NaHS restores mitochondrial function and inhibits autophagy by activating the PI3K/Akt/mTOR signalling pathway to improve functional recovery after traumatic brain injury Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-19 Kebin Xu, Fangfang Wu, Ke Xu, Zhengmao Li, Xiaojie Wei, Qi Lu, Ting Jiang, Fenzan Wu, Xinlong Xu, Jian Xiao, Daqing Chen, Hongyu Zhang
Traumatic brain injury (TBI) is one of the most serious public health problems in the world. TBI causes neurological deficits by triggering secondary injuries. Hydrogen sulfide (H2S), a gaseous mediator, has been reported to exert neuroprotective effects in central nervous system diseases, such as TBI. However, the molecular mechanisms involved in this effect are still unclear. The present study was designed to explore the ability of NaHS, a H2S donor, to provide neuroprotection in a mouse model of TBI and to discover the associated molecular mechanisms of these protective effects. Here, we found that administration of NaHS not only maintained the integrity of the blood brain barrier (BBB), protected neurons from apoptosis, and promoted remyelination and axonal reparation but also protected mitochondrial function. In addition, we found that autophagy was inhibited after treatment with NaHS following TBI, an effect that was induced by activation of the PI3K/AKT/mTOR signalling pathway. Our study indicated that H2S treatment is beneficial for TBI, pointing to H2S as a potential therapeutic target for treating TBI.
Mechanistic study on antibacterial action of zinc oxide nanoparticles synthesized using green route Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-15 Happy Agarwal, Soumya Menon, S. Venkat Kumar, S. Rajeshkumar
Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-14 Bai Hui Chen, Ji Hyeon Ahn, Joon Ha Park, Minah Song, Hyunjung Kim, Tae-Kyeong Lee, Jae Chul Lee, Young-Myeong Kim, In Koo Hwang, Dae Won Kim, Choong-Hyun Lee, Bing Chun Yan, Il Jun Kang, Moo-Ho Won
Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB.
Disruption of the zinc metabolism in rat fœtal brain after prenatal exposure to cadmium Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-14 Safa Ben Mimouna, Sana Boughammoura, Marouane Chemek, Zohra Haouas, Mohamed Banni, Imed Messaoudi
This study was carried out to investigate the effects of maternal Cd and/or Zn exposure on some parameters of Zn metabolism in fetal brain of Wistar rats. Thus, female controls and other exposed by the oral route during the gestation period to Cd (50 mg CdCl2/L) and/or Zn (ZnCl2 60 mg/L) were used. The male fetuses at age 20 days of gestation (GD20) were sacrificed and their brains were taken for histological, chemical and molecular analysis. Zn depletion was observed in the brains of fetuses issued from mothers exposed to Cd. Histological analysis showed that Cd exposure induces pyknosis in cortical region and CA1 region of the hippocampus compared to controls. Under Cd exposure, we noted an overexpression of the genes coding for membrane transporter involved in the intracellular incorporation of Zn (ZIP6) associated with inhibition of that encoding the transporters involved in the output of the Zn into the extracellular medium (ZnT1 and ZnT3). A decrease in the expression of the gene encoding the neuro-trophic factor (BDNF) associated with overexpression of the encoding the metal regulatory transcription factor 1 (MTF1), factor involved in the homeostasis of Zn, was also noted in Cd group. Interestingly, Zn supply provided a total or partial restauration of the changes induced by the Cd exposure. The depletion of brain Zn contents as well as the modification of the profile of expression of genes encoding membrane Zn transporters, suggest that the toxicity of Cd observed in fetal brain level are mediated, in part, by impairment of Zn metabolism.
Combinatorial drug delivery strategy employing nano-curcumin and nano-MiADMSA for the treatment of arsenic intoxication in mouse Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-13 Pramod Kushwah, Abhishek Yadav, S.J.S. Flora
Chelation therapy is the mainstream treatment for heavy metal poisoning. Apart from this, therapy using antioxidant/herbal extracts are the other strategies now commonly being tried for the treatment. We have previously reported individual beneficial efficacy of nanoparticle mediated administration of an antioxidant like ‘curcumin’ and an arsenic chelator ‘monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)’ for the treatment of arsenic toxicity compared to bulk drugs. The present paper investigates our hypothesis that a combination drug delivery therapy employing two nanosystems, a chelator and a strong antioxidant, may produce more pronounced therapeutic effects compared to individual effects in the treatment of arsenic toxicity.An in-vivo study was conducted wherein arsenic as sodium arsenite (100 ppm) was administered in drinking water for 5 months to Swiss albino mice. This was followed by a treatment protocol comprising of curcumin encapsulated chitosan nanoparticles (nano-curcumin, 15 mg/kg, orally for 1 month) either alone or in combination with MiADMSA encapsulated polymeric nanoparticles (nano-MiADMSA, 50 mg/kg for last 5 days) to evaluate the therapeutic potential of the combination treatment. Our results demonstrated that co-treatment with nano-curcumin and nano-MiADMSA provided beneficial effects in a synergistic way on the adverse changes in oxidative stress parameters and metal status induced by arsenic.
Exploring the interaction of silver nanoparticles with pepsin and its adsorption isotherms and kinetics Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-10 Xiangrong Li, Kaiwei Wang, Yanru Peng
Protective effect of rutin against carbon tetrachloride-induced oxidative stress, inflammation and apoptosis in mouse kidney associated with the ceramide, MAPKs, p53 and calpain activities Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-06 Jie-Qiong Ma, Chan-Min Liu, Wei Yang
Rutin, a natural flavonoid, possess beneficial health effects. However, its renoprotective effect against carbon tetrachloride (CCl4) induced injury and the underlying mechanism is not clarified. The current study aims is to identify the therapeutic effects of rutin on oxidative stress, inflammation and apoptosis in mouse kidney exposed to CCl4. ICR mice received CCl4 with or without rutin co-administration for one week. Compared with the control group, mice receiving CCl4 alone showed kidney injury as evidenced by elevation in serum biochemical markers, inflammation, caspase-3 activity and apoptosis in kidney, while rutin administration significantly attenuated these pathophysiological changes. Exploration of the underlying mechanisms of its action demonstrated that rutin reduced the ROS, calpain and ceramide levels in mouse kidneys. Rutin significantly decreased the p53, TNF-α, IL-1β activities and mitogen-activated protein kinase (MAPK) phosphorylation in the kidneys. In addition, rutin increased the levels of Bcl-2 protein and reduced levels protein of Bax. Rutin also inhibited the release of cytochrome C from mitochondria in kidneys of the CCl4-treated mice. Taken together, rutin ameliorates CCl4-induced oxidative stress, inflammation and apoptosis through regulating the ceramide, MAPK, p53 and calpain activities and thereby suppressing apoptosis by the mitochondrial pathway.
Association of N-acetyltransferase-2 and glutathione S-transferase polymorphisms with idiopathic male infertility in Vietnam male subjects Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-02 Nguyen Thi Trang, Vu Thi Huyen, Nguyen Thanh Tuan, Tran Duc Phan
N-acetyltransferase-2 (NAT2) and Glutathione S-transferases (GSTs) are phase-II xenobiotic metabolizing enzymes participating in detoxification of toxic arylamines, aromatic amines, hydrazines and reactive oxygen species (ROS), which are produced under oxidative and electrophile stresses. The purpose of this research was to investigate whether two common single-nucleotide polymorphisms (SNP) of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) associated with susceptibility to idiopathic male infertility. A total 300 DNA samples (150 infertile patients and 150 healthy control) were genotyped for the polymorphisms by ARMS - PCR. We revealed a significant association between the NAT2 variant genotypes (CT + TT (rs1799929), (OR: 3.74; p < 0.001)) and (GA + AA (rs1799930), (OR: 3.75; p < 0.001)) or GSTP1 variant genotypes (GA + AA (rs1695), (OR: 5.11; p < 0,001)) and (CT + TT (rs1138272), (OR: 7.42; p < 0,001) with idiopathic infertility risk. Our findings rate the effect of single-nucleotide polymorphisms of GSTP1 and/or NAT2 in modulation of the risk of male infertility in subjects from Vietnam. This pilot study is the first (as far as we know) to reveal that polymorphisms of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) are some novel genetic markers for susceptibility to idiopathic male infertility.
Cardioprotective effect of paeonol against epirubicin-induced heart injury via regulating miR-1 and PI3K/AKT pathway Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-02 Jing Wu, Chao Sun, Ruoyi Wang, Juan Li, Meng Zhou, Mi Yan, Xia Xue, Chuanxin Wang
L-carnitine mitigates UVA-induced skin tissue injury in rats through downregulation of oxidative stress, p38/c-Fos signaling, and the proinflammatory cytokines Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-27 Samir A. Salama, Hany H. Arab, Hany A. Omar, Hesham S. Gad, Gamil M. Abd-Allah, Ibrahim A. Maghrabi, Majed M. Al robaian
UVA comprises more than 90% of the solar UV radiation reaching the Earth. Artificial lightening lamps have also been reported to emit significant amounts of UVA. Exposure to UVA has been associated with dermatological disorders including skin cancer. At the molecular level, UVA damages different cellular biomolecules and triggers inflammatory responses. The current study was devoted to investigate the potential protective effect of L-carnitine against UVA-induced skin tissue injury using rats as a mammalian model. Rats were distributed into normal control group (NC), L-carnitine control group (LC), UVA-Exposed group (UVA), and UVA-Exposed and L-carnitine-treated group (UVA-LC). L-carnitine significantly attenuated UVA-induced elevation of the DNA damage markers 8-oxo-2′-deoxyguanosine (8-oxo-dG) and cyclobutane pyrimidine dimers (CPDs) as well as decreased DNA fragmentation and the activity of the apoptotic marker caspase-3. In addition, L-carnitine substantially reduced the levels of lipid peroxidation marker (MDA) and protein oxidation marker (PCC) and significantly elevated the levels of the total antioxidant capacity (TAC) and the antioxidant reduced glutathione (GSH) in the skin tissues. Interestingly, L-carnitine upregulated the level of the DNA repair protein proliferating cell nuclear antigen (PCNA). Besides it mitigated the UVA-induced activation of the oxidative stress-sensitive signaling protein p38 and its downstream target c-Fos. Moreover, L-carnitine significantly downregulated the levels of the early response proinflammatory cytokines TNF-α, IL-6, and IL-1β. Collectively, our results highlight, for the first time, the potential attenuating effects of L-carnitine on UVA-induced skin tissue injury in rats that is potentially mediated through suppression of UVA-induced oxidative stress and inflammatory responses.
Evidence for the involvement of TNF-α, IL-1β and IL-10 in the antinociceptive and anti-inflammatory effects of indole-3-guanylhydrazone hydrochloride, an aromatic aminoguanidine, in rodents Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-27 Silvia Sandes, Luana Heimfarth, Renan G. Brito, Priscila L. Santos, Daniele N. Gouveia, Alexandra Carvalho, Jullyana S.S. Quintans, Edeildo F. da Silva-Júnior, Thiago M. de Aquino, Paulo H.B. França, João X. de Araújo-Júnior, Ricardo L.C. Albuquerque-Júnior, Gokhan Zengin, Martine Schmitt, Jean-Jacques Bourguignon, Lucindo J. Quintans-Júnior
In-ovo exposed carbon black nanoparticles altered mRNA gene transcripts of antioxidants, proinflammatory and apoptotic pathways in the brain of chicken embryo Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-26 Dalia H. Samak, Yasser S. El-Sayed, Hazem M. Shaheen, Ali H. El-Far, Atsuto Onoda, Mohamed M. Abdel-Daim, Masakazu Umezawa
With ubiquitous applications of nanotechnology, there are increasing probabilities of exposure to manufactured nanoparticles (NPs), which might be posing emerging health concerns on the next generation. Recent data suggest that generation of reactive oxygen species may play an integral role in the carbon black nanoparticles (CBNPs)-induced oxidative injury; however, the exact molecular mechanism has not been clarified. Hence, the role of oxidative stress, inflammation and apoptosis pathways in the CBNPs-induced neuronal toxicity following in-ovo exposure of chicken embryo was elucidated. Specific pathogen-free fertilized Sasso eggs were inoculated with 4.8, 9.5 and 14 μg CBNPs/egg at the 3rd day of incubation alongside vehicle controls. In a concentration-dependent manner, CBNPs inoculation induced oxidative stress, which was ascertained by enhancement of lipid peroxides and diminishing total antioxidant capacity and glutathione levels, and catalase activity in brain tissues. mRNA transcript levels of antioxidant genes showed up-regulation of heme oxygenase-1 and superoxide dismutase-1, with marked down-regulation of glutathione S-transferase-α. Additionally, the pro-inflammatory genes; nuclear factor-κB1 was up-regulated, while interferon-γ was down-regulated. There is also a clear down-regulation in apoptotic markers caspase-8, caspase-3, cytochrome c and B-cell CLL/lymphoma 2 at the different concentrations, while caspase-2 is up-regulated only at higher concentration. Collectively, these results show that CBNPs exposure-mediated overproduction of the free radicals, particularly at higher concentration contributes to inflammation and subsequent cellular apoptosis at the gene expression level, thus unveiling possible molecular relationship between CBNPs and genes linked to the oxidant, inflammatory and apoptotic responses.
Nrf-2 transcriptionally activates P21Cip/WAF1 and promotes A549 cell survival against oxidative stress induced by H2O2 Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-24 Samarjit Jana, Kartick Patra, Jagannath Jana, Deba Prasad Mandal, Shamee Bhattacharjee
Cancer cells possess elevated ROS coupled with increased levels of antioxidant enzymes which render them resistant against cytotoxic chemotherapies. Therefore, an understanding of the interaction between key molecules involved in stress adaptive mechanisms is important to innovate strategies against cancer cell chemoresistance. Here, the lung adenocarcinoma cell line A549 with constitutively expressed Nrf2 was found to be more tolerant to H2O2 (0.1, 0.2, 0.5 and 1 mM) than normal lung cell line L132 or p53 null lung cancer cell line H1299. Maximum cytoprotection was observed at 0.2 mM H2O2 accompanied by a significant increase in p21, Nrf2 and antioxidant enzymes in A549 cells. The increased p21 expression was independent of p53 but dependent on Nrf2 as evident from qPCR, Western blotting and dual luciferase assays after silencing Nrf-2 gene. Highly conserved Nrf-2 binding sites were identified in p21 promoter by bioinformatics and homology modeling which was further confirmed by ChIP and reporter assay.
Phytol suppresses melanogenesis through proteasomal degradation of MITF via the ROS-ERK signaling pathway Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-24 Gyeong-A. Ko, Somi Kim Cho
Coralyne, a protoberberine alkaloid, causes robust photosenstization of cancer cells through ATR-p38 MAPK-BAX and JAK2-STAT1-BAX pathways Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-24 Rahul Bhattacharyya, Pooja Gupta, Sandip K. Bandyopadhyay, Birija Sankar Patro, Subrata Chattopadhyay
Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers.
Long noncoding RNA NKILA enhances the anti-cancer effects of baicalein in hepatocellular carcinoma via the regulation of NF-κB signaling Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-23 Xiaolan Yu, Wei Tang, Yingcheng Yang, Li Tang, Rongyang Dai, Bangming Pu, Chunhong Feng, Jiyi Xia
Hepatocellular carcinoma (HCC) is one of the most common cancer and leading cause of cancer-related death worldwide. Baicalein, a principle flavonoid, has shown attractive anti-cancer effects on HCC. However, the underlying molecular mechanisms and influencing factors contributing to the anti-cancer effects of baicalein on HCC are still largely unknown. Long noncoding RNAs (lncRNAs) have been revealed to be fascinating therapeutic targets for cancers. The roles of NF-κB Interacting LncRNA (NKILA) are recently explored in several cancers. However, the expressions, clinical significances, roles and action mechanisms of NKILA in the anti-cancer effects of baicalein on HCC are unknown. In this study, we found that NKILA is down-regulated in HCC and reduced expression of NKILA indicts poor survival of HCC patients. Functional assays showed that overexpression of NKILA enhances the roles of baicalein on HCC cell proliferation inhibition, apoptosis induction, and migration inhibition in vitro and tumor growth suppression in vivo. Conversely, knockdown of NKILA suppresses the effects of baicalein. Mechanistically, we found that NKILA inhibits IκBα phosphorylation, NF-κB nuclear translocation, and NF-κB activity. NKILA also enhances the inhibitory effects of baicalein on NF-κB signaling. Furthermore, the effects of NKILA on baicalein-induced NF-κB activity inhibition, cell growth inhibition, apoptosis induction, and migration inhibition are reversed by NF-κB nuclear translocation inhibitor JSH-23. Collectively, our data demonstrated that NKILA enhances the anti-cancer effects of baicalein on HCC in vitro and in vivo via the regulation of NF-κB signaling, and implied that the combination of NKILA and baicalein would be potential therapeutic strategies for HCC.
miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-23 Jaceline Sanches, Yunchao Xu, Iddrisu Baba Yabasin, Min Li, Ying Lu, Xiaoxin Xiu, Lu Wang, Limin Mao, Jie Shen, Bo Wang, Li Hou, Jingfang Ju, Junjun Zhao, Bo Song
Background Cervical cancer is the common gynecological deadly malignancy worldwide. Here we attempted to evaluate the effects and mechanisms of microRNA-501-5p (miR-501) on the cell proliferation, migration, invasion and the clinical significance in the cervical cancer. Methods Cervical cancer HeLa cells were transfected with miR-501 mimic or inhibitor or siRNA against Cylindromatosis (CYLD) using Lipofectamine 2000. miR-501 expression was assessed in HeLa cells and cervical cancer specimens by real-time qRT-PCR. The functional roles of miR-501 were determined by CCK-8, colony formation, scratch wound healing and transwell assays. The apoptosis rate was detected by flow cytometry assay. CYLD, BCL-2, BAX, NF-κ κ B p65 and phosphorylated p65 (p-p65) proteins were examined by western blotting. CYLD expression was evaluated by immunohistochemistry in cervical cancer tissues. Results miR-501 was upregulated, whereas CYLD was downregulated in cervical cancer tissues compared to normal cervical tissues. miR-501 overexpression and CYLD downregulation were positively correlated with poor differentiation, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. CYLD was downregulated by miR-501 at both mRNA and protein levels in HeLa cells. miR-501 promoted cell proliferation, migration and invasion in cervical cancer, while inhibited the apoptosis. This is possibly due to the downregulation of CYLD and subsequent activation of NF-κB p65. Conclusions miR-501 upregulation and CYLD downregulation are associated with the development and progression of cervical cancer. miR-501 promotes cervical cancer cell proliferation, migration and invasion possibly via downregulating CYLD and subsequently activating NF-κB p65. miR-501 might be a potential therapeutic target for cervical cancer.
Biochemical studies of Egyptian sweet orange hesperidin on Ehrlich ascites carcinoma (EAC) bearing mice Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-23 Thoria Donia, Marian Nabil, Tarek M. Mohamed
There are global increased interests to identify novel agents that can possess anti-tumor effects or maximize the anti-tumor effects of low doses for conventional anti-cancer drugs. The aim of this study was to investigate anti-tumor effects and protective role of isolated hesperidin from sweet orange on doxorubicin-induced toxicity in Ehrlich ascites carcinoma (EAC) bearing mice. Tumor cells were injected into Swiss albino mice followed by hesperidin administration either alone or in combination with doxorubicin. Biochemical parameters on serum and hepatic were measured. In addition, the effect of hesperidin on apoptotic genes (Caspase3 and Bax) and anti-apoptotic gene (Bcl2) on tumor cells were evaluated by RT- PCR. The results showed that addition of hesperidin to doxorubicin-induced higher anti-tumor responses than treatment with hesperidin or doxorubicin alone. Hesperidin and doxorubicin in combination prolonged the life span of EAC tumor-bearing mice which was associated with a decrease in the number of viable tumor cells and increases in dead tumor cells number. In addition, co-administration of hesperidin with doxorubicin ameliorated the alteration in serum ALT, AST, ALP, GGT and LDH activities, total protein, albumin, creatinine, urea and total lipids concentrations. Moreover, hesperidin alone and in combination with doxorubicin-treated group decreased hepatic, TBARS level significantly as compared with tumor bearing mice and doxorubicin treated group. In contrast, hesperidin alone and combined with doxorubicin ameliorated total antioxidant capacity, reduced glutathione level, and antioxidant enzymes activities such as GPx and CAT in liver tissues. Moreover, hesperidin induced apoptosis of tumor cells which appeared as DNA fragmentation by down-regulation of Bcl2 as anti-apoptotic gene and stimulation of Caspase3 and Bax genes expression as apoptotic genes. In conclusion, Egyptian citrus peels are a rich source of the antioxidant hesperidin. Moreover, it can ameliorate the cytotoxic effect of doxorubicin while enhancing its anti-tumor effect.
Synthesis, spectroscopic, physicochemical and structural characterization of tetrandrine-based macrocycles functionalized with acridine and anthracene groups: DNA binding and anti-proliferative activity Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-21 Viviana Calvillo-Páez, Rogerio R. Sotelo-Mundo, Mario Leyva-Peralta, Juan Carlos Gálvez-Ruiz, David Corona-Martínez, Ramón Moreno-Corral, Raymundo Escobar-Picos, Herbert Höpfl, Octavio Juárez-Sánchez, Karen Ochoa Lara
In vitro model to study cocaine and its contaminants Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-21 Aline Steinmetz, Luiza Steffens, Ana Moira Morás, Flávia Prezzi, Elizandra Braganhol, Jenifer Saffi, Rafael Scorsatto Ortiz, Helena M.T. Barros, Dinara Jaqueline Moura
Cocaine is one of the most popular illicit drug worldwide. Due its great addictive potential, which leads to euphoria and hyperactivity, it is considered a public health concern. At the central nervous system, the drug acts inhibiting catecholamine re-uptake. It is now known that in addition to the toxicity of the drug itself, the contaminants present in the street drug have raised concern about the harmful effects on health. Toxicological in vivo and in vitro studies have demonstrated the toxic effects of cocaine correlated with the generation of reactive oxygen species (ROS), which in turn lead to oxidative damage to the cells. Therefore the aim of this work was to propose an in vitro model that reunites the main parameters of toxicity of the cocaine already observed in the literature so far, and we tested this model using cocaine and seizure cocaine sample (SCS), kindly provided by Federal Police of Brazil. For that, we used a C6 glioblastoma cells and evaluated cell death, oxygen reactive species induction, oxidation of macromolecules as membrane lipids and DNA and loss of mitochondrial membrane potential after cocaine exposure. The results showed that cocaine can decrease cellular viability in a dose-dependent way in the C6 cell immortalized and astrocytes primary culture. Cocaine also induced cellular death by apoptosis. However, in the seizure cocaine sample (SCS), the predominant cell death was due to necrosis. Using dichlorofluorescein (DCF) assay, we confirmed ROS production after cocaine exposition. In agreement with these findings, occurred an increasing in MDA production, as well as increased superoxide dismutase (SOD) and catalase (CAT) activity. The induction of DNA damage was observed after cocaine. Our results demonstrate the occurrence of mitochondrial dysfunction by depolarization of mitochondrial membrane as a consequence of cocaine treatment. In summary, these results demonstrated that cocaine can induce reactive oxygen species formation, leading to oxidative stress. As a consequence of this unbalance, DNA damage, lipidic peroxidation and loss of mitochondrial membrane occurred, which could be an answer to cell death observed.
Oroxylin A prevents alcohol-induced hepatic steatosis through inhibition of hypoxia inducible factor 1alpha Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-21 Huanhuan Jin, Naqi Lian, Mianli Bian, Chenxi Zhang, Xingran Chen, Jiangjuan Shao, Li Wu, Anping Chen, Qinglong Guo, Feng Zhang, Shizhong Zheng
Melatonin attenuates scopolamine-induced cognitive impairment via protecting against demyelination through BDNF-TrkB signaling in the mouse dentate gyrus Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-21 Bai Hui Chen, Joon Ha Park, Tae-Kyeong Lee, Minah Song, Hyunjung Kim, Jae Chul Lee, Young-Myeong Kim, Choong-Hyun Lee, In Koo Hwang, Il Jun Kang, Bing Chun Yan, Moo-Ho Won, Ji Hyeon Ahn
Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-20 Seung-Bin Lee, Ji-Sun Shin, Hee-Soo Han, Hwi-Ho Lee, Jong Cheol Park, Kyung-Tae Lee
Kaempferol 7-O-β-D-glucoside (KPG), a natural flavonol isolated from Cudrania tricuspidata, has been reported to exert anti-cancer effects; however, its anti-inflammatory effects have not yet been reported. In this study, we demonstrate the suppressive effect of KPG on the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse bone marrow-derived macrophages. KPG downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level and iNOS, COX-2, TNF-α, IL-1β, and IL-6 at the mRNA level in LPS-treated RAW 264.7 macrophages. Moreover, we elucidated the underlying molecular mechanism, demonstrating that KPG attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 nuclear translocation, inhibiting κBα (IκBα) phosphorylation/degradation and IκB kinaseα/β (IKKα/β) phosphorylation. KPG additionally reduced LPS-induced activator protein-1 (AP-1) activity by inhibiting c-Fos expression in the nucleus, though c-Jun was not affected. Furthermore, we revealed that KPG significantly abrogated the LPS-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 (Ser 727, Tyr 701) and STAT3 (Tyr 705) through inhibiting the phosphorylation of Janus kinase (JAK) 1 and JAK2, its upstream activating proteins. Taken together, our data suggest that KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated RAW 264.7 macrophages, thus suppressing inflammatory mediators.
Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-19 Xia Lv, Jian-Bin Zhang, Xin-Xin Wang, Wen-Zhong Hu, Yu-Sheng Shi, Shu-Wen Liu, Da-Cheng Hao, Wei-Dong Zhang, Guang-Bo Ge, Jie Hou, Ling Yang
Amentoflavone (AMF), an abundant natural biflavonoid found in many medicinal plants, displays various beneficial effects including anti-inflammatory, anti-oxidative and anti-cancer. Despite the extensive studies on pharmacological activities, the toxicity or undesirable effects of AMF are rarely reported. In this study, the inhibitory effects of AMF on human UDP-glucuronosyltransferases (UGTs) were carefully investigated. AMF displayed strong inhibition towards most of human UGTs including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4 and 2B17, with the IC50 values ranging from 0.12 μM to 16.81 μM. Inhibition constants (Ki) of AMF against various human UGTs varied from 0.29 μM to 11.51 μM. Further investigation demonstrated that AMF was a noncompetitive inhibitor of UGT1A1 mediated NCHN-O-glucuronidation but functioned as a competitive inhibitor of UGT1A1 mediated 4-MU-O-glucuronidation. In addition, AMF was a competitive inhibitor of UGT1A4 mediated TFP-N-glucuronidation in both UGT1A4 and human liver microsomes, while functioned as a competitive inhibitor of UGT1A9 mediated propofol or 4-MU-O-glucuronidation. These findings demonstrated that AMF was a strong and broad-spectrum natural inhibitor of most human UGTs, which might bring potential risks of herb-drug interactions (HDIs) via UGT inhibition. Additionally, this study provided novel insights into the underlying mechanism of AMF-associated toxicity from the perspective of UGT inhibition.
Topical delivery of L-theanine ameliorates TPA-induced acute skin inflammation via downregulating endothelial PECAM-1 and neutrophil infiltration and activation Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-17 Wei-Jie Zeng, Zhi Tan, Xing-Fei Lai, Ya-Nan Xu, Chun-Lin Mai, Jun Zhang, Zhen-Jia Lin, Xian-Guo Liu, Shi-Li Sun, Li-Jun Zhou
l-theanine, the most abundant free amino acid in tea, has been documented to possess many different bioactive properties through oral or intragastrical delivery. However, little is known about the effect of topical delivery of l-theanine on acute inflammation. In the present study, by using 12-O-tetradecanoylphorbol-13-acetate (TPA, 2.5 μg/ear)-induced ear edema model in mice, we first found that single-dose local pretreatment of l-theanine 30 min before TPA time- and dose-dependently suppressed the increases in both skin thickness and weight. Subsequently l-theanine ameliorated TPA-induced erythema, vascular permeability increase, epidermal and dermal hyperplasia, neutrophil infiltration and activation via downregulating the expression of PECAM-1 (a platelet endothelial adhesion molecule-1) in blood vessels and the production of pro-inflammatory cytokines IL-1β, TNF-α, and mediator cyclooxygenase-2 (COX-2), which is mainly expressed in neutrophils. It highlighted the potential of l-theanine as a locally administrable therapeutic agent for acute cutaneous inflammation.
Potentiation of skin TSLP production by a cosmetic colorant leads to aggravation of dermatitis symptoms Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-17 Gabsik Yang, Hye Eun Lee, Kyung-Min Lim, Yong-Kyu Choi, Kyu-Bong Kim, Byung-Mu Lee, Joo Young Lee
Certain cosmetic colorants are irritant to skin or aggravate dermatitis. Thymic stromal lymphopoietin (TSLP) plays an important role in the initiation and progress of skin inflammation and atopic dermatitis by triggering Th2 immune responses. However, the effects of cosmetic colorants on TSLP production are unknown yet. Therefore, we investigated whether cosmetic colorants regulated TSLP production and dermatitis. Lithol Rubine B (LR-B, Pigment Red 57) and its calcium salt (LR-BCA), commonly used cosmetic colorants, potentiated phorbol-12-myristate-13-acetate-induced TSLP production in keratinocytes. In addition, the topical exposure to LR-B or LR-BCA on mouse ear upregulated a TSLP inducer (MC903)-induced TSLP production and Th2 cytokine expression. Dermatitis symptoms and serum IgE and histamine levels were also aggravated by LR-B or LR-BCA, implicating the role of increased TSLP expression in acute dermatitis. LR-B or LR-BCA induced IκBα degradation and NF-κB activation in keratinocytes, leading to TSLP expression. Collectively, our results demonstrate that LR-B and LR-BCA increase TSLP expression and Th2 immune responses, thereby aggravating acute dermatitis in the compromised skin. The results further suggest that certain cosmetic colorants such as LR-B may aggravate dermatitis under pro-inflammatory conditions by upregulating TSLP production.
Synthesis and biological investigation of new carbonic anhydrase IX (CAIX) inhibitors Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Kranthi Vanchanagiri, Daniel Emmerich, Monique Bruschke, Matthias Bache, Franziska Seifert, René Csuk, Dirk Vordermark, Reinhard Paschke
In this report, we describe the synthesis, characterization, in vitro anticancer activity and Carbonic anhydrase IX (CAIX) inhibition of new sulfamate conjugates of Betulin and Betulinic acid (BA). The betulinyl sulfamates were subjected to inhibit carbonic anhydrases (CA), e.g. CAIX, an attractive target for tumor-selective therapy strategies in cancer cells. Data on combined in vitro antitumor activity with CAIX inhibition are very rare. The betulinyl sulfamates were tested against five tumor cell lines and normal human skin fibroblasts. The mode of cell death on MCF7 breast cancer cells induced by the most active compounds CAI1, CAI3 and CAI6 was investigated by Fluorescence Activated Cell Sorting (FACS) experiments. The compounds showed inhibitory activity towards CAIX, which was determined via in vitro enz-yme assay. Our preliminary investigations revealed that all compounds showed potent anticancer properties with IC50 values below 20 μM against all tumor cells. Interestingly, among the panel of sulfamate conjugates, CAI3 found to be highly cytotoxic (average IC50 = 5–10 μM) and possess high inhibitory activity (Ki = 1.25 nM) towards CAIX. Our results suggest that betulinyl sulfamates seem to be attractive substances, due to their possibility of targeted drug delivery they deserve to be proceeded for further pre-clinical (kinetic studies) and in vivo investigations.
Sulfenamide and sulfonamide derivatives of metformin can exert anti-coagulant and pro-fibrinolytic properties Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Magdalena Markowicz-Piasecka, Kristiina M. Huttunen, Łukasz Mateusiak, Elżbieta Mikiciuk-Olasik, Joanna Sikora
Type 2 diabetes mellitus (T2DM) is characterised not only by hyperglycaemia and insulin resistance but also an impaired balance between the processes of coagulation and fibrinolysis. The aim of this study was to examine the effects of metformin, a widely-used oral anti-diabetic drug, phenformin and eight sulfenamide and sulfonamide derivatives of metformin on several haemostasis parameters. Thrombin Time (TT) tests were performed according to the available commercial method. The activity of factor X was conducted based on deficient plasma factor X. The activity of two main enzymes involved in haemostasis, thrombin and plasmin, was measured spectrophotometrically with chromogenic substrates. Protein C and antithrombin III (AT) activity assays using chromogenic substrates were conducted to determine the effect of the derivatives of metformin on these both naturally occurring anticoagulants. Two of the compounds, sulfenamide with hexyl tail and para-nitro-benzenesulfonamide significantly shortened TT. ortho-nitro sulfonamide at a concentration of 0.3–1.5 μmol/mL contributed to a significant decrease in the activity of factor X. However, sulfenamides with cyclohexyl, butyl and branched ethyl-hexyl tails at 1.5 of μmol/mL increased its activity, and simultaneously shortened PT. Additionally, ortho-nitro-benzenesulfonamide at concentrations of 1.5 μmol/mL was found to significantly decrease reaction velocity (↓ dA/dt) in the thrombin activity assay. On contrary, it was noticed that branched sulfenamide at the concentration of 1.5 μmol/mL significantly increased the enzymatic activity of plasmin. Metformin, phenformin and octyl and butyl sulfenamides were associated with a significant increase in the activity of AT. Hexyl sulfenamide and para-nitro- as well as para-trifluoro-ortho-nitro-benzenesulfonamide contributed to the decrease in the activity of protein C, while the other tested compounds did not affect its activity. In conclusion, 2-nitro-benzenesulfonamide derivative of metformin presents highly beneficial anticoagulant properties. This compound is therefore promising candidate for further in vitro and in vivo studies.
Synergistic and additive effects of ATRA in combination with different anti-tumor compounds Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Eduarda Schultze, Tiago Collares, Caroline Lucas, Fabiana K. Seixas
All-trans retinoic acid (ATRA), a derivative of vitamin A, has been shown to potentiate cancer chemotherapy due to its ability to induce signals for cell differentiation or death, and inhibit cell proliferation. The combination of ATRA with taxoids, kinase inhibitors, natural compounds, retinoids, ER or HER2 inhibitors, chemotherapeutic drugs, proteasome inhibitors and nanoformulations of tretinoin have demonstrated additive or synergistic effects in anti-cancer activities. The mechanisms by which the compounds exert their synergistic effects depend on the tumor and the cell type. However, several experiments demonstrated similar mechanisms such as reduction of PCK, c-myc, E2F and Bcl-2, as well as increase of p21 and TGF-β. When the apoptotic synergistic effect was observed, the predominant effect of ATRA was in differentiation induction. The results indicate that future combinations of ATRA and anti-tumor agents hold promise to enhance and improve anti-carcinogenic therapies.
Raffinose from Costus speciosus attenuates lipid synthesis through modulation of PPARs/SREBP1c and improves insulin sensitivity through PI3K/AKT Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Muthukumaran Padmanaban, Thiyagarajan Gopal, Arun Babu Rajendran, Baddireddi Subhadra Lakshmi
Among several metabolic disorders, the pathogenesis of insulin resistance is considered to be multifactorial. Raffinose, an oligosaccharide isolated from the rhizome of Costus speciosus showed ≤50% inhibition of lipid accumulation in differentiated HepG2 and 3T3-L1 cells through exhibiting partial agonism to PPARγ, and, an enhanced secretion of adiponectin in 3T3-L1 adipocytes. Raffinose was also observed to attenuate the expression of SREBP1c, ACC and FAS which are involved in the fatty acid synthesis. A corresponding upregulation of PPARα and ACO involved in fatty acid oxidation was observed in steatotic HepG2 hepatocytes and 3T3-L1 adipocytes. In vitro evaluation of its anti-diabetic potential showed a dose dependent enhancement of glucose uptake. Investigation of the insulin sensitizing efficacy of Raffinose revealed an increase in Glut4 translocation via phosphorylation of IRβ/PI3K/Akt in differentiated L6 myocytes and 3T3-L1 preadipocytes. In addition, Raffinose was potentially involved in glycogen synthesis by inhibiting the activation of GSK3β. Hence, Raffinose could be a useful therapeutic agent for metabolic maladies.
Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Yunyi Dai, Haojie Zhang, Jianping Zhang, Mingguang Yan
Isoquercetin (Iso) has been found to have neuroprotective effects against cerebral ischemic stroke. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. In this study, we aimed to evaluate the neuroprotective effects of Iso in primary culture of rat hippocampal neurons exposed to oxygen and glucose deprivation and reperfusion (OGD/R) injury and in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) injury. We found that rats treated with Iso exhibited a lower degree of infarct volume, and brain water content than the vehicle-treated rats. Treatment with Iso also improved the neurological deficits in MCAO/R rats as shown by the decreased modified neurological severity score. Iso treatment decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) production, and increased the activity of superoxide dismutase (SOD) and catalase (CAT) in brains of MCAO/R rats and primary culture of rat hippocampal neurons exposed to OGD/R. Iso treatment prevents I/R-induced neuronal apoptosis in vivo and in vitro as indicated by increased cell viability and decreased number of TUNEL-positive cells, accompanying with downregulation of cleaved caspase-3 protein and upregulation of Bcl-2 protein. Moreover, Nrf2 knockdown weakened the anti-apoptotic and anti-oxidant activities of Iso in primary culture of rat hippocampal neurons exposed to OGD/R. Interestingly, we found that Iso could induce Nrf2 translocation from cytoplasm to nucleus in primary culture of rat hippocampal neurons exposed to OGD/R. Iso activated the NOX4/ROS/NF-κB signaling pathway in in vivo and in vitro cerebral I/R injury models. Nrf2 knockdown blocked the inhibitory effect of Iso on protein expression of NOX4, p-IκBα and p-p65 in primary culture of rat hippocampal neurons exposed to OGD/R. All the data suggested that Iso protected against oxidative stress and neuronal apoptosis in in vivo and in vitro cerebral I/R injury models via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB signaling pathway. Our findings suggested that Iso could be a potential agent for I/R brain injury.
Selenium deficiency aggravates T-2 toxin-induced injury of primary neonatal rat cardiomyocytes through ER stress Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-16 Jing Xu, Shengchi Pan, Fang Gan, Shu Hao, Dandan Liu, Haibin Xu, Kehe Huang
Keshan disease is a potentially fatal cardiomyopathy in humans. Selenium deficiency, T-2 toxin, and myocarditis virus are thought to be the major factors contributing to Keshan disease. But the relationship among these three factors is poorly described. This study aims to explore whether selenium deficiency aggravates T-2 toxin-induced cardiomyocyte injury and its underlying mechanism. Cardiomyocytes were isolated from neonatal rat and cultured at the physiological (2.0 μM) or lower concentrations of selenium with different concentrations of T-2 toxin. Our results showed that selenium deficiencies aggravated T-2 toxin-induced cardiomyocyte injury in a concentration-dependent manner as demonstrated by MTT bioassay, LDH activity, reactive oxygen species levels and caspase 3 protein expressions. T-2 toxin treatment significantly increased mRNA expressions for stress proteins GRP78 and CHOP in cardiomyocytes compared with the control. Selenium deficiencies further promoted GRP78, CHOP and p-eIF2α expressions. Knockdown of CHOP by the specific small interfering RNA eliminated the effect of selenium deficiencies on T-2 toxin-induced injury. It could be concluded that selenium deficiency aggravates T-2 toxin-induced cardiomyocyte injury through initiating more aggressive endoplasmic reticulum stress.
Evaluation of lipid peroxidation and antioxidant defense mechanisms in the bone of rats in conditions of separate and combined administration of vanadium (V) and magnesium (Mg) Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-14 Agnieszka Ścibior, Dorota Gołębiowska, Agnieszka Adamczyk, Joanna Kurus, Magdalena Staniszewska, Ilona Sadok
Glycyrrhizin attenuates histamine-mediated MUC5AC upregulation, inflammatory cytokine production, and aquaporin 5 downregulation through suppressing the NF-κB pathway in human nasal epithelial cells Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-13 Haixia Li, Dandan Guo, Liangran Zhang, Xiao Feng
Allergic rhinitis (AR) is a chronic respiratory inflammatory disease. Glycyrrhizin is a main bioactive component of the licorice root extract and exhibits anti-inflammatory activity. However, the role of glycyrrhizin in AR has not been studied. The aim of the present study was to investigate the effect of glycyrrhizin on histamine-induced human nasal epithelial cells (HNEpCs). Here, we found that glycyrrhizin (20 or 40 μM) inhibited histamine-induced the mRNA expression and secretion of mucin 5 subtype AC (MUC5AC), interleukin (IL)-6 and IL-8 in HNEpCs. The expression levels of aquaporin 5 (AQP5) and phosphorylated cyclic adenosine monophosphate-responsive element binding protein (p-CREB) were decreased by histamine in HNEpCs and increased in cells treated with glycyrrhizin. The glycyrrhizin treatment inhibited histamine-induced expressions of p-NF-κB p65 and p-IκBα in HNEpCs, indicating that glycyrrhizin inhibited the activation of NF-κB pathway in histamine-induced HNEpCs. In addition, inhibition of the NF-κB pathway exhibited the similar effect with glycyrrhizin on histamine-induced HNEpCs. In summary, the results showed that glycyrrhizin reversed the effect of histamine on MUC5AC expression, inflammatory cytokine production, and AQP5 expression in HNEpCs, and the NF-κB pathway was involved in the effect. Glycyrrhizin might be used for complementary and alternative therapeutics of AR.
Corrigendum to “Transient gestational exposure to drinking water containing excess hexavalent chromium modifies insulin signaling in liver and skeletal muscle of rat progeny” [Chem. Biol. Interact. 277 (2017) 119–128] Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-09 N. Shobana, M.M. Aruldhas, L. Tochhawng, A. Loganathan, S. Balaji, M.K. Kumar, L.A.S. Banu, A.K. Navin, C. Mayilvanan, R. Ilangovan, K. Balasubramanian
Hyperpolarization by N-(3-oxododecanoyl)-L-homoserine-lactone, a quorum sensing molecule, in rat thymic lymphocytes Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-08 Yumiko Nishimura-Danjobara, Keisuke Oyama, Kumio Yokoigawa, Yasuo Oyama
To study the adverse effects of N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule, on mammalian host cells, its effect on membrane potential was examined in rat thymic lymphocytes using flow cytometric techniques with a voltage-sensitive fluorescent probe. As 3–300 μM ODHL elicited hyperpolarization, it is likely that it increases membrane K+ permeability because hyperpolarization is directly linked to changing K+ gradient across membranes, but not Na+ and Cl− gradients. ODHL did not increase intracellular Ca2+ concentration. ODHL also produced a response in the presence of an intracellular Zn2+ chelator. Thus, it is unlikely that intracellular Ca2+ and Zn2+ are attributed to the response. Quinine, a non-specific K+ channel blocker, greatly reduced hyperpolarization. However, because charybdotoxin, tetraethylammonium chloride, 4-aminopyridine, and glibenclamide did not affect it, it is pharmacologically hypothesized that Ca2+-activated K+ channels, voltage-gated K+ channels, and ATP-sensitive K+ channels are not involved in ODHL-induced hyperpolarization. Although the K+ channels responsible for ODHL-induced hyperpolarization have not been identified, it is suggested that ODHL can elicit hyperpolarization in mammalian host cells, disturbing cellular functions.
Limonene: Aroma of innovation in health and disease Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-07 A.J. Vieira, F.P. Beserra, M.C. Souza, B.M. Totti, A.L. Rozza
Natural products obtained in dietary components may aid the prevention and treatment of a variety of diseases. Reports in the scientific literature have demonstrated that the consumption of terpenes is a successful alternative in the treatment of several diseases, triggering beneficial biological effects in clinical and preclinical studies. The monoterpene limonene is largely used in alimentary items, cleaning products, and it is one of the most frequent fragrances used in cosmetics formulation. The therapeutic effects of limonene have been extensively studied, proving anti-inflammatory, antioxidant, antinociceptive, anticancer, antidiabetic, antihyperalgesic, antiviral, and gastroprotective effects, among other beneficial effects in health. In this review, we collected, presented, and analyzed evidence from the scientific literature regarding the usage of limonene and its activities and underlying mechanisms involved in combating diseases. The highlighting of limonene applications could develop a useful targeting of innovative research in this field as well as the development of a limonene-based phytomedicine which could be used in a variety of conditions of health and disease.
Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-05 Jing Xue, Rui Li, Xinrui Zhao, Congcong Ma, Xin Lv, Lidong Liu, Peishu Liu
Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-05 Ruma Rani, Shakti Dahiya, Dinesh Dhingra, Neeraj Dilbaghi, Ki-Hyun Kim, Sandeep Kumar
miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-05 Hao Luo, Hairong Liang, Yuting Chen, Shaoyun Chen, Yongchun Xu, Longmei Xu, Jiaxian Liu, Kairu Zhou, Jucheng Peng, Guoqiang Guo, Bei Lai, Li Song, Hui Yang, Linhua Liu, Jianming Peng, Zhidong Liu, Lin Tang, Wen Chen, Huanwen Tang
Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-03 Hadeer O. Abou-Hany, Hoda Atef, Eman Said, Hassan Elkashef, Hatem A. Salem
Diabetic Nephropathy (DN) is one of the main complications associated with diabetes mellitus. Persistently elevated blood glucose level drives histopathological changes in renal tissues that hinder normal kidney functions. In the current study, crocin; the main bioactive constituent of Crocus sativus was investigated as a reno-protective agent against DN by virtue of its numerous pharmacological activities. Diabetes was induced in male Sprague-Dawely rats through intravenous injection of streptozocin (STZ) (50 mg/kg), DN was confirmed eight weeks post diabetes induction. Daily oral crocin for eight weeks (20 mg/kg) significantly reduced blood glucose level with a significant increase in insulin level. Moreover, crocin improved impaired kidney functions as manifested in reduction of serum creatinine levels, blood urea nitrogen and proteinuria with concomitant increase in urinary creatinine clearance. Furthermore, biomarkers of cell injury and tissue necrosis like LDH were significantly reduced, kidney content of NOS significantly declined likewise. In addition, renal antioxidants such as SOD, GSH and serum catalase activity significantly increased with concomitant reduction of kidney MDA; biomarker of oxidative load. Kidney content of toll-like receptors 4 and IL-6 significantly declined as well. Furthermore, crocin inhibited progression of renal fibrosis as seen with reduction of renal hydroxyproline and collagen content. Histopathologically, crocin pretreatment was associated with minimal renal damage with fewer fibrotic lesions. There was a concomitant restoration of renal tubules integrity with preservation of glomerular space area. In conclusion, crocin's ameliorative impact on DN may be attributed to its deleterious free radicals scavenging properties, its ability to enhance host antioxidant defense system and to inhibit inflammatory cascade activation.
Ginsenoside F1 suppresses astrocytic senescence-associated secretory phenotype Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-03 Jingang Hou, Changhao Cui, Sunchang Kim, Changkeun Sung, Chulhee Choi
Senescence is one of the hallmarks of aging and identified as a potential therapeutic target in the treatment of aging and aging-related diseases. Senescent cells accumulate with age in a variety of human tissues where they develop a complex senescence-associated secretory phenotype (SASP). SASP in brain could contribute to age-related inflammation and chronic neurodegenerative diseases. We confirmed that senescent astrocytes express a characteristic of SASP in vitro by human cytokine antibody array. Ginsenoside F1 suppresses the SASP from astrocytes induced by D-galactose via suppressing p38MAPK-dependent NF-κB activity. A specific inhibitor of p38MAPK, SB203580 significantly decreased the secretion of IL-6 and IL-8, the major components of SASPs. Additionally, treatment of senescent astrocytes with NF-κB inhibitor, BAY 11–7092, also suppressed the secretion of IL-6 and IL-8, suggesting NF-κB was required for SASP. Importantly, conditioned media from senescent astrocytes promoted the migration of glioblastoma cells, such as U373-MG, U251-MG and U87-MG assessed by scratch wound healing. This migration was significantly decreased by F1 treatment in senescent astrocytes. Interestingly, IL-8, the main mediator regulating glioblastoma cell invasion, was suppressed in both transcriptional and protein level. Herein, we propose ginsenoside F1 as a potential therapeutic strategy for reducing the deleterious contribution of senescent astrocytes in aged brain and related diseases.
Involvement of bone morphogenetic protein–related pathways in the effect of aucubin on the promotion of osteoblast differentiation in MG63 cells Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-03 Yutong Li, Wenji Hu, Guanghong Han, Wenqian Lu, Dongxu Jia, Min Hu, Di Wang
Aucubin, an iridoid glycoside found in several plants, such as Eucommia ulmoide and Rehmannia, has various pharmacological effects. Bone formation is a complex process in which osteoblast differentiation plays an important role. This study aimed to investigate the promotion effects of aucubin on osteoblast differentiation in MG63 cells, a human osteoblast-like cell line. Aucubin not only improved osteoblast differentiation, as shown by enhanced ALP (alkaline phosphatase) concentration and mineralization in cells, but increased the expression of various cytokines, including collagen I, osteocalcin, osteopontin, integrin β1, and Osterix. Aucubin strongly enhanced the levels of BMP2 (bone morphogenetic proteins-2) in MG63 cells, which play a central role during osteoblast differentiation. Further data show that aucubin exposure after 1 day, 7 days, and 14 days enhanced the expression of Smad1, 5, and 8, and the phosphoresced levels of MAPKs (mitogen-activated protein kinases) family Erk (extracellular signal–regulated kinases), JNK (c-Jun-NH2-terminal kinases), P38, and Akt (serine/threonine protein kinase)/mTOR (mammalian target of rapamycin)/p70s6k in MG63 cells. This study shows the improved effects of aucubin on osteoblast differentiation in MG63 cells, related to the signaling of BMP2-mediated Smads (drosophila mothers against decapentaplegic proteins), MAPKs, and Akt/mTOR/p70S6K. This study indicates the potential of aucubin for osteoporosis treatment.
Drug-induced thrombocytopenia: Focus on platelet apoptosis Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-02 Enoli De Silva, Hugh Kim
Thrombocytopenia is a serious and potentially fatal complication of drug therapy that results either from a decrease in bone marrow platelet production or the excessive destruction of circulating platelets. Although multiple mechanisms are responsible for deregulated platelet clearance, the role of programmed platelet death (apoptosis) in drug-induced thrombocytopenia has been relatively under-investigated until recently. Here we review apoptotic signaling pathways in platelets, with a focus on current data that provide mechanistic insights into drug-induced apoptosis and thrombocytopenia.
New 1,3-benzodioxole derivatives: Synthesis, evaluation of in vitro schistosomicidal activity and ultrastructural analysis Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-31 Luana Maria Mariz Gomes da Silva, Jamerson Ferreira de Oliveira, Willams Leal Silva, Anekecia Lauro da Silva, Antônio Sérgio Alves de Almeida Junior, Victor Hugo Barbosa dos Santos, Luiz Carlos Alves, Fábio André Brayner dos Santos, Vlaudia Maria Assis Costa, André de Lima Aires, Maria do Carmo Alves de Lima, Monica Camelo Pessoa de Azevedo Albuquerque
Schistosomiasis is considered a serious public health problem in 78 countries and territories located in Africa, Asia and America and it is estimated in more than 249 million people infected by any of the species of Schistosoma. The exclusive use of praziquantel (PZQ), effective drug against all species of Schistosoma, has been the basis of the development of a possible resistance against the strains of this parasite. In addition, PZQ is not effective against young forms of worms. Thus, there is a need for the development of new drugs with schistosomicidal activity. The objective of this work was to synthesize and to evaluate the therapeutic potential of new benzodioxole derivatives (3–14) candidates for schistosomicidal drugs. All compounds synthesized showed in vitro schistosomicidal activity. The derivative 12 was considered the best compound, since it took 100% of worms to mortality in the first 72 h of exposure at the concentration of 100 μM and 83.3% at the concentration of 50 μM. Furthermore, male and female adult worms, incubated for 24 h with the compound 12 showed tegument damages characterized by extensive desquamation and edema, tuber destruction, bubble formation and exposure of the muscle layer. This compound has a restricted structure, where the thiazolidinone is attached to the 4-position of the 1,3-benzodioxol ring. The structural conformation of derivative 12 was probably responsible for the promising schistosomicidal activity, where the presence of an electron/conformational restriction of the thiazolidine ring, as well as the action of bromine as a bulk substitute, favored an increase in biological activity. In addition, tegumentary changes caused by derivative 12 may also have been responsible for the death of adult worms of Schistosoma mansoni. Therefore, we verified that the results obtained in this study make benzodioxole derivatives possible candidates for prototypes of new schistosomicidal drugs.
Effects of cerium oxide nanoparticles on differentiated/undifferentiated human intestinal Caco-2 cells Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-31 Laura Vila, Alba García-Rodríguez, Constanza Cortés, Antonia Velázquez, Noel Xamena, Adriana Sampayo-Reyes, Ricard Marcos, Alba Hernández
Since ingestion constitute one of the main routes of nanoparticles (NPs) exposure, intestinal cells seems to be a suitable choice to evaluate their potential harmful effects. Caco-2 cells, derived from a human colon adenocarcinoma, have the ability to differentiate forming consistent cell monolayer structures. For these reasons Caco-2 cells, both in their undifferentiated or differentiated state, are extendedly used. We have used well-structured monolayers of differentiated Caco-2 cells, as a model of intestinal barrier, to evaluate potential harmful effects associated to CeO2NPs exposure via ingestion. Different parameters such as cell toxicity, monolayer integrity and permeability, cell internalization, translocation through the monolayer, and induction of DNA damage were evaluated. No toxic effects of CeO2NPs were observed, independently of the differentiated state of the Caco-2 cells. In the same way, no effects on the monolayer integrity/permeability were observed. Although important cell uptake was demonstrated in undifferentiated cells (by using confocal microscopy), CeO2NPs remained mostly attached to the apical membrane in the differentiated cells. In spite of this apparent lack of uptake in differentiated cells, translocation of CeO2NPs to the basolateral chamber was observed by using confocal microscopy. Finally no genotoxic effects were observed when the comet assay was used, although decreases in the levels of oxidized bases were observed, supporting the antioxidant role of CeO2NPs.
Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-31 Pablo Zambrano, Mario Suwalsky, Malgorzata Jemiola-Rzeminska, Kazimierz Strzalka
Memantine is an NMDA receptor antagonist clinically used for the treatment of moderate to severe Alzheimer's disease. Currently, it is the only NMDA receptor antagonist drug marketed against this disease. Despite the large number of publications regarding its clinical and therapeutic use, studies related to its mechanism of action are still inconclusive. Knowledge of drug interactions with cell membranes may lead to the development of novel drugs for neurodegenerative diseases. The present mini-review aims to give an overview of the latest findings regarding the interaction of memantine with cell membranes, specifically with that of the human erythrocyte.
Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-17 Aïcha Sassi, Mouna Maatouk, Dorra El gueder, Imen Mokdad Bzéouich, Saïda Abdelkefi-Ben Hatira, Saloua Jemni-Yacoub, Kamel Ghedira, Leila Chekir-Ghedira
Caffeine-supplemented diet modulates oxidative stress markers and improves locomotor behavior in the lobster cockroach Nauphoeta cinerea Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-13 Cícera Simoni da Silva, Rita de Cássia Gonçalves de Lima, Olusola Olalekan Elekofehinti, Yetunde Ogunbolude, Antonia Eliene Duarte, João Batista Teixeira Rocha, Irwin Rose Alencar de Menezes, Luiz Marivando Barros, Appolinaire Tsopmo, Kiven Erique Lukong, Jean Paul Kamdem
The in vitro radiosensitizer potential of resveratrol on MCF-7 breast cancer cells Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12 Isabel Cristina da Costa Araldi, Fernando Primitivo Romero Bordin, Francine Carla Cadoná, Fernanda Barbisan, Verônica Farina Azzolin, Cibele Ferreira Teixeira, Tadeu Baumhardt, Ivana Beatrice Mânica da Cruz, Marta Maria Medeiros Frescura Duarte, Liliane de Freitas Bauermann
Radiation therapy is commonly applied in breast cancer (BC) patients. However, radioresistance and side effects are limiting factors of this practice. Therefore, studying substances that can enhance the radiation effect and, at the same time, protect normal cells is very relevant. Thus, the aim of this work was to assess the radiosensitizer effect of resveratrol (RV) on BC cells (MCF-7). A high cytotoxic and antiproliferative effect was observed in the treatment with 10 μM of RV + 3 Gy ionizing radiation (IR). Our results indicate that, 24 h after the exposition of cell cultures to RV + IR, an induction of necrosis/senescence has occurred. Furthermore, was observed the activation of extrinsic apoptosis pathway through a decrease of the Bax/Bcl-2 ratio and a high activity of caspase 8. Moreover, our data show that this treatment affected the oxidative cell metabolism, increasing oxidative protein, lipid and membrane damage and also acted to decrease the antioxidant enzymes activity. The antiproliferative effect on 72 h cultures may be associated with a high expression of p53 and an interruption of cell cycle in the S phase. Therefore, our results suggest that RV is a potential radiosensitizer of MCF-7 BC cells.
Effects of rutin on the physicochemical properties of skin fibroblasts membrane disruption following UV radiation Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12 Izabela Dobrzyńska, Agnieszka Gęgotek, Ewelina Gajko, Elżbieta Skrzydlewska, Zbigniew A. Figaszewski
Human skin provides the body's first line of defense against physical and environmental assaults. This study sought to determine how rutin affects the membrane electrical properties, sialic acid content, and lipid peroxidation levels of fibroblast membranes after disruption by ultraviolet (UV) radiation. Changes in cell function may affect the basal electrical surface properties of cell membranes, and changes can be detected by electrokinetic measurements. The charge density of the fibroblast membrane surface was measured as a function of pH. A four-component equilibrium model was used to describe the interaction between ions in solution and ions on the membrane surface. Agreement was found between experimental and theoretical charge variation curves of fibroblast cells between pH 2.5 and 8. Sialic acid content was determined by Svennerholm's resorcinol method, and lipid peroxidation was estimated by measuring the malondialdehyde level. Compared to untreated cells, ultraviolet A (UVA)- or ultraviolet B (UVB)-treated skin cell membranes exhibited higher concentrations of acidic functional groups and higher average association constants with hydroxyl ions, but lower average association constants with hydrogen ions. Moreover, our results showed that UVA and UVB radiation is associated with increased levels of sialic acid and lipid peroxidation products in fibroblasts. Rutin protected cells from some deleterious UV-associated membrane changes, including changes in electrical properties, oxidative state, and biological functions.
Protective effect of patchoulene epoxide against ethanol-induced gastric ulcer in rats: Influence on oxidative stress, inflammation and apoptosis Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12 Jiali Liang, Yaoxing Dou, Xue Wu, Huilin Li, Jiazhen Wu, Qionghui Huang, Dandan Luo, Tiegang Yi, Yuhong Liu, Ziren Su, Jianping Chen
Patchoulene epoxide (PAO), a tricyclic sesquiterpene isolated from the long-strored patchouli oil, has been demonstrated the anti-inflammatory activity in vivo based on our previous study. However, the gastroprotective effect of PAO still remains unknown. Therefore, in the present study, ethanol-induced gastric ulcer in rats was carried out to evaluate the anti-ulcerogenic activity of PAO and to elucidate the potential mechanisms that involved. According to our results, macroscopic examination revealed that pre-treatment with PAO signficantly reduced ethanol-induced gastric ulcer areas as compared with the vehicle group, which was also supported by histological evaluation. In addition, PAO was able to enhance the expressions of antioxidant enzymes including glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) as well as suppress lipid peroxidation indicated by down-regulation of malonaldehyde (MDA). Besides, the anti-inflammatory activity of PAO also contributed to gastroprotection characterized by reversing the imbalance between pro- and anti-inflammatory cytokines and modulating the expressions of NF-κB pathway-related proteins including p-IκBα, IκBα, p-p65 and p65. Furthermore, immunohistochemistry analysis exhibited potent anti-apoptosis effect of PAO as well, which appeared as down-regulation of caspase-3, Fas and Fasl protein expression. In conclusion, these findings suggested that PAO has gastroprotective activity against ethanol and this might be related to its positive influence on oxidative stress, inflammatory response and apoptosis cascade.
In vitro and in vivo metabolic activation of rhein and characterization of glutathione conjugates derived from rhein Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-11 Yang Xu, Xu Mao, Boyang Qin, Ying Peng, Jiang Zheng
Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH. M1 was also observed in rat and human liver microsomal incubations after exposure to RH. A total of three (GSH) conjugates (M2, M3 and M5) were detected in bile of rats treated with RH. We concluded that M2-M3 were directly derived from parent compound RH through spontaneous reaction with GSH. M5 was derived from M1 by reaction with GSH, which required cytoslic GSTs. M5 was further metabolized to the corresponding NAC conjugate (mercapturic acid) and was excreted in urine. P450 2C9 was mainly involved in the oxidation of RH.
Gallic acid attenuates type I diabetic nephropathy in rats Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10 Mayuresh Sudamrao Garud, Yogesh Anant Kulkarni
Literatures suggest that TGF-β1 have a central role in the progression of diabetic nephropathy and its down regulation can improve the disease condition. Oxidative stress, generation of advanced glycation end products and activation of renin angiotensin system are the connecting links between hyperglycemia and TGF-β1 over expression. Gallic acid is a phytochemical having wide range of biological activities. Gallic acid is reported to have antioxidant and advanced glycation inhibitory activity. It has also shown inhibitory effects on angiotensin converting enzyme. Gallic acid qualifies as a drug candidate to be tested in the diabetic nephropathy, one of the important complication of diabetes. Streptozotocin (55 mg/kg body weight, i.p.) induced diabetic nephropathy was used as an experimental model. Gallic acid was evaluated for its possible effect at the dose of 20 and 40 mg/kg body weight. Gallic acid treatment significantly lowered plasma levels of the creatinine and blood urea nitrogen and elevated the levels of the protein and albumin. Gallic acid also improved creatinine clearance. Determination of oxidative stress parameters showed that the oxidative stress in kidney tissues was reduced significantly in gallic acid treated animals. Results of the Plasma, urine and oxidative stress parameters were also reflected in the histo-pathological evaluation showing improvement in kidney patho-physiology. ELISA assay for circulating TGF-β1 evaluation and immunohistochemical study for determination of kidney expression of TGF-β1 revealed that gallic acid significantly lowered both the circulating and tissue levels of TGF-β1. Results supports the hypothesis that gallic acid can be effectively used in the treatment of diabetic nephropathy.
Salinomycin induces primary chicken cardiomyocytes death via mitochondria mediated apoptosis Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10 Xiuge Gao, Yani Zheng, Xiangchun Ruan, Hui Ji, Lin Peng, Dawei Guo, Shanxiang Jiang
Salinomycin, as a polyether ionophore antibiotic, is extensively used as a feed additive against coccidiosis in poultry and as a growth promoter of ruminants worldwide. Owing to its narrow therapeutic index, numerous intoxication have been reported in target/non-target animals by overdosage, misuse or drug interactions as well as human who consumed salinomycin accidently. Salinomycin-induced cardiotoxicity in chicken and non-target animals is considered as a major contributor to animal death. In the current study, we aim to elucidate the underlying mechanism of its myocardial toxicity using primary chicken myocardial cell as an in vitro model. The results showed that salinomycin altered cellular morphology and induced cell death in a concentration-dependent manner. Salinomycin treatment elevated the permeability of the cell membrane and leaded to the efflux of enzymes, including creatine kinase (CK) and lactate dehydrogenase (LDH). Flow cytometry analysis indicated the number of apoptotic cells increased significantly by salinomycin exposure. Furthermore, caspase-3 and caspase-9 were activated at gene and protein level rather than caspase-8, along with the up-regulation of apoptosis genes Bax, Cytochrome C, Apoptotic peptidase activating factor 1 (Apaf-1) and the down-regulation of Bcl-2. Salinomycin-induced mitochondrial dysfunction was accompanied by the significant decrease of mitochondrial membrane potential (MMP) and the severe ultrastructure damage. In conclusion, these findings suggest that the toxic dose of salinomycin induces severe cardiomyocytes death through mitochondria mediated apoptosis pathway.
Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10 Zhenyu Shen, Yu Wang, Zhenhui Su, Ruirui Kou, Keqin Xie, Fuyong Song
Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.
Bioactivation of 1-chloro-2-hydroxy-3-butene, an in vitro metabolite of 1,3-butadiene, by rat liver microsomes Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10 Ye Wang, Ying-Xin Yu, Yang Luan, Jing An, Dong-Guang Yin, Xin-Yu Zhang
Coagonist of GLP-1 and glucagon decreases liver inflammation and atherosclerosis in dyslipidemic condition Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-08 Vishal Patel, Amit Joharapurkar, Samadhan Kshirsagar, Brijesh Sutariya, Maulik Patel, Dhreerendra Pandey, Hiren Patel, Ramchandra Ranvir, Shekhar Kadam, Dipam Patel, Rajesh Bahekar, Mukul Jain
Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects. Here, we investigated the role of coagonist of GLP-1 and glucagon receptors in complications of diet-induced dyslipidemia in hamsters and humanized double transgenic mice. Hamsters fed on high fat high cholesterol diet were treated for 8 weeks with coagonist of GLP-1 and glucagon receptors (75 and 150 μg/kg). Pair-fed control was maintained. Cholesterol fed transgenic mice overexpressing hApoB100 and hCETP with coagonist (300 μg/kg) for 4 weeks. After the completion of treatment, biochemical estimations were done. Coagonist treatment reduced triglycerides in plasma, liver and aorta, plasma cholesterol and hepatic triglyceride secretion rate. Expressions of HMG-CoA reductase and SBREBP-1C were reduced and expressions of LDLR, CYP7A1, ABCA1 and ABCB11 were increased in liver, due to coagonist treatment. Coagonist treatment increased bile flow rate and biliary cholesterol excretion. IL-6 and TNF-α were reduced in plasma and expression of TNF-α, MCP-1, MMP-9 and TIMP-1 decreased in liver. Treatment with coagonist reduced oxidative stress in liver and aorta. Energy expenditure was increased and respiratory quotient was reduced by coagonist treatment. These changes were correlated with reduced hepatic inflammation and lipids in liver and aorta in coagonist treated hamsters. Coagonist treatment also reduced lipids in cholesterol-fed transgenic mice. These changes were independent of glycaemia and anorexia observed after coagonist treatment. Long term treatment with coagonist of GLP-1 and glucagon receptor ameliorated diet-induced dyslipidemia and atherosclerosis by regulating bile homeostasis, liver inflammation and energy expenditure.
Interaction of DNA with water soluble complex of Nickle and formation of DNA cross-links Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-08 Maryam Nejat Dehkordi, Bjorn Akerman
Interaction of double stranded DNA with bulky and hydrophobic Salen type Schiff base complex: [N, N′ Bis [3- tert-butyl-5-[triphenyl-phosphonium – methyl] - salicylidene] 1,2 ethylene-diamine nickel(III) acetate (refer to Ni Salen complex) was extensively investigated using the spectroscopic techniques and gel electrophoresis. Absorption titration experiment showed the hypochromic effect and the significant red shift of the complex absorption. In competition experiments with ethidium bromide (EB), Ni Salen complex exhibited non-competitive binding at high concentrations. UV-vis absorption and fluorescence emission data agreed on a binding constant of (1.64 ± 0.01) μM−1, thereby showing the strong interaction of the complex with DNA; also, a binding site size of 2.33 ± 0.01 base pairs per complex was achieved. Thermal denaturation experiment showed that Tm of calf thymus-DNA was increased by approximately 10 °C at a molar ratio of the dye/base of 0.2. The CD spectra of DNA exhibited an increase in both positive and negative peaks without any shift in the position of bands upon addition of the complex. The amplitude of the LD spectra of DNA was decreased in the presence of the complex. Reduced linear dichroism (LDred) revealed that the transition moment of complex was parallel to the DNA helix axis. Gel electrophoresis experiments confirmed that Ni Salen complex had no nuclease/DNA cleaving activity; also, DNA-DNA cross links were formed at high concentrations of complex, leading to the aggregation of DNA.
Arctigenin protects against ultraviolet-A-induced damage to stemness through inhibition of the NF-κB/MAPK pathway Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-06 See-Hyoung Park, Jae Youl Cho, Sae Woong Oh, Mingyeong Kang, Seung Eun Lee, Ju Ah Yoo, Kwangseon Jung, Jienny Lee, Sang Yeol Lee, Jongsung Lee
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