies demonstrate that PA-2 and DOX synergistically induce mitochondria-dependent apoptosis as PA-2 inhibits the PI3K/Akt, ERK1/2 and p38 pathways in HGC27 cells. These findings suggest that the combination treatment with PA-2 and DOX may represent a potent therapy for gastric cancer.

    更新日期:2019-12-17
  • Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: An in vitro approach
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-13
    Neelima Ayyalasomayajula; Madhuri Bandaru; Prasanna Kumar Dixit; Rajanna Ajumeera; Chellu S. Chetty; Suresh Challa

    Environmental pollutant, Lead (Pb) is known to induce neurotoxicity in human. The central nervous system is the most vulnerable to the minute levels of Pb induced toxicity. Pb has been linked to Alzheimer's disease (AD) as a probable risk factor, as it shows epigenetic and developmental link associated with Alzheimer's disease-like pathology. Beta amyloid peptides were considered as the crucial factors in the beta amyloid plaque formation in Alzheimer's disease brain. In this context, we investigated the molecular mechanism involved in the development of Pb induced Alzheimer's disease in in vitro. Previous data from our studies have reported that Pb in the presence of beta Amyloid peptide (1–40) and (25–35) induces more apoptosis than individual exposures. Here, to further evaluate the molecular mechanism underlying Pb induced Alzheimer's disease; we focussed on the involvement of calcium signalling in inducing cell death. Our experimental observations suggesting that Pb in the presence of beta amyloid peptide alters intracellular calcium levels, which leads to the increased beta-secretase activity, which further promotes the generation of beta amyloid peptides. It also showed depression in the levels of GAP-43 expression, inhibition of PKC activity and altering synaptic activity further leads to cell death.

    更新日期:2019-12-13
  • Licocoumarone induces BxPC-3 pancreatic adenocarcinoma cell death by inhibiting DYRK1A
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-12
    Chao Zhao; Dun Wang; Zexuan Gao; Hongfeng Kan; Feng Qiu; Lixia Chen; Hua Li
    更新日期:2019-12-13
  • iTRAQ-based quantitative proteomics and target-fishing strategies reveal molecular signatures on vasodilation of Compound Danshen Dripping Pills
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-12
    Xin Wu; Xiujiang Han; Lili Li; Simiao Fan; Pengwei Zhuang; Zhen Yang; Yanjun Zhang
    更新日期:2019-12-13
  • Stearoyl-CoA desaturase and tumorigenesis
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-12
    Kohtaro Kikuchi; Hidekazu Tsukamoto

    Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also stimulates canonical Wnt pathway and YAP activation in support of stemness and tumorigenesis. SCD facilitates metabolic reprogramming in cancer which is mediated, at least in part, by regulation of AKT, AMPK, and NF-kB via MUFAs. Our research has revealed the novel positive loop to amplify Wnt signaling through stabilization of LRP5/6 in both hepatic stellate cells and liver tumor-initiating stem cell-like cells. As such, this loop is pivotal in promoting liver fibrosis and liver tumor development. This review summarizes the mechanisms of SCD-mediated tumor promotion described by recent studies and discusses the future prospect for SCD-mediated signaling crosstalk as a potential therapeutic target for cancer.

    更新日期:2019-12-13
  • Farrerol alleviates high glucose-induced renal mesangial cell injury through the ROS/Nox4/ERK1/2 pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-12
    Zhao Chen; Heyan Gao; Li Wang; Xiaotao Ma; Lifang Tian; Weihao Zhao; Ke Li; Yani Zhang; Fangxia Ma; Jiamei Lu; Lining Jia; Yanyan Yang; Rongguo Fu

    Hyperproliferation and oxidative stress induced by hyperglycemia in mesangial cells plays crucial roles in the pathological process of diabetic nephropathy. Farrerol, isolated from rhododendron leaves, possesses broad anti-oxidative and anti-inflammatory properties towards several diseases, but its role in diabetic neuropathy remains unclear. The aim of this study was to evaluate the effects of farrerol in high glucose induced mesangial cell injury, and to explore underlying molecular mechanisms. Our results showed that high glucose in vitro conditions significantly stimulated cell proliferation, inflammatory cytokine secretion, extracellular matrix deposition, excessive oxidative stress, and NADPH oxidase activity in mesangial cells. Levels of NADPH oxidase 4 (Nox4) expression, ERK1/2 phosphorylation, and TGF-β1/Smad2 activation were significantly induced by high glucose conditions in mesangial cells. Inversely, farrerol treatments at 40, 60, and 80 μM concentrations, dose-dependently alleviated this molecular damage by high glucose in mesangial cells. We also found that restoration of Nox4 expression abolished the protective effects of farrerol on high glucose-induced proliferation and reactive oxygen species generation. Furthermore, pretreatment with the Nox4 inhibitor diphenyliodonium or the ERK1/2 pathway inhibitor PD98059, displayed similar ameliorated effects of farrerol on high glucose-induced mesangial cell damage. Taken together, these data suggest that farrerol displays protective effects on high glucose induced mesangial cell injury, partly through the Nox4-mediated ROS/ERK1/2 signaling pathway. These observations may provide novel insights into the application of farrerol as a diabetic neuropathy treatment.

    更新日期:2019-12-13
  • Propranolol inhibits proliferation and induces apoptosis of hemangioma-derived endothelial cells via Akt pathway by down-regulating Ang-2 expression
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-12
    Bin Sun; Changxian Dong; Hongzhao Lei; Yubin Gong; Miaomiao Li; Yuanfang Zhang; Hongyu Zhang; Longlong Sun

    Hemangioma is one of the commonest benign vascular tumors among children. Propranolol is the first-line therapeutic drug for hemangioma. However, the effects and mechanisms of propranolol in hemangioma have not been thoroughly elaborated. In this study, the effects and mechanisms of propranolol were explored using hemangioma-derived endothelial cells (HemECs). The expression of GLUT1 were determined by immunofluorescence staining. qRT-PCR assay was conducted to detect the mRNA expressions of angiopoietin-2 (Ang-2) and Tie-2. Western blot assay was carried out to measure the protein levels of Ang-2, Tie-2, protein kinase-B (Akt) and phospholyrated-Akt (p-Akt). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay and Western blot of Ki67 protein level. Cell apoptosis was measured by flow cytometry analysis and Western blot of Bax and Bcl-2 levels. We found that propranolol inhibited proliferation and induced apoptosis in human umbilical vein endothelial cells (HUVECs) and HemECs. Moreover, propranolol inhibited the expressions of Ang-2 and Tie-2 in HUVECs and HemECs. Functional analysis revealed that Ang-2 attenuated the effects of propranolol on HemEC proliferation and apoptosis. Mechanistical analysis showed that propranolol inhibited the Akt pathway by regulating Ang-2 expression in HemECs. Futhermore, inhibition of the Akt pathway attenuated the effects of Ang-2 on proliferation and apoptosis in HemECs. In conclusion, propranolol inhibited proliferation and induced apoptosis of HemECs via Akt pathway by down-regulating Ang-2 expression, which contributes to our understanding on the pathogenesis of hemangioma and promotes the development of therapeutic approaches for hemangioma.

    更新日期:2019-12-13
  • Activated FXR promotes xenobiotic metabolism of T-2 toxin and attenuates oxidative stress in broiler chicken liver
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-09
    Depeng Dai, Yuanhu Pan, CuiPing Zeng, Shenghui Liu, Yi Yan, Xiaoxiong Wu, Lisheng Zhang

    The transmission of T-2 toxin and its metabolites into the edible tissues of poultry has potential effects on human health. The bile acid and xenobiotic system composes an intricate physiological network of chemoprotective and transporter-related functions, which ensures the detoxification and removal of harmful xenobiotic and endobiotic compounds from the body. This study revealed that cholic acid (CA), as one of the bile acids, promoted the metabolism of T-2 toxin in vivo by inducing the xenobiotic metabolism enzymes expression, thereby increasing the stress resistance and attenuating the oxidative stress. This study also indicated that dietary supplementation of 1% CA alleviated the mortality caused by T-2 toxin. Liver histology results demonstrated that CA supplementation significantly reduced inflammatory cell infiltration, sinusoidal expansion and congestion. Biochemistry results showed that the elevations of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and the increase in concentration of hydrogen peroxide (H2O2) in liver induced by the T-2 toxin were decreased by dietary supplementation of 1% CA. Additionally, CA supplementation led to the increase in superoxide dismutase (SOD) activity, but the decrease in catalase (CAT) activity in broiler chicken livers. Based on these findings, we propose that activation of FXR promotes T-2 toxin xenobiotic metabolism, and FXR plays a hepatoprotection role in liver injury induced by T-2 toxin.

    更新日期:2019-12-11
  • Zafirlukast protects blood-brain barrier integrity from ischemic brain injury
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-06
    Chaosheng Zeng, Desheng Wang, Cong Chen, Lin Chen, Bocan Chen, Li Li, Min Chen, Huaijie Xing

    Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.

    更新日期:2019-12-07
  • 12-HETE is a regulator of PGE2 production via COX-2 expression induced by a snake venom group IIA phospholipase A2 in isolated peritoneal macrophages
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-12-04
    Vanessa Moreira, José María Gutiérrez, Bruno Lomonte, Marco Aurélio Ramirez Vinolo, Rui Curi, Gérard Lambeau, Catarina Teixeira

    The snake venom miotoxin (MT)-III is a group IIA secreted phospholipase A2 (sPLA2) with pro-inflammatory activities. Previous studies have demonstrated that MT-III has the ability to stimulate macrophages to release inflammatory lipid mediators derived from arachidonic acid metabolism. Among them, we highlight prostaglandin (PG)E2 produced by the cyclooxygenase (COX)-2 pathway, through activation of nuclear factor (NF)-κB. However, the mechanisms coordinating this process are not fully understood. This study investigates the regulatory mechanisms exerted by other groups of bioactive eicosanoids derived from 12-lipoxygenase (12-LO), in particular 12-hydroxyeicosatetraenoic (12-HETE), on group IIA sPLA2-induced (i) PGE2 release, (ii) COX-2 expression, and (iii) activation of signaling pathways p38 mitogen-activated protein kinases p38 mitogen-activated protein kinases (p38MAPK), protein C kinase (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-κB. Stimulation of macrophages with group IIA sPLA2 resulted in release of 12-HETE without modification of 12-LO protein levels. Pre-treatment of these cells with baicalein, a 12-LO inhibitor, decreased the sPLA2-induced PGE2 production, significantly reduced COX-2 expression, and inhibited sPLA2-induced ERK; however, it did not affect p38MAPK or PKC phosphorylation. In turn, sPLA2-induced PGE2 release and COX-2 expression, but not NF-κB activation, was attenuated by pre-treating macrophages with PD98059 an inhibitor of ERK1/2. These results suggest that, in macrophages, group IIA sPLA2-induced PGE2 release and COX-2 protein expression are distinctly mediated through 12-HETE followed by ERK1/2 pathway activation, independently of NF-κB activation. These findings highlight an as yet undescribed mechanism by which 12-HETE regulates one of the distinct signaling pathways for snake venom group IIA sPLA2-induced PGE2 release and COX-2 expression in macrophages.

    更新日期:2019-12-04
  • 更新日期:2019-11-30
  • Emerging therapeutic potential of the iridoid molecule, asperuloside: A snapshot of its underlying molecular mechanisms
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-28
    Yinghan Chan, Sin Wi Ng, Joycelin Zhu Xin Tan, Gaurav Gupta, Murtaza M. Tambuwala, Hamid A. Bakshi, Harish Dureja, Kamal Dua, Muhammad Ishaq, Vanni Caruso, Dinesh Kumar Chellappan

    Over the years, the attention of researchers in the field of modern drug discovery and development has become further intense on the identification of active compounds from plant sources and traditional remedies, as they exhibit higher therapeutic efficacies and improved toxicological profiles. Among the large diversity of plant extracts that have been discovered and explored for their potential therapeutic benefits, asperuloside, an iridoid glycoside, has been proven to provide promising effects as a therapeutic agent for several diseases. Although, this potent substance exists in several genera, it is primarily found in plants belonging to the genus Eucommia. Recent decades have seen a surge in the research on Asperuloside, making it one of the most studied natural products in the field of medicine and pharmacology. In this review, we have attempted to study the various reported mechanisms of asperuloside that form the basis of its wide spectrum of pharmacological activities.

    更新日期:2019-11-29
  • Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-28
    Shruti Surendran, Rekha Sapkal, David Paul, Satheeshkumar Nanjappan
    更新日期:2019-11-29
  • MiR-107 overexpression attenuates neurotoxicity induced by 6-hydroxydopamine both in vitro and in vivo
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-26
    Li Sun, Tingting Zhang, Wenna Xiu, Wenhui Cao, Mengfei He, Wenqiang Sun, Weina Zhao

    Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disease characterized by neuronal atrophy in various brain regions. The expression of miR-107 is down-regulated in AD patients and target genes of miR-107 have been shown to directly involved in AD. In this study, we aimed to investigate the potential neuroprotective effects of miR-107. We first assessed brain activity in health controls and patients with AD. Then we examined miR-107 expression in SH-SY5Y and PC12 cells treated with 6-hydroxydopamine (6-OHDA), and investigated its function in cytotoxicity induced by 6-OHDA. We predicted a potential miR-107 target and assessed its role in miR-107 mediated effects and explored the intracellular signaling pathways downstream of miR-107. Finally, we assessed the function of miR-107 in the mouse model insulted by 6-OHDA. We found that 6-OHDA suppressed miR-107 expression and miR-107 played neuroprotective effects against 6-OHDA mediated cytotoxicity. We showed that miR-107 targeted programmed cell death 10 (PDCD10). MiR-107 suppressed PDCD10 expression and exogenous expression of PDCD10 inhibited miR-107 mediated neuroprotection. Additionally, we found that Notch signal pathway was downstream of miR-107/PDCD10. Finally, we found that 6-OHDA treatment suppressed miR-107 in mice and restoration of miR-107 alleviated motor disorder in the mouse model. Our study shows that miR-107 plays important neuroprotective roles against neurotoxicity both in vitro and in vivo by inhibiting PDCD10. Our findings confirm that miR-107 may be involved in AD pathogenesis and may be a therapeutic target for the treatment of AD-related impairments.

    更新日期:2019-11-27
  • Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington's disease
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-26
    Charles C. Caldwell, Giselle M. Petzinger, Michael W. Jakowec, Enrique Cadenas

    Background Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG140 knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age. Objective This study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG140 KI mouse model of HD after motor symptoms have emerged. Methods CAG140 KI mice at 13–15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD+/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod. Results Exercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase. Conclusions These changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.

    更新日期:2019-11-26
  • In vitro metabolism of naphthalene and its alkylated congeners by human and rat liver microsomes via alkyl side chain or aromatic oxidation
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-23
    Danlei Wang, Ben Bruyneel, Lenny Kamelia, Sebastiaan Wesseling, Ivonne M.C.M. Rietjens, Peter J. Boogaard

    Mineral oils widely are applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.

    更新日期:2019-11-26
  • Assessing the utility of in vitro microtubule assays for studying mechanisms of peripheral neuropathy with the microtubule inhibitor class of cancer chemotherapy
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-21
    C. Genualdi, S.C. Feinstein, L. Wilson, M.A. Jordan, N.J. Stagg

    The microtubule inhibitor (MTI) class of chemotherapeutics provide an effective treatment for several different types of cancers, however, severe chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting toxicity in patients that limits their use. While CIPN was predicted with MTIs based on histopathology and functional effects in non-clinical toxicology studies, these investigations often require large numbers of animals and long term studies. As in vitro MT assays have been used for decades to study mechanisms of efficacy, we hypothesized that those same assays could be used to study mechanisms of peripheral neuropathy and predict severe CIPN. We analyzed published data on in vitro microtubule (MT) properties for different MTIs that cause varying levels of peripheral neuropathy in patients. Eribulin, vinorelbine and vinfluinine, which all have less severe CIPN than the vinca alkaloids or taxanes, have unique MT properties consisting of reduced affinity and limited binding to MTs (i.e. bind only to the ends and not along the length). Binding more potently to tubulin in the absence of neuronal BIII tubulin was also observed with eribulin and may suggest specificity for tumor tubulin over neuronal tubulin. These are possible mechanisms for causing less severe deleterious effects on MTs in peripheral nerves leading to reduced severity of CIPN. Our analyses demonstrated that in vitro tools used to study the mechanisms of action in inducing severe CIPN (i.e MTI interactions with MTs) warrant further investigation and may be useful for developing next generation MTIs with reduced CIPN.

    更新日期:2019-11-22
  • Distribution of positively charged amino acid residues in antimicrobial peptide epinecidin-1 is crucial for in vitro glioblastoma cytotoxicity and its underlying mechanisms
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-20
    Bor-Chyuan Su, Tsung-Han Wu, Chun-Hua Hsu, Jyh-Yih Chen

    Epinecidin-1 (epi) was identified from orange-spotted grouper (Epinephelus coioides) and exhibits diverse biological activities. The aims of this study were to investigate how the distribution of positively charged amino acid residues affects epi-mediated cytotoxicity and to examine the molecular mechanism underlying epi-induced cytotoxicity in U87MG human glioblastoma cells. MTS/PMS and trypan blue exclusion assay were used to measure cell viability. Necrotic cell death was confirmed by detecting cyclophilin A release and propidium iodide incorporation. DNA damage was evaluated by measuring phosphorylated H2AX. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry using dihydroergotamine. Mitochondrial membrane potential was detected by flow cytometry using tetramethylrhodamine, ethyl ester. Overall, we found that epi caused cytotoxicity in U87MG cells by inducing DNA damage and necrosis through mitochondrial hyperpolarization and subsequent ROS production. The proper folding of epi into an α-helical structure was essential for epi-mediated anti-glioblastoma effects. In addition, NFκB signaling was activated in U87MG cells after exposure to epi. Suppression of NFκB further enhanced epi-induced cytotoxicity, ROS generation and DNA damage, indicating that NFκB may play a protective role in epi-induced cytotoxicity. Our findings may be useful for the design and improvement of antimicrobial peptides with anti-cancer activity.

    更新日期:2019-11-21
  • Structure-activity relationship studies of Longicalcynin A analogues, as anticancer cyclopeptides
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-17
    Mohammadreza Gholibeikian, Abdolhamid Bamoniri, Mohammad Hassan HoushdarTehrani, Bi Bi Fatemeh Mirjalili, Hamid Reza Bijanzadeh

    Cancer has emerged as the main cause of the highest rate of mortality in the world. Drugs used in cancer, although, show some beneficial effects on cancerous organs, demonstrate side effects on other normal tissues. On the other hand, anticancer peptides, being effective on target tissues, should be safe and less harmful on healthy organs, since peptides have several advantages, i.e., high activity, specificity, affinity, being less immunogenic and not accumulate in the body. In the present work, analogues of Longicalcynin A, a naturally occurring anticancer cyclopeptide, were synthesized and evaluated their cytotoxicity in order to gain information from structure-activity relationships of the such cyclopeptides which may lead to find novel and safer anticancer peptide compound(s) to be used in clinic. Peptides were prepared by the solid-phase peptide synthesis method using trityl-resin. Peptide cyclization was performed in liquid phase. To study anticancer activity of the peptide analogues of Longicalycinin A, several methods including MTT, flow cytometry analysis and Lysosomal membrane integrity assay were employed using two cell lines HepG2 and HT-29. Fibroblast cells were used to control the safety of the synthesized cyclopeptides on normal cells. Two cyclopeptides 11 and 17 with the sequences of cyclo-(Thr-Val-Pro-Phe-Ala) and cyclo-(Phe-Ser-Pro-Phe-Ala), respectively were cytotoxic against the colon as well as hepatic cancer cells with safety profile against fibroblast cells, probably with the mechanism of apoptosis as lysosomal membrane integrity damaged. These cyclopeptides showed to be more favorable compounds better than Longicalycinin A and good candidates to develop cyclopeptides as anticancer agents.

    更新日期:2019-11-18
  • Preclinical toxicity of innovative molecules: In vitro, in vivo and metabolism prediction
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-16
    D.R. Tonholo, V.G. Maltarollo, T. Kronenberger, I.R. Silva, P.O. Azevedo, R.B. Oliveira, L.C.R. Souza, C.A. Tagliati

    The lack of predictivity of animal's models has increased the failure rate of drug candidates. Thus, the reversion of this scenario using preliminary in vitro assays and metabolism prediction can reduce the unnecessary use of animals, as well as predict toxic effects at preclinical and clinical stages. The present study aimed to evaluate safety of four biologically active molecules (RN104, RI78, ICH, PCH) with potential therapeutic applications synthesized in our laboratory. Initially, we used MTT cytotoxicity against A549, H9C2, HepG2, LLC-PK1 and NEURO-2 cell lines. RN104 showed the lowest cytotoxicity and further studies were conducted with it. The neutral red (NR) test was performed according to OECD-129 and then acute toxicity test (OECD-423). According to NR results we administered at 300 mg/kg on animals; however, no toxic effect was observed, while 2000 mg/kg resulted in the death of one animal per group. After, metabolism prediction studies, performed using both ligand-based and structure-based, suggests three potential metabolites. In silico results suggested that potential metabolites could be fast eliminated and, then, this could be an explanation for lower observed toxicity in in vivo experiments. The results showed limitations of the NR as a predictor of the initial dose for the acute toxicity study, which may be related to metabolism. Therefore, the combination of theoretical and experimental studies is relevant to a general understanding of new molecule's toxicity.

    更新日期:2019-11-18
  • Novel indol-3-yl-thiosemicarbazone derivatives: Obtaining, evaluation of in vitro leishmanicidal activity and ultrastructural studies
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-15
    Paula Roberta da Silva, Jamerson Ferreira de Oliveira, Anekécia Lauro da Silva, Camila Marques Queiroz, Ana Paula Sampaio Feitosa, Denise Maria Figueiredo Araújo Duarte, Aline Caroline da Silva, Maria Carolina Accioly Brelaz de Castro, Valéria Rêgo Alves Pereira, Rosali Maria Ferreira da Silva, Luiz Carlos Alves, Fábio André Brayner dos Santos, Maria do Carmo Alves de Lima

    Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 μM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and > 481.52 μM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 μM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.

    更新日期:2019-11-15
  • Predictive early gene signature during mouse Bhas 42 cell transformation induced by synthetic amorphous silica nanoparticles
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-15
    Anaïs Kirsch, Hélène Dubois-Pot-Schneider, Caroline Fontana, Hervé Schohn, Laurent Gaté, Yves Guichard

    Synthetic amorphous silica nanoparticles (SAS) are used widely in industrial applications. These nanoparticles are not classified for their carcinogenicity in humans. However, some data still demonstrate a potential carcinogenic risk of these compounds in humans. The Bhas 42 cell line was developed to screen chemicals, as tumor-initiators or -promoters according to their ability to trigger cell-to-cell transformation, in a cell transformation assay. In the present study, we performed unsupervised transcriptomic analysis after exposure of Bhas 42 cells to NM-203 SAS as well as to positive (Min-U-Sil 5® crystalline silica microparticles, and 12-O-tetradecanoylphorbol-13-acetate) and negative (diatomaceous earth) control compounds. We identified a common gene signature for 21 genes involved in the early stage of the SAS- Min-U-Sil 5®- or TPA-induced cell transformation. These genes were related to cell proliferation (over expression) and cell adhesion (under expression). Among them, 12 were selected on the basis of their potential impact on cell transformation. RT-qPCR and western blotting were used to confirm the transcriptomic data. Moreover, similar gene alterations were found when Bhas 42 cells were treated with two other transforming SAS. In conclusion, the results obtained in the current study highlight a 12-gene signature that could be considered as a potential early “bio-marker” of cell transformation induced by SAS and perhaps other chemicals.

    更新日期:2019-11-15
  • Linagliptin protects human chondrogenic ATDC5 cells against advanced glycation end products (AGEs)-induced apoptosis via a mitochondria-dependent pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-13
    Yanjie Zhang, Xiaohan Huang, Yanhao Yuan

    Chondrocytes in joints are responsible for the formation and remodeling of articular cartilage. The accumulation of advanced glycation end products (AGEs) in cartilage is detrimental to the survival of chondrocytes. Linagliptin is one of the most commonly used anti-diabetes agents, and recent work indicates that it exerts an anti-inflammatory effect in different cell types. In this study, we showed that Linagliptin had a protective role in AGEs-induced chondrocyte injury. The presence of Linagliptin ameliorated AGEs-induced reactive oxygen species (ROS) induction and reduced cellular protein carboxyl content. Linagliptin mitigated AGEs-induced mitochondrial membrane potential (ΔΨm) reduction and NAPDH oxidase subunit NOX-4 induction, indicating that Linagliptin is a potent anti-ROS agent in chondrocytes. Additionally, Linagliptin inhibited AGEs-induced production of high mobility group box chromosomal protein 1 (HMGB-1), and the expression of matrix metalloproteases (MMPs)-2 and −9. Flow cytometry experimentation showed that Linagliptin inhibited AGEs-induced apoptotic subpopulation. Moreover, Linagliptin inhibited the AGEs-induced increased ratio of Bax to Bcl-2, translocation of cytochrome C from mitochondria to the cytoplasm, and release of cleaved caspase-3. Collectively, our data indicate that the anti-diabetes drug Linagliptin has a new role in rescuing chondrocyte from insult by AGEs, and may, therefore, have the potential to treat joint disorders.

    更新日期:2019-11-13
  • Renoprotective effect of calycosin in high fat diet-fed/STZ injected rats: Effect on IL-33/ST2 signaling, oxidative stress and fibrosis suppression
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-11
    Nehal M. Elsherbiny, Eman Said, Hoda Atef, Sawsan A. Zaitone

    Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF–α, IL-1β, MDA, and TGF-β contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.

    更新日期:2019-11-13
  • Synergistic but not additive effect between ACPA and lithium in the dorsal hippocampal region on spatial learning and memory in rats: Isobolographic analyses
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-09
    Salar Vaseghi, Vahab Babapour, Mohammad Nasehi, Mohammad-Reza Zarrindast

    Lithium and cannabinoids can disrupt learning and memory performance. The goal of the present study is to investigate the additive or synergistic effect of lithium and cannabinoid combination doses on spatial learning and memory in rats by isobolographic analyses. Although several studies have suggested synergistic effects of cannabinoids or lithium in response to other compounds, in most of them isobolographic analyses were not used; Thus, there is a need for more detailed studies using isobolographic analyses. In this study, spatial memory was evaluated in the Morris Water Maze (MWM) apparatus by eight trials in the training day and one trial in the test day. Lithium was injected intraperitoneal and ACPA (cannabinoid type 1 receptor agonist) was injected into the dorsal hippocampal region (intra-CA1). For the isobolographic analyses, the ED50 of lithium (2.5 mg/kg) and ACPA (0.5 μg/rat) was measured by linear regression analysis, considering the doses were tested in our previous research. The results showed that, combinations of low, medium and high doses of lithium (0.312 mg/kg, 0.625 mg/kg and 1.25 mg/kg, respectively) and ACPA (0.0625 μg/rat, 0.125 μg/rat and 0.25 μg/rat, respectively) had synergistic but not additive effect on spatial learning and spatial memory. In conclusion, we suggest that combination doses of lithium and ACPA have synergistic but not additive effect on spatial learning and memory in the rat's dorsal hippocampal region.

    更新日期:2019-11-11
  • 更新日期:2019-11-11
  • Promotion of myotube differentiation and attenuation of muscle atrophy in murine C2C12 myoblast cells treated with teaghrelin
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-07
    Sheng-Kuo Hsieh, Hsin-Yi Lin, Chun-Jung Chen, Cian-Fen Jhuo, Keng-Ying Liao, Wen-Ying Chen, Jason T.C. Tzen
    更新日期:2019-11-08
  • Polydatin attenuates orbital oxidative stress in Graves’ orbitopathy through the NRF2 pathway
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-06
    Hong Li, Jie Min, Yuting Chen, Hongyan Li, Yali Zhang

    Graves’ orbitopathy (GO) is a sight-threatening ocular disease that occurs in patients with hyperthyroidism and is especially associated with oxidative stress. Polydatin (PD) is a major active component of Polygonum cuspidatum Sieb. et Zucc. It has various therapeutic effects including anti-inflammatory and antioxidant properties. In the present study, we investigated the effects of PD on H2O2-induced oxidative stress in orbital fibroblasts in vitro and in a GO mouse model of orbital oxidative stress in vivo. The mechanisms responsible for these effects were investigated using standard molecular techniques. Our initial findings in GO mice were that PD attenuated orbital muscle adipose tissue expansion and lipid droplet accumulation through a nuclear factor E2-related factor 2 (NRF2)-mediated oxidative stress response involving the Keap1/Nrf2/ARE pathway. The results demonstrated that PD could reverse the accumulation of lipid droplets and production of reactive oxygen species (ROS) induced by H2O2 and increase the expression of antioxidant genes such as NAD(P)H dehydrogenase, quinone 1 (NQO1). NQO1 levels were the lowest in the GO mouse model. In addition, PD enhanced NRF2 nuclear translocation in cultured orbital fibroblasts. We also found that silencing NRF2, using RNA interference, reduced the protective effects of PD against H2O2-induced oxidative stress in orbital fibroblasts in vitro. Taken together, our results indicate that PD can reduce the production of ROS and inhibit adipogenesis in orbital fibroblasts in vitro and in vivo.

    更新日期:2019-11-07
  • Structural, functional, and molecular impact on the cardiovascular system in ApoE−/- mice exposed to aerosol from candidate modified risk tobacco products, Carbon Heated Tobacco Product 1.2 and Tobacco Heating System 2.2, compared with cigarette smoke
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-06
    Justyna Szostak, Bjoern Titz, Walter K. Schlage, Emmanuel Guedj, Alain Sewer, Blaine Phillips, Patrice Leroy, Ansgar Buettner, Laurent Neau, Keyur Trivedi, Florian Martin, Nikolai V. Ivanov, Patrick Vanscheeuwijck, Manuel C. Peitsch, Julia Hoeng

    Aim To investigate the molecular, structural, and functional impact of aerosols from candidate modified risk tobacco products (CMRTP), the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2, compared with that of mainstream cigarette smoke (CS) on the cardiovascular system of ApoE−/- mice. Methods Female ApoE−/- mice were exposed to aerosols from THS 2.2 and CHTP 1.2 or to CS from the 3R4F reference cigarette for up to 6 months at matching nicotine concentrations. A Cessation and a Switching group (3 months exposure to 3R4F CS followed by filtered air or CHTP 1.2 for 3 months) were included. Cardiovascular effects were investigated by echocardiographic, histopathological, immunohistochemical, and transcriptomics analyses. Results Continuous exposure to CMRTP aerosols did not affect atherosclerosis progression, heart function, left ventricular (LV) structure, or the cardiovascular transcriptome. Exposure to 3R4F CS triggered atherosclerosis progression, reduced systolic ejection fraction and fractional shortening, caused heart LV hypertrophy, and initiated significant dysregulation in the transcriptomes of the heart ventricle and thoracic aorta. Importantly, the structural, functional, and molecular changes caused by 3R4F CS were improved in the smoking cessation and switching groups. Conclusion Exposure to CMRTP aerosols lacked most of the CS exposure-related functional, structural, and molecular effects. Smoking cessation or switching to CHTP 1.2 aerosol caused similar recovery from the 3R4F CS effects in the ApoE−/- model, with no further acceleration of plaque progression beyond the aging-related rate.

    更新日期:2019-11-06
  • P-glycoprotein modulates oleanolic acid effects in hepatocytes cancer cells and zebrafish embryos
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-05
    Maya Kayouka, Aline Hamade, Eliane Saliba, Fadia Najjar, David Landy, Hélène Greige-Gerges

    Oleanolic acid (OA) is a triterpenoid, widely found in plants and possesses antitumor activity in many cancer lines. However, cancer cells develop multidrug resistance (mdr) hindering the effect of anticancer drugs. P-glycoprotein (P-gp) is a major cause of mdr. Therefore, the cytotoxic effect of OA was evaluated on human breast cancer MDA-MB-231 and human liver cancer HepG2 with absence and presence of P-gp, respectively. OA reduced MDA-MB-231 viability in a dose dependent manner, whereas no remarkable effect was observed on HepG2 in the same range of concentrations (1–60 μM). Moreover, cytotoxicity studies were conducted in the presence of verapamil (20 mg/L), a P-gp inhibitor. OA exhibited the same effect on MDA-MB-231 in the absence and presence of verapamil. However, the cytotoxicity was greatly enhanced for HepG2 cells in the presence of verapamil (cell viability dropped from 63.7% to 25% after 72 h at 60 μM). The results were then confirmed in vivo on zebrafish embryos. Increased mortality and malformations were observed in verapamil pretreated group between 5 and 15 μM of OA compared to control; also, all embryos died at 20 μΜ OA and above. These results demonstrate that inhibiting P-gp enhances the chemotherapeutic activity of OA.

    更新日期:2019-11-06
  • Pregnane X receptor activation by its natural ligand Ginkgolide-A improves tight junction proteins expression and attenuates bacterial translocation in cirrhosis
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-04
    Sundhar Mohandas, Balasubramaniyan Vairappan

    Background and aims Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. Methods Swiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage every day. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. Results When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. Conclusion In conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.

    更新日期:2019-11-04
  • AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-02
    Hyllana C.D. Medeiros, Carina Colturato-Kido, Letícia S. Ferraz, Claudia A. Costa, Vivian W.R. Moraes, Edgar Julian Paredes-Gamero, Ivarne L.S. Tersariol, Tiago Rodrigues
    更新日期:2019-11-04
  • Protective effects of Salidroside on spermatogenesis in streptozotocin induced type-1 diabetic male mice by inhibiting oxidative stress mediated blood-testis barrier damage
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-02
    Ya-Ping Jiang, Rui-Juan Ye, Jia-Mei Yang, Ning Liu, Wen-Jin Zhang, Lin Ma, Tao Sun, Jian-Guo Niu, Ping Zheng, Jian-Qiang Yu

    Spermatogenic dysfunction is one of the major secondary complications of male diabetes. Salidroside (SAL) is the important active ingredients isolated from Herba Cistanche, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. The present study was designed to determine whether SAL contributes to the recovery from spermatogenic dysfunction in streptozotocin (STZ) induced type-1 diabetic mice. SAL (25, 50, or 100 mg/kg) and Clomiphene citrate (CC, 5 mg/kg) were orally administered to male type-1 diabetic mice for 10 weeks. Testis tissues were collected for histopathological and biochemical analysis. Moreover, reproductive organ weight, sperm parameters, and testicular cell DNA damage were estimated. The results revealed that SAL significantly improved the weight of the reproductive organs, sperm parameters and testicular morphology to different degrees in type-1 diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked downregulation the fluorescence expressions of p38 MAPK phosphorylation and upregulation the protein expressions of ZO-1, Occludin, Claudin-11 and N-cadherin after SAL administration (100 mg/kg) compared with the type-1 diabetic group. In conclusion, these results demonstrated that SAL exerts protective effects on type-1 diabetes-induced male spermatogenic dysfunction, which is likely mediated by inhibiting oxidative stress-mediated blood testis barrier damage.

    更新日期:2019-11-04
  • 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) targets tubulin and DNA to induce anticancer activity and overcome multidrug resistance in colorectal cancer cells
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-01
    Zhaoshi Bai, Xiaolin Liu, Qi Guan, Nianyang Ding, Qing Wei, Bending Tong, Min Zhao, Weige Zhang, Lingman Ma

    Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) reduces the efficiency of anticancer drugs. Therefore, the development of novel anticancer drugs that are highly active against CRC with MDR is urgently needed. Our previous study showed that 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is not a P-glycoprotein (P-gp) substrate and has a potent anticancer effect against paclitaxel -sensitive or -resistant non-small-cell lung cancer (NSCLC) in vitro and in vivo. In the present study, we found that BZML exhibited strong anticancer activity not only in sensitive CRC cells (SW480 and HCT-116 cells) but also in intrinsically drug-resistant CRC cells (Caco2 cells). In addition, by targeting the colchicine binding site, BZML inhibited tubulin polymerization, which induced G2/M phase arrest, and it caused DNA damage by directly targeting DNA or producing ROS. Further, BZML induced apoptosis through the time-dependent ROS-mediated mitochondrial apoptotic pathway in the CRC cells. Additionally, BZML inhibited P-gp-mediated drug efflux and enhanced the inhibition of the cell growth that had been induced by paclitaxel or doxorubicin in Caco2 cells. In summary, BZML is a multi-targeted anticancer drug that targets tubulin and DNA, and the mechanisms underlying its potent anticancer activity involve disrupting microtubule assembly, causing DNA damage, inducing cell cycle arrest and eventually activating the ROS-mediated mitochondrial apoptotic pathway in SW480, HCT-116 and Caco2 cells. Therefore, the novel compound BZML is a promising anticancer drug that has tremendous potential for CRC treatment, especially for the treatment of drug-resistant CRC.

    更新日期:2019-11-01
  • Rifampicin activates AMPK and alleviates oxidative stress in the liver as mediated with Nrf2 signaling
    Chem. Biol. Interact. (IF 3.407) Pub Date : 2019-11-01
    Eun Hye Lee, Su Youn Baek, Ji Young Park, Young Woo Kim

    Although rifampicin could have a hepatic toxic effect, it has also been shown that this chemical acts as a cellular protectant against oxidative stress. Therefore, we wondered whether rifampicin has a beneficial effect such as an anti-oxidant in the liver, because the efficacy of some drugs sometimes relates with their toxicity as well as protective effects. The present study aimed to investigate the antioxidant effect of rifampicin against arachidonic acid (AA) plus iron (AA + iron) cotreatment and against acetaminophen (APAP, 500 mg/kg)-induced oxidative stress, in vitro and in vivo, respectively. In vivo, oral administration of rifampicin (100 or 200 mg/kg) attenuated elevation of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), serum liver injury markers, against APAP treatment and, histologically, ameliorated tissue damage. Under in vitro examination, MTT assays were used to assess the cell death inhibitory effect of rifampicin against AA + iron-induced oxidative stress. In addition, DCFH-DA and Rh 123 staining showed that rifampicin treatment reduced reactive oxygen species (ROS) production and mitochondrial membrane damage, which had been induced by AA + iron treatment. Further, we explored whether rifampicin treatment enhanced phosphorylation of AMP-activated protein kinase (AMPK) by activation of liver kinase B1 (LKB1), the upstream kinase of AMPKα. Activated AMPKα induced activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which are proteins functioning in redox balance. Moreover, we confirmed a reversed cell protective effect of rifampicin under compound C (an AMPK inhibitor) treatment. Overall, our data demonstrate that rifampicin effectively protects the liver against cellular oxidative stress through AMPKα and Nrf2 pathway.

    更新日期:2019-11-01
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