New insights into the role of melatonin in plants and animals Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-13 Evgenios Agathokleous, Mitsutoshi Kitao, Edward J. Calabrese
Melatonin is a hormone produced in animals by the pineal gland and in plants under stress. Melatonin research has expanded rapidly, affecting an impressive enhancement in the understanding of its functions in plants and animals. However, far less focus has been directed to clarifying the nature of melatonin dose-response relationships. Here, we provide substantial evidence of melatonin-induced biphasic dose-response relationships from a series of independent studies involving plant and animal models. The characteristics of these dose responses are similar to those of the broad toxicological and pharmacological hormesis literature. Our analysis suggests that melatonin, in coordination with the circadian rhythms, is involved in stress adaptive responses, and may act as a conditioning agent protecting organisms against subsequent health threats within an hormetic framework. Incorporation of melatonin-induced hormesis in research protocols has the potential to enhance the treatment of neuropsychiatric diseases, cancers, and other animal diseases, as well as protection against environmental stress and to increase plant productivity.
Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-13 Kamal Dua, Vamshikrishna Malyla, Gautam Singhvi, Ridhima Wadhwa, Rapalli Vamshi Krishna, Shakti Dhar Shukla, Madhur D. Shastri, Dinesh Kumar Chellappan, Pawan Kumar Maurya, Saurabh Satija, Meenu Mehta, Monica Gulati, Nicole Hansbro, Trudi Collet, Rajendra Awasthi, Gaurav Gupta, Alan Hsu, Philip M. Hansbro
Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
Subterminal hydroxyeicosatetraenoic acids: Crucial lipid mediators in normal physiology and disease states Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-10 Sherif M. Shoieb, Ahmed A. El-Sherbeni, Ayman O.S. El-Kadi
Cytochrome P450 (P450) enzymes are superfamily of monooxygenases that hold the utmost diversity of substrate structures and catalytic reaction forms amongst all other enzymes. P450 enzymes metabolize arachidonic acid (AA) to a wide array of biologically active lipid mediators. P450-mediated AA metabolites have a significant role in normal physiological and pathophysiological conditions, hence they could be promising therapeutic targets in different disease states. P450 monooxygenases mediate the (ω-n)-hydroxylation reactions, which involve the introduction of a hydroxyl group to the carbon skeleton of AA, forming subterminal hydroxyeicosatetraenoic acids (HETEs). In the current review, we specified different P450 isozymes implicated in the formation of subterminal HETEs in varied tissues. In addition, we focused on the role of subterminal HETEs namely 19-HETE, 16-HETE, 17-HETE and 18-HETE in different organs, importantly the kidneys, heart, liver and brain. Furthermore, we highlighted their role in hypertension, acute coronary syndrome, diabetic retinopathy, non-alcoholic fatty liver disease, ischemic stroke as well as inflammatory diseases. Since each member of subterminal HETEs exist as R and S enantiomer, we addressed the issue of stereoselectivity related to the formation and differential effects of these enantiomers. In conclusion, elucidation of different roles of subterminal HETEs in normal and disease states leads to identification of novel therapeutic targets and development of new therapeutic modalities in different disease states.
Methyl ferulic acid attenuates liver fibrosis and hepatic stellate cell activation through the TGF-β1/Smad and NOX4/ROS pathways Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-11 Qi Cheng, Chen Li, Cheng-fang Yang, Yu-juan Zhong, Dan Wu, Lin Shi, Li Chen, Yong-wen Li, Li Li
Liver fibrosis is a pathological wound-healing response caused by chronic liver damage due to a virus, autoimmune disorder, or drugs. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Methyl ferulic acid (MFA), a biologically active monomer, has a protective effect on liver injury. However, the effects and roles of MFA in liver fibrosis remain unknown. The purpose of the current study was to investigate the effect of MFA on hepatic fibrosis and the underlying mechanisms. Human hepatic stellate LX-2 cells were exposed to 5 μg/L TGF-β1 for 48 h to stimulate liver fibrosis in vitro. Using MTT, RT-PCR and Western blot analysis, we revealed that MFA significantly inhibited the proliferation of LX-2 cells as well as decreased the expressions of α-SMA and type I collagen in LX-2 cells. SD rats were fed with ethanol, and this combined with the intraperitoneal injection of CCl4 induced liver fibrosis in vivo. We found that the administration of MFA markedly decreased the levels of hyaluronic acid (HA), procollagen type III (PC-III), type IV collagen (CIV) and laminin (LN) in the serum, inhibited the expression of α-smooth muscle actin (α-SMA) as well as type I and type III collagen, and up-regulated the ratio of MMP-2/TIMP-1 in rats. The antifibrotic effects of MFA were also evaluated by H&E staining and Masson's trichrome staining. In addition, further studies suggested that this protection by MFA from liver fibrosis was possibly related to the inhibition of TGF-β1/Smad and NOX4/ROS signalling. In conclusion, our results demonstrate that MFA attenuated liver fibrosis and hepatic stellate cell activation by inhibiting the TGF-β1/Smad and NOX4/ROS signalling pathways.
A new pyrrole based small molecule from Tinospora cordifolia induces apoptosis in MDA-MB-231 breast cancer cells via ROS mediated mitochondrial damage and restoration of p53 activity Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-10 K.C. Rashmi, M. Harsha Raj, Manoj Paul, Kesturu S. Girish, Bharathi P. Salimath, H.S. Aparna
Approximately 15% of globally diagnosed breast cancers are designated as triple negative breast cancer (TNBC). In this study, we investigated the effect of the natural compound, Bis(2- ethyl hexyl) 1H-pyrrole-3,4-dicarboxylate (TCCP), purified from Tinospora cordifolia on MDA-MB-231, a TNBC cell line. The pro-apoptotic nature of TCCP on MDA-MB-231 was determined by assessing various apoptotic markers. ROS generation, intracellular calcium, mitochondrial membrane potential (ΔΨm), MPTP, cardiolipin peroxidation and caspase activity were determined fluorometrically. BAX, BCL-2, cytochrome c, caspases, and p53 protein expressions were determined by immunoblotting. Further, the effect of TCCP on DNA and cell death was determined by DNA fragmentation assay, annexin-V staining, and cell cycle analysis. TCCP treatment caused endogenous ROS generation, increase in intracellular calcium and phosphorylation of p53 in a concentration-dependent manner, which was reverted upon pre-treatment with pifithrin-μ. This led to the downstream altered expression of Bcl-2 and Bax proteins, mitochondrial membrane depolarization, MPTP, and cardiolipin peroxidation. TCCP induced cytochrome c release into the cytosol, caspase activation, ultimately resulting in DNA fragmentation. Further, induction of apoptosis and morphological alterations were evident from the phosphatidylserine externalization and increase in sub G1 population. The in vivo Ehrlich ascites tumor (EAT) mouse study revealed the effectiveness of TCCP in reducing the tumor burden and resulted in a ∼2 fold increase in mice survival with minimal hepato-renal toxicity. Overall, TCCP was shown to be efficient in inducing ROS and mitochondrial-mediated apoptosis by restoring p53 activity in MDA-MB-231 cells and also induced EAT cell death in vivo thereby inhibiting tumor proliferation.
Protein S-glutathionylation: The linchpin for the transmission of regulatory information on redox buffering capacity in mitochondria Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-08 Adrian Young, Robert Gill, Ryan J. Mailloux
Protein S-glutathionylation reactions are a ubiquitous oxidative modification required to control protein function in response to changes in redox buffering capacity. These reactions are rapid and reversible and are, for the most part, enzymatically mediated by glutaredoxins (GRX) and glutathione S-transferases (GST). Protein S-glutathionylation has been found to control a range of cell functions in response to different physiological cues. Although these reactions occur throughout the cell, mitochondrial proteins seem to be highly susceptible to reversible S-glutathionylation, a feature attributed to the unique physical properties of this organelle. Indeed, mitochondria contain a number of S-glutathionylation targets which includes proteins involved in energy metabolism, solute transport, reactive oxygen species (ROS) production, proton leaks, apoptosis, antioxidant defense, and mitochondrial fission and fusion. Moreover, it has been found that conjugation and removal of glutathione from proteins in mitochondria fulfills a number of important physiological roles and defects in these reactions can have some dire pathological consequences. Here, we provide an updated overview on mitochondrial protein S-glutathionylation reactions and their importance in cell functions and physiology.
Carbon disulfide induces embryo loss by perturbing the expression of the mTOR signalling pathway in uterine tissue in mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-12-03 Fengyan Huang, Yuan Sun, Han Gao, Hanbin Wu, Zhiping Wang
Understanding of the mechanism of embryo loss is critical for successful pregnancy considering an increase in the incidence of infertility. In this study, we focus on the effect of alterations in the expression of the AKT/AMPK/mTOR signalling pathway in mouse uterine tissue after embryo loss induced by harmful environmental exposure to carbon disulfide (CS2). CS2 is a material used in certain production processes, and women are sometimes exposed to it in occupational settings. We created an animal model of gestating mice exposed to CS2 on gestation days 3 (GD3), 4 (GD4), 5 (GD5) and 6 (GD6) with various corresponding endpoints after the exposure. The uterine tissue was collected according to the endpoint time series to detect the expression levels of mTOR, p-mTOR, pAKT, and pAMPK using western blot, RT-PCR, immunohistochemistry staining, and ELISA. Dietary supplementation with N-carbamoyl glutamic acid (NCG) was used to verify the effect of the mTOR signalling pathway on embryo loss caused by CS2. We detected down-regulation of the levels of the mTOR and p-mTOR proteins; the levels of these two proteins were decreased by 49.35% and 51.44% at the GD5 endpoint after GD3 exposure and by 38.55% and 59.51% after GD4 exposure, respectively. The change in the expression level of mTOR mRNA was consistent with the protein expression, and the mRNA level at the GD5 endpoint was decreased by 55.0% after GD4 exposure (P < 0.05). Additionally, protein expression levels of pAKT were decreased by 49.05%, and the levels of pAMPK were increased by 25.51% at the GD5 endpoint after GD4 exposure (P < 0.05). A similar trend was observed for pAKT and pAMPK at the GD4 endpoint after GD3 exposure, at the GD6 endpoint after GD5 exposure, and at the GD7 endpoint after GD6 exposure (P < 0.05). Supplementation with NCG contributed to recovery from the effects of CS2 by increasing the protein expression levels of mTOR and pAKT by 47.54% and 63.79% (P < 0.05), respectively, while the pAMPK protein level was decreased by 37.15% (P < 0.05) at the GD5 endpoint after GD4 exposure. It should be noted that the number of implanted embryos was significantly increased after supplementation with NCG. Our results indicate that down-regulation of mTOR at the time of implantation is regulated by pAKT and pAMPK, that may be an important factor for embryo loss induced by CS2.
TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-30 Jingya Yan, Shen Shen, Yuting He, Zhiqing Li
BackgroundLiver injury is a serious threat for human health and life. Toll-like receptor 5 (TLR5) has reported to be a vital mediator in flagellin or tetrachloride (CCl4)-induced liver injury. However, the roles and etiology of TLR5 in hyperammonaemia (HA)-induced liver injury are poor defined.MethodsHA rats were generated by intragastric administration using ammonium chloride solution. Liver status was assessed by haematoxylin and eosin (H&E) staining and measuring serum levels of liver injury markers. Immunohistochemistry (IHC) assay was used to visualize protein expression in tissues. Apoptotic index in tissues was determined by TUNEL assay. RT-qPCR assay was employed to test mRNA expression. Oxidative stress responses was assessed by detecting levels of reactive oxygen species (ROS) and related indicators. NF-κB activity was examined by TransAM NF-κB colorimetric kit.ResultsTLR5 was highly expressed in liver tissues of HA rats. TLR5 knockdown ameliorated HA-induced liver injury by inhibiting liver cell apoptosis. TLR5 depletion inhibited HA-induced pro-inflammatory cytokine expression in liver tissues, but had no effect on the infiltration of T and macrophage cells into liver tissues. TLR5 silencing impaired HA-induced oxidative stress responses in hepatocytes, but not in hepatic stellate cells (HSCs). TLR5 downregulation inhibited HA-induced activation on TLR5/NF-κB and TLR5/MAPK signaling pathways.ConclusionTLR5 silencing reduced HA-induced liver injury by inhibiting hepatocyte apoptosis, oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals, deepening our understanding on the molecular mechanism of HA-induced liver injury and providing a potential therapeutic target for alleviating liver injury.
Changes in physicochemical properties of kidney cells membrane as a consequence of hypertension and treatment of hypertensive rats with FAAH inhibitor Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-28 Izabela Dobrzyńska, Barbara Szachowicz-Petelska, Jolanta Weresa, Zbigniew A. Figaszewski, Elżbieta Skrzydlewska
Hypertension is a civilization disease leading to remodeling and damage of blood vessels, impaired renal function and premature death. The aim of this study was to compare the effect of chronic administration of URB597, the FAAH (fatty acid amide hydrolase) inhibitor, to rats with primary (SHRs) and secondary (DOCA-salt hypertensive rats) hypertension on electrical and physicochemical properties of kidney cells membranes. Changes in the electrical charge of the membrane may affect the cell functions. The electrical properties of the kidney cells (surface charge density, zeta potential) were measured by electrophoresis. Qualitative and quantitative composition of the membrane (phospholipids and proteins) was determined by HPLC and lipid peroxidation product (4-hydroxy-2E-hexenal; 4-HHE) level was examined by GCMSMS, while the sialic acid content was measured by resorcinol method. In rats with primary hypertension (SHR) and secondary hypertension (DOCA-salt), changes in electrical properties (increase of electric charge and zeta potential) and membrane composition (increase in sialic acid and protein concentration and decrease in phospholipid level) of kidney cells are observed in comparison to control animals. Greater changes were observed in DOCA-salt hypertensive rats. Changes in membrane properties caused by URB597 depend on the type of hypertension. The administration of URB597 to rats with primary hypertension partially prevents changes in the electrical properties (electrical charge, zeta potential) of the membrane caused by hypertension as well as in the sialic acid and proteins content. However, there is no reduction in oxidative stress, assessed by the level of 4-HHE, which may affect the metabolic function of the kidneys. URB597 administered to rats with DOCA salt does not prevent, but rather intensifies, changes caused by hypertension in the kidney. In conclusion, URB597 given to individuals with hypertension, particularly with secondary hypertension, enhancing some disturbances in electric and physicochemical properties of kidney cells observed in hypertension what may lead to additional kidney disorders. Therefore, further researches are necessary.
Anti-proliferative and cytotoxic activities of the flavonoid isoliquiritigenin in the human neuroblastoma cell line SH-SY5Y Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-28 Stephane J.de M. Escobar, Genevieve M. Fong, Sheila M.B. Winnischofer, Martin Simone, Lenka Munoz, Joanne M. Dennis, Maria Eliane M. Rocha, Paul K. Witting
Neuroblastoma is a common childhood cancer with high mortality. We evaluated the capacity of the flavonoid, isoliquiritigenin (4,2’,4’-trihydroxychalcone; ISL) to inhibit cellular proliferation and migration in the human neuroblastoma cell line SH-SY5Y. Incubation of cultured SH-SY5Y cells with 20–100 μM ISL decreased cell confluency (15–70%) after 24 h incubation, while 10–100 μM ISL (24 h) depleted intracellular ATP stores (15–90% vs vehicle-treated control) after 24 h incubation. ISL-mediated cell toxicity did not involve intracellular caspase 3/7 activation, externalization of phosphatidylserine on the cell membrane or stimulation of TNF and IL-1β release, all indicating that the flavonoid did not induce apoptosis. Pre-treatment of cells with necrostatin-1, a necroptosis inhibitor, significantly restored ATP levels (ATP levels increased 12–42%) in ISL-treated neuroblastoma cells indicative of enhanced viability. By contrast, RIP1 phosphorylation status remained unchanged in cells treated with ISL although the intracellular ratio of phosphorylated/total parental RIP1 increased after ISL treatment on SH-SY5Y cells indicating that ISL decreased levels of native RIP1. In addition, ISL treatment inhibited SH-SY5Y cell migration/proliferation in a scratch assay and arrested cell cycle transition by significantly decreasing the number of cells in G0/G1 phase and increasing populations by ∼10% in S (primarily) and G2/M (lesser extent) phases. The intracellular ratio of phosphorylated/total ERK 1/2 and p38 remained unchanged after ISL treatment (up to 40 μM); ERK activation was only determined at ISL dose well above the experimental IC50 value as judged by ELISA analyses and this did not correlate with ISL cytotoxicity at lower dose <40 μM; Western blot assay confirmed the detection of phosphorylated (p-)ERK1/2 and (p-)p38 in ISL treated cells. Together the results suggest that ISL exerts anti-proliferative and cytotoxic activity on SHSY5Y cells through the loss of ATP, induction of cell cycle arrest, and cell death largely via a necroptotic mechanism in the absence of apoptotic activity.
A novel exposure system generating nebulized aerosol of sulfur mustard in comparison to the standard submerse exposure Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-28 Amelie Tsoutsoulopoulos, Markus Siegert, Harald John, Tabea Zubel, Aswin Mangerich, Annette Schmidt, Harald Mückter, Thomas Gudermann, Horst Thiermann, Dirk Steinritz, Tanja Popp
Inhalation of the chemical warfare agent sulfur mustard (SM) is associated with severe acute and long-term pulmonary dysfunctions and health effects. The still not completely elucidated molecular toxicology and a missing targeted therapy emphasize the need for further research. However, appropriate human data are extremely rare. In vivo animal experiments are often regarded as gold standard in toxicology but may exhibit significant differences compared to the human pulmonary anatomy and physiology. Thus, alternative in vitro exposure methods, adapted to the human in vivo situation by exposing cells at the air-liquid interface (ALI), are complimentary approaches at a cellular level. So far, it is unclear whether the enhanced experimental complexity of ALI exposure, that is potentially biologically more meaningful, is superior to submerged exposures which are typically performed.Aim of our study was the evaluation of an appropriate in vitro exposure system (CULTEX® Radial Flow System (RFS) equipped with an eFlow® membrane nebulizer) for the exposure of cultivated human lung cells (A549) with SM under ALI conditions. Cellular responses (i.e. cell viability) and formation of SM-specific DNA-adducts were investigated and compared between ALI and submerse SM exposures.Our results proved the safe applicability of our ALI exposure system setup. The aerosol generation and subsequent deposition at the ALI were stable and uniform. The technical CULTEX® RFS setup is based on ALI exposure with excess of aerosol from that only some is deposited on the cell layer. As expected, a lower cytotoxicity and DNA-adduct formation were detected when identical SM concentrations were used compared to experiments under submerged conditions. A distinct advantage of SM-ALI compared to SM-submerse exposures could not be found in our experiments. Though, the CULTEX® RFS was found suitable for SM-ALI exposures.
Azure B affects amyloid precursor protein metabolism in PS70 cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-28 Kevser Biberoglu, Melike Yuksel, Ozden Tacal
Alzheimer's disease (AD), the most common form of dementia, is characterized by abundant deposition of amyloid-β (Aβ) peptide that is the result of sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase. Several studies have documented that inhibition of Aβ peptide synthesis or facilitating its degradation is one of the attractive therapeutic strategies in AD. Methylene blue (MethB), which has recently been investigated in Phase II clinical trials, is a prominent inhibitor in reducing Aβ oligomers. Herein, we wonder whether the mitigating effects of MethB on amyloid metabolism are related to the activity of its major metabolite azure B. The goal of this study was to investigate the effects of azure B, which is also a cholinesterase inhibitor, on APP processing by using Chinese hamster ovary cells stably expressing human wild-type APP and presenilin 1 (PS70). Azure B significantly decreased the levels of secreted APPα (sAPPα) and Aβ40/42 in culture medium with a dose-dependent manner. A significant decrease was also observed in the levels of intracellular APP without affecting the cell viability. In parallel with the decrease of APP and APP metabolites, the activity of β-secretase 1 (BACE1) was significantly attenuated compared to control. Overall, our results show that azure B has a large contribution for the pharmacological profile of MethB in APP metabolism.
Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-28 Salma A. El-Marasy, Sally A. El Awdan, Reham M. Abd-Elsalam
Hepatic encephalopathy (HE) is a serious neuropsychiatric syndrome due to either acute or chronic hepatic failure. This study aimed to investigate the possible neuroprotective effect of chrysin, a natural flavenoid on thioacetamide (TAA)-induced hepatic encephalopathy in rats. Also the effect of chrysin on motor impairment, cognitive deficits, oxidative stress, neuroinflammation, apoptosis and histopathological damage was assessed. HE was induced in Wistar rats by intraperitoneal (i.p.) injection of TAA (200 mg/kg) for three alternative days. Normal and control groups received the vehicle for 21 days. Chrysin was administered orally for 21 days (25, 50, 100 mg/kg) and starting from day 17, rats received i.p. dose of TAA (200 mg/kg) at three alternative days. Then behavioral, biochemical, histopathological and immunohistochemical analyses were conducted. Chrysin improved TAA-induced motor incoordination as it reduced final falling latency time in rotarod test, ameliorated cognitive deficits in object recognition test (ORT) and attenuated serum ammonia, hepatic liver enzymes namely, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) brain contents. Chrysin administration also reduced Toll-4 receptor (TLR-4) gene expression, caspase-3 protein expression, hepatic necrosis and astrocyte swelling. This study depicts that chrysin exerted neuroprotective effect in TAA-induced HE rats, evidenced by improvement of cognitive deficits, motor incoordination and histopathological changes such as astrocyte swelling and vacuolization; hallmarks in HE, via reducing hyperammonia, ameliorating hepatic function, in addition to its anti-oxidant, inactivation of TLR-4/NF-κBinflammatory pathway, and anti-apoptotic effects.
Interaction of the anti-tuberculous drug bedaquiline with artificial membranes and rat erythrocytes Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-26 Konstantin N. Belosludtsev, Nikita V. Penkov, Kirill S. Tenkov, Eugeny Yu Talanov, Natalia V. Belosludtseva, Alexey V. Agafonov, Anastasia E. Stepanova, Vlada S. Starinets, Olga V. Vashchenko, Sergey V. Gudkov, Mikhail V. Dubinin
Bedaquiline (BDQ) is a new drug from the family of diarylquinolines, which has a potent bactericidal activity against Mycobacterium tuberculosis. This paper has examined the interaction of BDQ with model membranes (liposomes and BLM) and rat erythrocytes. It was shown that BDQ (1–10 mol%) changed the thermotropic phase behavior of DMPC liposomes, leading to the lateral phase separation in the lipid bilayer and the formation of membrane microdomains. BDQ (10–50 μM) was also demonstrated to cause permeabilization of lecithin liposomes loaded with the fluorescent dye sulforhodamine B. At the same time, it did not alter the ionic conductivity of BLM. A dynamic light scattering study showed that BDQ led to the emergence of two populations of light-scattering particles in the suspension of lecithin liposomes, suggesting that an aggregation of the vesicles took place. In rat erythrocytes, BDQ was found to induce changes in their size and shape, as well as aggregation and lysis of the cells.
Oleanolic acid promotes orofacial antinociception in adult zebrafish (Danio rerio) through TRPV1 receptors Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-26 Isabel C.R. Soares, Sacha Aubrey A.R. Santos, Regina F. Coelho, Yuri A. Alves, Antônio E. Vieira-Neto, Kaio César S. Tavares, Francisco Ernani A. Magalhaes, Adriana R. Campos
This study aimed to evaluate the antinociceptive effect of oleanolic acid (AO) using adult zebrafish models of orofacial pain. Acute nociception was induced by formalin, capsaicin, cinnamaldehyde, menthol, acidified saline or glutamate (cutaneous modes) and hypertonic saline (corneal model). In another set of experiments, animals were pre-treated with naloxone, L-NAME, methylene blue, ketamine, camphor, HC-030031, mefenamic acid, ruthenium red or amiloride to investigate the mechanism of antinociception. The involvement of central afferent C-fibers was also investigated. A molecular docking was performed using the TRPV1 channel. Motor activity was evaluated with the open field test. Pre-treatment with OA significantly reduced nociceptive behavior associated with acute pain. Antinociception was effectively inhibited by ruthenium red and capsaicin-induced desensitization. Presence of trpv1 was confirmed by RT-PCR in cerebral tissue of zebrafish. In line with in vivo experiments, docking studies indicated that OA may interact with TRPV1. Results confirm the potential pharmacological relevance of OA as an inhibitor of orofacial nociception mediated by TRPV1.
Acetaminophen absorption and metabolism in an intestine/liver microphysiological system Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-26 Talita Miguel Marin, Nathalia de Carvalho Indolfo, Silvana Aparecida Rocco, Fernanda Luisa Basei, Murilo de Carvalho, Kaliandra de Almeida Gonçalves, Eduardo Pagani
This study describes the characterization of pharmacokinetic (PK) properties of acetaminophen (APAP) in the Two-Organ-Chip platform (2-OC), a two-chamber device able to cultivate 3D tissues under flow. The APAP intestinal absorption and hepatic metabolism were emulated by human intestine and liver equivalents respectively. The intestinal barrier was produced using Caco-2 and HT-29 cells. The liver spheroids were produced with HepaRG and HHSTeC cells. Cell viability and toxicity were assessed by MTT assay, histology, confocal immunohistochemistry, and multiparametric high content analysis. Gene expression of intestine and liver equivalents were assessed by real-time PCR. Three assemblies of Microphysiological System (MPS) were applied: Intestine 2-OC, Liver 2-OC, and Intestine/Liver 2-OC. The oral administration was emulated by APAP placement over the apical side of the intestinal barrier and the intravenous routes were mimic by the application in the medium. Samples were analyzed by HPLC/UV. APAP 12 μM or 2 μM treatment did not induce cytotoxicity for the intestinal barrier (24 h time-point) or for the liver spheroids 12 h time-point), respectively. All preparations showed slower APAP absorption than reported for humans: Peak time (Tmax) = 12 h for Intestine 2-OC and 6 h for Intestine/Liver 2-OC in both static and dynamic conditions, against reported Tmax of 0,33 to 1,4 h after oral administration to humans. APAP metabolism was also slower than reported for humans. The APAP half-life (T1/2) was 12 h in the dynamic Liver 2-OC, against T1/2 = 2 ± 0,4 h reported for humans. Samples taken from the Liver 2-OC static preparation did not show APAP concentration decrease. These findings show the MPS capability and potential to emulate human PK properties and highlight the critical role of mechanical stimulus over cell functionality, especially by demonstrating the clear positive influence of the microfluidic flow over the liver equivalents metabolic performance.
Decreased 8-oxoguanine DNA glycosylase 1 (hOGG1) expression and DNA oxidation damage induced by Cr (VI) Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-27 Hailing Xia, Shibo Ying, Lingfang Feng, Haiming Wang, Chunji Yao, Tao Li, Yixiao Zhang, Sanjun Fu, Donger Ding, Xinnian Guo, Yan Tong, Xiaofeng Wang, Zhijian Chen, Zhaoqiang Jiang, Xing Zhang, Bernardo Lemos, Jianlin Lou
Occupational exposure to Cr (VI) can cause DNA damage, genetic instability and elevate the risk of cancer. Here we investigated Cr (VI)-induced DNA damage and 8-oxoguanine DNA glycosylase 1 (hOGG1) gene expression in electroplating workers. The hOGG1 gene encodes a DNA repair enzyme that is crucial in DNA oxidation damage repair. Deficiency in hOGG1 DNA repair capacity contributes to the accumulation of DNA damage and genetic instability. To address the issues, we collected peripheral blood samples and urine samples from 162 electroplating workers and 84 control subjects. We measured blood chromium levels, urine chromium levels, DNA damage, and hOGG1 mRNA expression. We found significantly higher levels of blood chromium, urine chromium, and DNA damage in electroplating workers compared with controls, whereas mRNA levels of the hOGG1 gene were significantly lower in the exposed workers. Furthermore, in electroplating workers we found that blood Cr had a positive association with DNA damage as measured with the tail DNA%. Meanwhile, tail DNA% was positively associated with hOGG1 mRNA expression. Finally, the effect of potassium dichromate treatment was investigated in a human B lymphoblastoid cell line (LCL). We observed that potassium dichromate induced a concentration-dependent decrease in hOGG1 mRNA. After removing the K2Cr2O7-containing medium for 3 days and 7 days, the abundance of hOGG1 mRNA expression recovered to a similar level as the controls. Collectively, our findings suggest that decreased hOGG1 mRNA expression in occupationally exposed populations partially contribute to Cr (VI) induced DNA damage.
Disturbance of energetic homeostasis and oxidative damage provoked by trichlorfon as relevant toxicological mechanisms using silver catfish as experimental model Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-24 Matheus D. Baldissera, Carine F. Souza, Sharine N. Descovi, Renato Zanella, Osmar D. Prestes, Antonio F.I.M. de Matos, Aleksandro S. da Silva, Bernardo Baldisserotto
Recent evidences have suggested the involvement of phosphoryl transfer, catalyzed by creatine kinase (CK), adenylate kinase (AK) and pyruvate kinase (PK), to metabolic alterations and impairment of bioenergetics homeostasis linked to adenosine triphosphate (ATP) production, and utilization during exposure to pesticides. It is recognized that sublethal concentrations of trichlorfon alter hepatic and branchial metabolism, but the pathways involved in this process remains unknown. Thus, the aim of this study was to evaluate whether phosphoryl transfer network can be a pathway involved in the hepatic and branchial metabolic alterations during exposure to sublethal concentrations of trichlorfon. Hepatic and branchial CK (cytosolic and mitochondrial isoforms) and PK activities were inhibited after 48 h of exposure to 11 and 22 mg/L trichlorfon compared to control group, while AK activity did not differ between groups. In addition, sodium-potassium pump (Na+, K+-ATPase) activity was lower after 48 h of exposure to 22 mg/L trichlorfon compared to control group. Thiobarbituric acid reactive substances (TBARS) were higher in liver samples after 24 h of exposure to 22 mg/L trichlorfon compared to control group, as well as after 48 h of exposure to 11 and 22 mg/L trichlorfon in liver and gills. Finally, hepatic and branchial non-protein thiol (NPSH) levels were lower after 48 h of exposure to 11 and 22 mg/L trichlorfon. All evaluated parameters did not recover after 48 h in clean water. Based on these evidence, the impairment of phosphoryl transfer network can be considered a pathway involved in the hepatic and branchial metabolic alterations during exposure to sublethal concentrations of trichlorfon. Moreover, alterations on CK and PK activities provoke an impairment on Na+, K+-ATPase activity, which can be mediated by lipid oxidative damage and reduction of NPSH content.
Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-24 Haoran Wang, Bing Shao, Hongyan Yu, Feibo Xu, Peiyan Wang, Kaiyuan Yu, Yanfei Han, Miao Song, Yanfei Li, Zheng Cao
Many reports demonstrated that aluminum maltolate (Almal) has potential toxicity to human and animal. Our study has demonstrated that Almal can induce oxidative damage and apoptosis in PC12 cells and SH-SY5Y Cells, two in vitro models of neuronal cells. Hyperforin (HF) is a well-known antioxidant, anti-inflammatory, anti-amyloid and anti-depressant compound extracted from Hypericum perforatum extract. Here, we investigated the neuroprotective effect of HF against Almal-induced neurotoxicity in cultured PC12 cells and SH-SY5Y cells, mainly caused by oxidative stress. In the present study, HF significantly inhibited the formation of reactive oxygen species (ROS), decreased the level of lipid peroxide and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) compared with Almal group in PC12 cells and SH-SY5Y cells. Additionally, HF suppressed the reduction of the mitochondrial membrane potential (MMP), cytochrome c (Cyt-c) release, activation of caspase-3, and the down-regulation of Bcl-2 expression and up-regulation of Bax expression induced by Almal in PC12 cells and SH-SY5Y cells. In summary, HF protects PC12 cells and SH-SY5Y cells from damage induced by Almal through reducing oxidative stress and preventing of mitochondrial-mediated apoptosis.
8-Cetylcoptisine, a new coptisine derivative, induces mitochondria-dependent apoptosis and G0/G1 cell cycle arrest in human A549 cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-22 Bing Han, Pu Jiang, Heshan Xu, Wuyang Liu, Jian Zhang, Siqi Wu, Liangyu Liu, Wenyu Ma, Xuegang Li, Xiaoli Ye
Lung cancer is the worldwide leading cause of cancer-related death. Here, we described the synthesis and the anticancer activity of a novel coptisine derivative 8-cetylcoptisine (CCOP) on lung carcinoma in vitro and in vivo. CCOP inhibited the cell viability of A549, BGC-823, MDA-MB-231, HCT-116 and HepG2 cell lines. In A549 cells, CCOP induced apoptosis, G0/G1 cell cycle arrest and decreased mitochondrial membrane potential (MMP) in a dose-dependent manner. Western blot analysis showed that CCOP increased the expression of Bcl-2-associated X protein (Bax), cleaved caspase 3 and 9, while decreased B-cell lymphoma 2 (Bcl-2), cyclins D and E, cyclin dependent kinases (CDKs) 2, 4 and 6, along with the inactivation of the upstream phosphoinositide 3-kinase (Pi3k)/protein kinase B (Akt) signaling. Further in vivo studies showed that CCOP (10 mg/kg) significantly delayed tumor growth in A549 xenograft nude mice, which is stronger than that of coptisine (100 mg/kg). These data suggested that CCOP could be a candidate for lung cancer therapy.
Mahanine induces apoptosis, cell cycle arrest, inhibition of cell migration, invasion and PI3K/AKT/mTOR signalling pathway in glioma cells and inhibits tumor growth in vivo Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-20 Maohua Chen, Xiangqian Yin, Chuan Lu, Xiaodong Chen, Huajun Ba, Jianyong Cai, Jun Sun
Gliomas are among the most frequent types of primary malignancies in the central nervous system. The main treatment for glioma includes surgical resection followed by a combination of radiotherapy and chemotherapy. Despite the availability of several treatments, the average survival for patients with glioma at advanced stages still remains 16 months only. Therefore, there is an urgent need to look for novel and more efficient drug candidates for the treatment of glioma. In the current study the anticancer activity of Mahanine was evaluated against a panel of glioma cells. The results revealed that Mahanine exerted significant anticancer effects on the glioma HS 683 cells with an IC50 of 7.5 μM. However, the cytotoxic effects were less pronounced on the normal human astrocytes. Further the results showed that the anticancer effects were mainly due to induction of apoptosis and G2/M cell cycle arrest. Western blotting showed that Mahanine caused upregulation of Bax, cytochrome c, cleaved caspase 3 and 9 and cleaved PARP. However, the expression of cell cycle related proteins pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1 was significantly downregulated. The effect of Mahanine on the migration and invasion of HS 683 cells was also determined and results indicated that Mahanine inhibited the cell migration and invasion at IC50. Additionally, Mahanine-inhibited cell growth was simultaneous with suppression of p-PI3K, p-AKT and p-mTOR. Taken together these results indicate that Mahanine may prove to be an important lead molecule for the treatment of glioma and warrants further investigation.
Pyrrolizidine alkaloid-induced alterations of prostanoid synthesis in human endothelial cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-19 Johanna Ebmeyer, Jessica Behrend, Mario Lorenz, Georgia Günther, Raymond Reif, Jan G. Hengstler, Albert Braeuning, Alfonso Lampen, Stefanie Hessel-Pras
Pyrrolizidine alkaloids (PA) are a group of secondary plant metabolites belonging to the most widely distributed natural toxins. PA intoxication of humans leads to severe liver damage, such as hepatomegaly, hepatic necrosis, fibrosis and cirrhosis. An acute consequence observed after ingestion of high amounts of PA is veno-occlusive disease (VOD) where the hepatic sinusoidal endothelial cells are affected. However, the mechanisms leading to VOD after PA intoxication remain predominantly unknown. Thus, we investigated PA-induced molecular effects on human umbilical vein endothelial cells (HUVEC). We compared the effects of PA with the effects of PA metabolites obtained by in vitro metabolism using liver homogenate (S9 fraction). In vitro-metabolized lasiocarpine and senecionine resulted in significant cytotoxic effects in HUVEC starting at 300 μM. Initial molecular effect screening using a PCR array with genes associated with endothelial cell biology showed PA-induced upregulation of the Fas receptor, which is involved in extrinsic apoptosis, and regulation of a number of interleukins, as well as of different enzymes relevant for prostanoid synthesis. Modulation of prostanoid synthesis was subsequently studied at the mRNA and protein levels and verified by increased release of prostaglandin I2 as the main prostanoid of endothelial cells. All effects occurred only with in vitro-metabolically activated PA lasiocarpine and senecionine. By contrast, no effect was observed for the PA echimidine, heliotrine, lasiocarpine, senecionine, senkirkine and platyphylline in the absence of an external metabolizing system up to the highest tested concentration of 500 μM. Overall, our results confirm the metabolism-dependent toxification of PA and elucidate the involved pathways. These include induction of inflammatory cytokines and deregulation of the prostanoid synthesis pathway in endothelial cells, linking for the first time PA-dependent changes in prostanoid release to distinct alterations at the mRNA and protein levels of enzymes of prostanoid synthesis.
Omeprazole protects against cisplatin-induced nephrotoxicity by alleviating oxidative stress, inflammation, and transporter-mediated cisplatin accumulation in rats and HK-2 cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-16 Huan Gao, Sixi Zhang, Tingting Hu, Xiaoyu Qu, Jinghui Zhai, Yueming Zhang, Lina Tao, Jianyuan Yin, Yanqing Song
The present study assessed the therapeutic potential of omeprazole (OME), the most commonly prescribed proton pump inhibitor (PPI) used to treat gastroesophageal hyperacidity, against cisplatin (CP)-induced toxicity in human renal tubular HK-2 cells and rat kidneys. Herein, we observed that exposure of HK-2 cells to OME reversed the injury caused by CP, including enhancing cell viability and alleviating intracellular reactive oxygen species (ROS) generation and membrane damage. Concomitantly, acute exposure of male SD rats to CP induced histopathological changes, which were prevented by co-administration with OME. Inflammation and oxidative stress were inhibited by OME during CP-induced renal injury by increasing the activity of superoxide dismutase, and reducing the levels of malondialdehyde, both in vivo and in vitro. The expression levels of major inflammatory response markers were significantly decreased in HK-2 cells and rat kidneys in response to OME. OME reduced CP cellular uptake through organic cation transporters 2 (OCT2) and the prompt efflux of CP by P-glycoprotein (P-gp), thereby reducing the accumulation of CP in kidney tissue and increasing its serum levels. These data demonstrate that CP-induced kidney damage is positively correlated with its cellular accumulation. Concurrently, OME showed renoprotective effect against CP-induced toxicity in HK-2 cells and rat kidneys, by suppressing oxidative stress and mediating NF-κB-dependent inflammation, apoptosis, and transporter function. As OME is commonly used in combination with CP during chemotherapy treatment, this study highlights the clinical significance of OME in alleviating CP-induced nephrotoxicity.
Oenothein B induced human non-small cell lung cancer A549 cell death by ROS-mediated PI3K/Akt/NF-κB signaling pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-16 Xiaodong Pei, Junsong Xiao, Yumeng Zhang, feng Lin, Zhaocheng Xiong, Guang Fu Pang, Yan Jiang, Lu Lan, Lihe Jiang
Oenothein B has a wide range of biological activities. This study assessed the possible mechanism of Oenothein B on lung cancer A549 cell. The results showed that Oenothein B effectively inhibited the proliferation of A549 cells by inducing apoptosis, arrested cell at G1 stage. On the one hand, Oenothein B not only increased the level of intracellular reactive oxygen species (ROS), but induced some apoptotic-related protein expression (cleavage caspase-3, PARP, cytochrome c level in the cytoso, Bax). Moreover, ROS inhibitor and PI3K agonist exhibited significant protection against cell death by Oenothein B. ROS inhibitor significantly abrogated the activation of caspase3/7 and 9 by Oenothein B. On the other hand, the levels of p-Akt and p-Akt, p-NF-κB suppressed by Oenothein B could be offset by treatment with ROS inhibitor. To summarize, these results demonstrated that Oenothein B was able to prevent cell growth by maybe via ROS-mediated PI3K/Akt/NF-κB signaling pathway.
Tocolytic activity of the Lippia alba essential oil and its major constituents, citral and limonene, on the isolated uterus of rats Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-14 Luís Pereira-de-Morais, Andressa de Alencar Silva, Renata Evaristo Rodrigues da Silva, Roger Henrique Sousa da Costa, Álefe Brito Monteiro, Cristina Rodrigues dos Santos, Thaís de Souza Amorim, Irwin Rose Alencar de Menezes, Marta Regina Kerntopf, Roseli Barbosa
The species Lippia alba (Mill.) N. E. Brown belongs to the Verbenaceae family. It is abundant and grows spontaneously throughout the Brazilian territory. Popularly known as “erva-cidreira”, it is widely used because of its sedative, carminative and analgesic properties. The objective of this study was to investigate the mechanism of action of the L. alba essential oil (EOLa) and its major constituents citral and limonene, on isolated rat uterus muscle. To evaluate the EOLa, citral and limonene effect, cumulative concentrations curves for EOLa and citral (1–600 μg/mL) and for limonene (1–1200 μg/mL) were constructed from contractions of rat uterine strips under a 1 g tension. EOLa, citral and limonene dose-dependently relaxed myometrial preparations pre-contracted with 60 mM KCl, 10-2 IU/mL oxytocin, serotonin (10 μM), or ACh (10 μM). The results demonstrate that the EOLa, citral and limonene cause relaxation of the uterine smooth muscle. These results suggest that the relaxation induced by EOLa, citral and limonene is caused by inhibition of L-type VOCC, inhibiting the Ca2+ current through these channels, although other mechanisms of action are likely to contributing to relaxant activity. There was no involvement of K+ channels (BKca, KATP, KV) or cyclooxygenase on the relaxation promoted by EOLa. Then studies of the tocolytic effects of EOLa, citral and limonene may yield new insights into their therapeutic use.
Altered electrical properties with controlled copper doping in ZnO nanoparticles infers their cytotoxicity in macrophages by ROS induction and apoptosis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-10 Bikram Keshari Das, Suresh K. Verma, Tanushree Das, Pritam Kumar Panda, Kajal Parashar, Mrutyunjay Suar, S.K.S. Parashar
The present study reports the regulation of cytotoxicity of Cu doped ZnO nanoparticles in macrophages (RAW 264.7) due to altered physiochemical properties changes like electrical properties by controlled doping of Cu in ZnO. Cu-doped ZnO nanoparticles were prepared by High Energy Ball Milling technique (HEBM) and formed single phase Zn1-xCuxO (x = 0.0, 0.01, 0.02, 0.03) were called as pure ZnO, Cu1%, 2%, 3% respectively. Hexagonal wurtzite structure with size range of 22–26 nm was verified. FE-SEM with EDX analysis indicated the Cu doping effect on the surface morphology of ZnO. Zeta potential of Zn1-xCuxO was found to be elevated with increase in doping percentage of Cu (−36.6 mV to +18.2 mV). Dielectric constant was found to be decreased with increasing doping percentage. Increase in doping percentage enhanced cytotoxicity of Zn1-xCuxO in macrophages with LC50 of 62 μg/ml, 51 μg/ml, 40 μg/ml, 32 μg/ml. Granularity change of macrophages suggested doping influenced cellular uptake as consequence of zeta potential and dielectric properties changes. 3% Cu doped ZnO shown a higher ROS signal and apoptosis than 2% and 1% Cu doping with exhibition of ROS scavenging nature leading to apoptosis of prepared Cu doped ZnO nanoparticles. Our findings revealed mechanism of cytotoxicity of Zn1-xCuxO as a consequence of alteration in electric properties eliciting ROS scavenging leading to higher apoptosis with increasing doping percentage of Cu in ZnO.
Lactic acid induced microRNA-744 enhances motility of SiHa cervical cancer cells through targeting ARHGAP5 Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-10 Chao Li, Linyan Jia, Yongsheng Yu, Liping Jin
High-risk (hr) human papillomaviruses (HPV) infection and integration has caused the majority of cervical cancer, of which E6 and E7 oncogenes are invariably retained and expressed to immortalize cells probably via affecting cell migration and invasion, and tumor metastasis. However, the underlying mechanism that mediates the procedure such as motility of cervical cancer cells within the tumor microenvironment is not well understood. Herein, we examined one possible factor—extracellular lactic acid, an end up chemical in glycolytic tumor cells, on the motility in HPV16 positive SiHa cells. The results showed that lactic acid enhanced cell migration and invasion behavior via stimulating the expression of miR-744. ARHGAP5 was confirmed to be a target of miR-744, and silencing ARHGAP5 exhibited an inhibiting effect on cell migration and invasion as that observed by suppressing miR-744. In addition, lactic acid down-regulated E6 and E7 protein levels, and overexpression of either miR-744 or ARHGAP5 could also reduce E6 and E7 levels. Overall, our findings suggest that the miR-774/ARHGAP5 axis may provide a vital role in triggering lactic acid-induced migration and invasion in SiHa cells, regardless of the diminished effect due to the partial inhibition of E6 and E7 expression.
A synthetic chalcone derivative, 2-hydroxy-3′,5,5′-trimethoxychalcone (DK-139), triggers reactive oxygen species-induced apoptosis independently of p53 in A549 lung cancer cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-05 Ha Na Gil, Euitaek Jung, Dongsoo Koh, Yoongho Lim, Young Han Lee, Soon Young Shin
The possible ameliorative effect of simvastatin versus sulfasalazine on acetic acid induced ulcerative colitis in adult rats Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-05 Nema A. Soliman, Walaa A. Keshk, Fatma H. Rizk, Marwa A.A. Ibrahim
Objective Inflammatory bowel diseases (IBD) are chronic and recurrent disorders of the gastrointestinal tract with unknown etiology and have two major forms, ulcerative colitis (UC) and Crohn diseases. In view of the adverse effects and incomplete efficacy of currently administered drugs, it is essential to investigate new and harmless drugs with more desirable beneficial effects. Statins have many additional pleiotropic effects other than their lipid-lowering effect. This study aims to investigate the role of simvastatin (SIM) at different doses against induced UC in rats. Methods SIM (10, 20 mg/kg), and sulfasalazine as a standard therapy (100 mg/kg) were given from five days before and seven days after induction of UC by acetic acid (AA). Colonic mucosal inflammation was evaluated macroscopically and microscopically. Furthermore, the colonic tissue tumor necrosis factor-α (TNF-α), interleukin 1beta (IL 1B), nod-like receptor family pyrin domain-1 containing 3 (NLRP3), malondialdehyde (MDA), reduced glutathione (GSH) and super oxide dismutase (SOD) were assayed in addition to immunohistochemistry of caspase-1 and cyclooxygenase-2 (COX2). Results SIM in a dose dependant manner significantly improved macroscopic and histological scores, diminished colonic levels of IL 1B, TNF-α, NLRP3, MDA, caspase-1 and COX2 and elevated GSH and SOD. Conclusion SIM has anti-inflammatory, cytoprotective and antioxidants effects that are not directly related to its cholesterol lowering activity against AA induced colitis this makes it a new therapeutic target for UC.
Necrosulfonamide – Unexpected effect in the course of a sulfur mustard intoxication Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-02 Georg Menacher, Frank Balszuweit, Simon Lang, Horst Thiermann, Kai Kehe, Thomas Gudermann, Annette Schmidt, Dirk Steinritz, Tanja Popp
Although its first military use in Ypres was 100 years ago, no causal therapy for sulfur mustard (SM) intoxications exists so far. To improve the therapeutic options for the treatment of SM intoxications, we developed a co-culture of keratinocytes (HaCaT cells) and immunocompetent cells (THP-1 cells) to identify potential substances for further research. Here, we report on the influence of necrosulfonamide (NSA) on the course of a SM intoxication in vitro. The cells were challenged with 100, 200 and 300 μM SM and after 1 h treated with NSA (1, 5, 10 μM). NSA was chosen for its known ability to inhibit necroptosis, a specialized pathway of programmed necrosis. However, in our settings NSA showed only mild effects on necrotic cell death after SM intoxication, whereas it had an immense ability to prevent apoptosis. Furthermore, NSA was able to reduce the production of interleukin-6 and interleukin-8 at certain concentrations. Our data highlight NSA as a candidate compound to address cell death and inflammation in SM exposure.
Cytotoxicity of benzophenone-3, an organic ultraviolet filter, caused by increased intracellular Zn2+ levels in rat thymocytes Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-02 Hidekazu Utsunomiya, Riko Hiraishi, Kouji Kishimoto, Sarii Hamad, Shin Abe, Yusuke Bekki, Norio Kamemura
Benzophenone-3 (BP-3) is often used as an ultraviolet (UV) light filter in sunscreen products. Although BP-3 protects the human skin and hair from damage caused by excessive UV radiation, it is reported to exhibit toxic effects in human. However, the cytotoxicity of BP-3 on various cells is still not well understood. In the present study, the cytotoxicity of BP-3 against rat thymocytes was evaluated using a flow cytometric technique with fluorescent probes. Cell mortality increased significantly after 3 h of exposure to 300 μM BP-3, whereas the mean intensity of 5-chloromethylfluorescein diacetate (5-CMF) fluorescence and cellular content of non-protein thiols decreased significantly. However, the membrane potential of thymocytes was not change by BP-3 treatment. Moreover, intracellular Zn2+ levels increased significantly in a concentration-dependent manner in response to 30 μM BP-3 or higher. The BP-3-induced changes in intracellular Zn2+ levels and non-protein thiol content increased the vulnerability of thymocytes to oxidative stress. We concluded that BP-3-induced cytotoxicity may be caused by oxidative stress associated with an increase in intracellular Zn2+ levels.
Amyloid-β1-42 dynamically regulates the migration of neural stem/progenitor cells via MAPK-ERK pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-11-03 Zhu Wang, Yantian Chen, Xueyi Li, Pinky Sultana, Ming Yin, Zejian Wang
Neural stem/progenitor cell (NSPC) based therapy represents an attractive treatment for Alzheimer's disease (AD), the most common neurodegenerative disorder with no effective treatment to date. This can be achieved by stimulating endogenous NSPCs and/or administrating exogenously produced NSPCs. Successful repair requires the migration of NSPCs to the loci where neuronal loss occurs, differentiation and integration into neural networks. However, the progressive loss of neurons in the brain of AD patients suggests that the repair by endogenous NSPCs in the setting of AD may be defective. The production and deposition of amyloid-β1-42 (Aβ1-42) peptides is thought to be a central event in the pathogenesis of AD. Here we report that Aβ1-42 peptides inhibit the migration of in vitro cultured NSPCs by disturbing the ERK-MAPK signal pathway. We found that the migratory capacity of NSPCs was compromised upon treatment with oligomeric Aβ1-42; the inhibitory effect occurred in a dose-dependent manner. Our previous studies have shown that Aβ1-42 triggers the expression of GRK2 by unknown mechanism. Herein we found that the Aβ1-42 evoked upregulation of GRK2 expression was attenuated upon treatment with the ERK inhibitor SCH772984 at 2.5 μM, but not with inhibitors for p38 or JNK. We detected a dose-dependent increase in levels of phosphorylated ERK1/2 after incubation of cells with oligomeric Aβ1-42 peptides for 3 days. We observed that an increase in the phosphorylation of p38 and JNK coincided with reduced phosphorylation of ERK1/2 upon treatment with Aβ1-42 for 6 and/or 9 days. We hypothesize that the divergence of the activation of the MAPK family of pathways may contribute to the inhibition of NSPCs migration after the long-term incubation with Aβ1-42. Pretreatment with 1 μM MEK inhibitor U0126 reversed the effects of Aβ1-42 on GRK2 expression of and NSPC migration. Together, our results suggest that Aβ1-42 oligomers compromise the migratory capacity of NSPCs through the MEK-ERK pathway.
Pro- and antioxidant activity of chromium(III), iron(III), molybdenum(III) or nickel(II) and their mixtures Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-30 Sylwia Terpilowska, Andrzej Krzysztof Siwicki
The aim of this study was to examine the effect of chromium(III), iron(III), molybdenum(III) and nickel(II) and their combinations on pro- and antioxidant activity in mouse embryo fibroblasts and liver cancer cells. The present study shows that chromium(III), iron(III), nickel(II) and molybdenum(III) induce oxidative stress. In the case of chromium(III), nickel(II) and molybdenum(III) the intracellular ROS were dominant. However, in the case of iron(III) MDA was dominant - the end product of lipid peroxidation. Antioxidant activity of superoxide dismutase and catalase increased in low concentration of chromium(III); however, they decreased in higher concentrations. The same enzymes decreased after iron(III), nickel(II) and molybdenum(III) treatment in dose dependent manner. The activity of glutathione peroxidise decreased in dose dependent manner in all used microelements. Additions of Cr(III) at 200 μM plus Fe(III) at 1000 μM showed synergistic effect in ROS production and in lowering antioxidant activity. The same type of interaction in pairs Cr(III) at 1000 μM plus Fe(III) or Ni(II) or Mo(III) at concentration of 200 μM was observed. The protective effects of Cr(III) in antioxidant activity and in lowering intracellular ROS production in pairs of Cr(III) at 200 μM and Ni(II) or Mo(III) at concentration of 1000 μM were observed.
Differential proteome analysis of rat plasma after diisopropyl fluorophosphate (DFP) intoxication, a surrogate of nerve agent sarin Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-30 Kalyani Chaubey, Syed Imteyaz Alam, Chandra Kant Waghmare, Lokendra Singh, Nalini Srivastava, Bijoy K. Bhattacharya
Diisopropyl fluorophosphate (DFP), a surrogate of nerve agent sarin, is an organophosphorus (OP) compound which inhibits neuronal enzyme acetylcholinesterase (AChE). Exposure of this compound leads to a wide range of toxic symptoms and survivors may exhibit long term neurotoxicity related to cognitive and memory defects. Due to ease of availability and similar mechanism of action to other highly toxic nerve agent, DFP is widely used as model compound to trace changes associated with nerve agent exposures. Proximal fluids are widely used for the elucidation of biomarkers for exposure to toxic substances and to study the mechanism of toxicity. Using a rat model of OP intoxication, the present study was carried out to elucidate proteomic changes in plasma associated with DFP intoxication. Rats were exposed to a single dose (0.5 LD50) of DFP and their plasma proteome was studied, one day post exposure by two dimensional gel electrophoresis - mass spectrometry (2DE-MS). Some of the milestone changes were validated by Western blot analysis. A total 15 proteins showed significant fold changes in expression with respect to control after 1 day of DFP intoxication. Most of the proteins showing changes in expression at initial stages were related to immunogenic function, acute phase response, blood coagulation, and stress response. Experiments reported here demonstrate that 0.5 LD50 DFP intoxication leads to AChE inhibition, modulation of immunogenic function, and generation of stress at an early stage. Although, some proteins and their putative functional ramifications indicated similarity with those observed in our previous plasma proteome study, neurodegenerative changes were not observed in plasma of 0.5 LD50 DFP treated animals.
Nothofagin suppresses mast cell-mediated allergic inflammation Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-28 Byeong-Cheol Kang, Min-Jong Kim, Soyoung Lee, Young-Ae Choi, Pil-Hoon Park, Tae-Yong Shin, Taeg Kyu Kwon, Dongwoo Khang, Sang-Hyun Kim
Mast cells play a major role in immunoglobulin E-mediated allergic inflammation, which is involved in asthma, atopic dermatitis, and allergic rhinitis. Nothofagin has been shown to ameliorate various inflammatory responses such as the septic response and vascular inflammation. In this study, we assessed the inhibitory effect of nothofagin on allergic inflammation using cultured/isolated mast cells and an anaphylaxis mouse model. Nothofagin treatment prevented histamine and β-hexosaminidase release by reducing the influx of calcium into the cytosol in a concentration-dependent manner. Nothofagin also inhibited the gene expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-4 by downregulating the phosphorylation of Lyn, Syk, Akt and nuclear translocation of nuclear factor-κB. To confirm these effects of nothofagin in vivo, we used a passive cutaneous anaphylaxis mouse model. Topical administration of nothofagin suppressed local pigmentation and ear thickness. Taken together, these results suggest nothofagin as a potential candidate for the treatment of mast cell-involved allergic inflammatory diseases.
Acrylamide induces adipocyte differentiation and obesity in mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-26 Hee-Weon Lee, Suhkneung Pyo
Cr (VI) induces crosstalk between apoptosis and autophagy through endoplasmic reticulum stress in A549 cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-25 Hong Ge, Zhiguo Li, Liping Jiang, Qiujuan Li, Chengyan Geng, Xiaofeng Yao, Xiaoxia Shi, Yong Liu, Jun Cao
Hexavalent chromium [Cr (VI)], which is widely found in occupational environments, is a recognized human carcinogen. In this study, the role of endoplasmic reticulum (ER) stress in Cr (VI)-induced crosstalk of apoptosis and autophagy was investigated. Cr (VI) resulted in ER stress by upregulating the expression of GRP78 and p-PERK. 4-Phenylbutyric acid (4PBA), an inhibitor of ER stress, reduced both Cr (VI)-induced apoptosis and autophagy, suggesting that ER stress played an important role in Cr (VI)-induced apoptosis and autophagy in A549 cells. Furthermore, Cr (VI)-induced apoptosis preceded autophagy. Z-VAD-FMK, the suppressor of apoptosis, repressed Cr (VI)-induced autophagy. Pretreatment with 3-MA, the inhibitor of autophagy, increased Cr (VI)-induced apoptosis. Exposure to Cr (VI) significantly reduced mitochondrial membrane potential (MMP) during Cr (VI) treatment for 6–12 h. However, Cr (VI)-reduced MMP rescued significantly after treatment with Cr (VI) for 24 h compared with that of 6 h and 12 h groups, suggesting that Cr (VI)-induced autophagy at 24 h might rescue Cr (VI)-induced decrease of MMP through engulfing damaged mitochondria and then inhibit apoptosis in A549 cells. Above all, our results indicated that Cr (VI)-induced ER stress plays an important role in the crosstalk between apoptosis and autophagy. The autophagy might be apoptosis-dependent and subsequently prevents apoptosis cell death to keep A549 cells resistant to Cr (VI)-induced further toxicity. This maybe underlies the mechanism of Cr (VI)-induced carcinogenesis.
Identification of nafamostat mesilate as an inhibitor of the fat mass and obesity-associated protein (FTO) demethylase activity Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-25 Xinxin Han, Ning Wang, Junya Li, Ying Wang, Ruiyong Wang, Junbiao Chang
Hydrophilic scaffolds of oxime as the potent catalytic inactivator of reactive organophosphate Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-25 Shengzhuang Tang, Pamela T. Wong, Jayme Cannon, Kelly Yang, Sierra Bowden, Somnath Bhattacharjee, Jessica J. O'Konek, Seok Ki Choi
MicroRNA-454 contributes to sustaining the proliferation and invasion of trophoblast cells through inhibiting Nodal/ALK7 signaling in pre-eclampsia Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-24 Ziyun Shi, Kaie She, Hong Li, Xiaohua Yuan, Xi Han, Yaqin Wang
Protein kinase Cδ knockout mice are protected from cocaine-induced hepatotoxicity Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-25 Huynh Nhu Mai, Sung Hoon Lee, Garima Sharma, Dae-Joong Kim, Naveen Sharma, Eun-Joo Shin, Duc Toan Pham, Quynh Dieu Trinh, Choon-Gon Jang, Seung-Yeol Nah, Ji Hoon Jeong, Hyoung-Chun Kim
Long-term diosbulbin B treatment induced liver fibrosis in mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-25 Yi Zhang, Hui Miao, Huida Guan, Changhong Wang, Zhengtao Wang, Lili Ji
Airpotato yam is a traditional Chinese medicine used for treating thyroid disease and cancer in China. Diosbulbin B (DB) is reported to be the main hepatotoxic compound isolated from Airpotato yam. A variety of reports have shown the acute liver injury induced by DB in vivo. However, whether long-term administration of DB will cause liver fibrosis in mice is unknown. This study aims to investigate the liver fibrosis induced by long-term DB treatment in mice. C57BL/6 mice were orally given with DB (25, 50 mg/kg) for 1 or 2 month, respectively. Liver hydroxyproline content, hepatic collagen deposition and immune cells infiltration were increased in mice treated with DB (50 mg/kg) for 2 months. Serum amounts of hyaluronic acid and laminin were increased in mice treated with DB for 1 or 2 months. DB (50 mg/kg) induced hepatic stellate cells (HSCs) activation when mice were treated with DB for 2 months. Liver mRNA expression of Col1a1, Col1a2, Col3a1, fibronectin (Fn1), vimentin (Vim) and fibroblast-specific protein 1 (FSP1) were all increased in DB-treated mice. Hepatic protein expression of Vim, FSP1 and collagen 1 (COL1) were increased in DB-treated mice. Additionally, DB induced nuclear factor κB (NFκB) activation and increased the expression of pro-inflammatory molecules including tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular cell adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in mice. In conclusion, long-term administration of DB induced liver fibrosis in mice. HSCs activation, epithelial-mesenchymal transition (EMT) and liver inflammation contributed to DB-induced liver fibrosis in mice.
Delphinidin protects β2m−/Thy1+ bone marrow-derived hepatocyte stem cells against TGF-β1-induced oxidative stress and apoptosis through the PI3K/Akt pathway in vitro Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Jiang Chen, Hong-Yu Li, Di Wang, Xiao-Zhong Guo
β2m−/Thy1+ bone marrow-derived hepatocyte stem cells (BDHSCs) have a potential to be applied for cellular treatment in liver cirrhosis. However, the resultant tissue regeneration is restricted by transplanted cells' death. The accumulation of transforming growth factor beta 1 (TGF-β1) in liver fibrosis local microenvironment may play an essential role in the rapid cell death of implanted β2m−/Thy1+ BDHSCs. The main mechanism of poor survival of the target stem cells is still unknown. Delphinidin, an anthocyanidin, has potent antioxidant and anti-inflammatory activities. However, whether this bio-active ingredient can substantially contribute to β2m−/Thy1+ BDHSCs’ protection from TGF-β1 induced apoptosis in vitro remains to be elucidated. In the present research, we determined whether delphinidin pretreatment can improve the survival of β2m−/Thy1+ BDHSCs during exposure to TGF-β1 and elucidated its underlying mechanisms. By using TGF-β1, we induced the apoptosis of β2m−/Thy1+ BDHSCs and assessed the apoptotic rates up to 24 h by flow cytometry. β2m−/Thy1+ BDHSC proliferation was gauged using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl- 2H-tetrazolium bromide (MTT) assay. The expression grades of Bcl-2, Akt, caspase-3, and Bax were observed through Western blot analysis. We found that delphinidin can significantly impede TGF-β1-induced apoptosis dose-dependently, scavenge reactive oxygen species (ROS), and inhibit the discharge of caspase-3 in β2m−/Thy1+ BDHSCs. We also demonstrated that delphinidin can activate the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. The suppression of ROS and succeeding apoptosis was achieved by pretreatment with LY294002, a PI3K/Akt pathway inhibitor. In summary, our findings revealed that delphinidin can protect β2m−/Thy1+ BDHSCs from apoptosis and ROS-dependent oxidative stress induced by the TGF-β1 via PI3K/Akt signaling pathway. On the basis of these data, delphinidin can be regarded as a promising anti-apoptotic agent for enhancing β2m−/Thy1+ BDHSC survival during cell transplantation in liver cirrhosis patients.
Isoquercitrin, a flavonoid glucoside, exerts a positive effect on osteogenesis in vitro and in vivo Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Jing Li, Xuxia Wang, Yingzi Wang, Chengyan Lu, Dehua Zheng, Jun Zhang
Isoquercitrin (quercetin-3-O-β-d-glucopyranoside) possess various pharmacological effect as a biologically active compound. The aim of the present study was to investigate its potential effects on the proliferation and osteoblastic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) in vitro and bone formation in the mid-palatal suture during rapid maxillary expansion (RME) in vivo. Cell proliferation of rat BMSCs was detected by cell-counting kit- 8 (CCK-8) assay. Alkaline phosphatase (ALP) activity assay and alizarin red staining were used to evaluate osteogenic differentiation of BMSCs. Furthermore, the expression levels of osteogenesis-related genes including runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP) and activating transcription factor 6 (ATF6) were measured by real-time RT-PCR. In vivo, thirty-six male 6-week-old Wistar rats with or without suture expansion receive systemic administration of isoquercitrin or saline solution. Micro-CT, HE and Masson staining were used to compare the morphological changes between the groups. Bone morphogenetic protein 2 (BMP2) expression in the suture was detected using immunohistochemical staining. Our results showed that isoquercitrin significantly promoted cell proliferation, ALP activity and mineral deposition in the range from 0.01 to 1 μM. Moreover, the expression levels of Runx2, BSP and ATF6 were also upregulated. The measurement of micro-CT imaging and histological examinations demonstrated that daily oral administration of isoquercitrin (10 mg/kg) increased bone formation compared to the other groups. Furthermore, the expression level of BMP2 was also augmented in the presence of isoquercitrin. Consequently, those findings showed that isoquercitrin exerts stimulatory effects on osteogenesis in vitro and in vivo, suggesting that isoquercitrin could be a potential candidate for preventing relapse following RME within palatal sutures.
Vitexin alleviates streptozotocin-induced sexual dysfunction and fertility impairments in male mice via modulating the hypothalamus–pituitary–gonadal axis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Zhi-Mei Li, Ning Liu, Ya-Ping Jiang, Jie Zheng, Miao Sun, Yu-Xiang Li, Tao Sun, Jing Wu, Jian-Qiang Yu
Knockdown of galectin-1 facilitated cisplatin sensitivity by inhibiting autophagy in neuroblastoma cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Jie Gao, Wenying Wang
Neuroblastoma (NB) is a type of solid extracranial tumor that usually occurs in babies and children. Chemotherapy is a common method for NB treatment, however, the drug resistance exerts during the chemotherapy of NB. Galectin-1 is a member of galectin family and plays a potent role in the development of chemotherapy and radiotherapy resistance. However, the effect of galectin-1 on cisplatin resistance in NB remains unknown. The present study aimed to investigate the role of galectin-1 in cisplatin resisitance and the potential mechanism. Human neuroblastoma SH-SY5Y and SK-N-SH cells were treated with cisplatin and/or galectin-1/siRNA targeting galectin-1 (si-Gal-1). The cell viability was measured by MTT assay. The IC50 values for cisplatin of neuroblastoma cells were calculated. The expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3B), Beclin-1, and p62 were detected by western blot. We found that cisplatin inhibited cell viability of SH-SY5Y and SK-N-SH in a dose-dependent manner. Cisplatin induced the ratio of LC3B-II/LC3B-I and Beclin-1 expression, and inhibited the p62 expression. Knockdown of galectin-1 decreased the IC50 for cisplatin of SH-SY5Y and SK-N-SH cells and inhibited cisplatin-induced autophagy. Moreover, inhibition of autophagy suppressed galectin-1-induced increase in IC50 for cisplatin. In conclusion, galectin-1 knockdown enhanced cisplatin sensitivity of neuroblastoma cells by inhibiting autophagy. The findings might provid a novel therapeutic target to overcome cisplatin resistance in chemotherapy of NB.
Preventive effect of bergenin against the development of TNBS-induced acute colitis in rats is associated with inflammatory mediators inhibition and NLRP3/ASC inflammasome signaling pathways Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Guilherme Antônio Lopes de Oliveira, Catalina Alarcón de la Lastra, Maria Ángeles Rosillo, Maria Luisa Castejon Martinez, Marina Sánchez-Hidalgo, Jand Venes Rolim Medeiros, Isabel Villegas
Rutin alleviates hypoxia/reoxygenation-induced injury in myocardial cells by up-regulating SIRT1 expression Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-23 Han Yang, Chao Wang, Lingyan Zhang, Jun Lv, Hongzao Ni
Rutin possesses multiple pharmacological activities, including the cardioprotective effect. The present study aimed to evaluate the protective effects of rutin on hypoxia/reoxygenation (H/R)-induced myocardial injury and its underlying mechanism involved. H9c2 cells were pretreated with 50 μM rutin or combined with 1 μM silent information regulator 1 (SIRT1) inhibitor (EX-527) for 1 h, and subjected to hypoxia for 6 h, followed by reoxygenation for 24 h. SIRT1 expression was detected by qRT-PCR and western blot. The effects of rutin or combined with EX-527 on cell viability, myocardial injury, apoptotic rate, and oxidative stress in H/R-stimulated H9c2 cells were assayed. The results showed that rutin elevated SIRT1 expression in H9c2 cells, as well as H/R-stimulated H9c2 cells. Rutin increased cell viability in H9c2 cells exposed to H/R. H/R stimulation induced myocardial injury, as evidenced by the increased levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and aspartate transaminase (AST), which were abolished in the presence of rutin. Rutin attenuated H/R-induced increase of apoptotic rate and caspase-3 activity in H/R-treated cells. Moreover, H/R-induced decrease in the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and increase in malondialdehyde (MDA) content were reversed by rutin treatment. The presence of EX-527 abolished these protective effects of rutin. In conclusion, rutin protected H9c2 cells against H/R injury through increasing SIRT1 expression. Our findings suggested that rutin might be a potential therapeutic agent for the treatment of myocardial H/R injury.
Beta-caryophyllene protects diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-19 Dareen A. Youssef, Hassan M. El-Fayoumi, Mona F. Mahmoud
Pharmalogical activities of antroquinonol - Mini review Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-19 M. Shanmugavadivu, Bharath Kumar Velmurugan
Studies on relationships between essential and toxic elements in selected body fluids, cells and tissues Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-21 Maria Długaszek
Processes occurring in the cellular and extracellular environment with the participation of elements both essential due to their vital functions and harmful to organism are complex and depend on many factors. The type of element and its chemical form as well as chemical composition of environment in which they occur play the significant role in the processes. But quantitative relationships between elements are also important, since both the excess and deficiency perturb their homeostasis in the organism. They can interact with each other at the absorption stage, transport in the blood, distribution in tissues and excretion. Quantitative correlations between Ca, Mg, Zn, Cu, Fe, Mn, Cr, Ni, Pb, Cd, and Al in some body fluids (serum, urine), cells (red blood cells) and tissues (human and animal hair, muscle and bone tissue, liver, kidney, stomach) are presented in the paper. It was stated that the following pairs of elements correlate most often: Ca-Mg, Mg-Zn, Cu-Zn, Fe-Cd, and Pb-Cd. It seems that the crucial role in the correlations between elements play their similarity in chemical and physical properties (first of all the size of ions radius and electric charge), the life processes in which the elements participate and the common environmental origin).
The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-18 Thierry Franck, Iyas Aldib, Karim Z. Boudjeltia, Paul G. Furtmüller, Christian Obinger, Philippe Neven, Martine Prévost, Jalal Soubhye, Pierre Van Antwerpen, Ange Mouithys Mickalad, Didier Serteyn
A water-soluble curcumin lysinate incorporated into hydroxypropyl-β-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-β-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼107 M−1 s−1) but not for Compound II (∼103 M−1 s−1) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by π-stacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-β-cyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropyl-β-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.
The linear no-threshold model is less realistic than threshold or hormesis-based models: An evolutionary perspective Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-17 David Costantini, Benny Borremans
The linear no-threshold (LNT) risk model is the current human health risk assessment paradigm. This model states that adverse stochastic biological responses to high levels of a stressor can be used to estimate the response to low or moderate levels of that stressor. In recent years the validity of the LNT risk model has increasingly been questioned because of the recurring observation that an organism's response to high stressor doses differs from that to low doses. This raises important questions about the biological and evolutionary validity of the LNT model. In this review we reiterate that the LNT model as applied to stochastic biological effects of low and moderate stressor levels has less biological validity than threshold or, particularly, hormetic models. In so doing, we rely heavily on literature from disciplines like ecophysiology or evolutionary ecology showing how exposure to moderate amounts of stress can have severe impacts on phenotype and organism reproductive fitness. We present a mathematical model that illustrates and explores the hypothetical conditions that make a particular kind of hormesis (conditioning hormesis) ecologically and evolutionarily plausible.
Biomarkers of obstructive nephropathy using a metabolomics approach in rat Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-17 Zhi-Hao Zhang, Jun-Qiu He, Wei-Wei Qin, Ying-Yong Zhao, Ning-Hua Tan
Chronic kidney disease (CKD) has become a major public health problem worldwide and has a great impact on the quality of life of millions of people. Long-term obstructive uropathy is an important cause of CKD. We hypothesized diagnostic biomarkers for early stage obstructive nephropathy can be discovered by metabolomic profiling of biofluid. Unilateral ureteral occlusion (UUO) surgery was performed on rats to induce renal interstitial fibrosis. Sham-operated rats were used as controls. Plasma and urine metabolites were analyzed by UPLC-MS based metabolomic approach. Significant metabolic profiling separations were found between UUO rats and controls at different time points. 13 differential plasma metabolites and 14 differential urine metabolites were identified at the first postoperative day. The altered metabolic pathways included glycerophospholipid metabolism, tryptophan metabolism, glutamate metabolism and purine metabolism. We further identified a panel of five plasma biomarkers which offer good diagnostic performance (areas under the curve of 1.0 in the discovery set and validation set) for early diagnosis of obstructive nephropathy. These findings demonstrate that early stage obstructive nephropathy can be diagnosed in an animal model based on plasma metabolomics which is a powerful tool for characterizing metabolic disturbances. This method has strong potential for clinical translation.
Capsaicin alleviates hyperlipidemia, oxidative stress, endothelial dysfunction, and atherosclerosis in Guinea pigs fed on a high-fat diet Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-17 Siyuan Yang, Lin Liu, Like Meng, Xuanyi Hu
Capsaicin has anti-inflammatory and antioxidant effects, as well as some benefits on the cardiovascular system. The exact effects of capsaicin on atherosclerosis are poorly understood. To investigate the effects of capsaicin on hyperlipidemia and atherosclerosis in guinea pigs fed on a high-fat diet, as well as its potential mechanisms. Guinea pigs (n = 48) were randomly divided into six groups (n = 8/group): normal diet (control); high fat diet (model); model + low-dose capsaicin (2.5 mg/kg); model + moderate-dose capsaicin (5 mg/kg); model + high-dose capsaicin (10 mg/kg), and model + simvastatin (1.5 mg/kg) (positive control). After 14 weeks, serum lipids, apolipoprotein B100, malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and endothelin-1 were measured. Aortic atherosclerotic lesions were histologically examined. eNOS and iNOS were assessed by immunohistochemistry. The model group developed severe dyslipidemia and associated histologic changes and endothelial dysfunction. All doses of capsaicin decreased total cholesterol, triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B-100, and increased high-density lipoprotein cholesterol (all P < 0.05). Capsaicin alleviated the plaque area (−17.9–70.5%), plaque area to intima ratio (−18.0–73.6%), and intima thickness (−20.5–83.6%) (all P < 0.05). Capsaicin decreased MDA (−45.5–76.1%), ET-1 (−19.6–51.6%), and average gray value (AGV) of eNOS (−10.9–48.8%), and increased SOD activity (+31.7–76.1%), NO (+11.2–36.8%), and AGV of iNOS (+6.8-+93.0%) (all P < 0.05). Similar changes were observed with simvastatin. Capsaicin alleviated hyperlipidemia and atherosclerosis in guinea pigs fed on a high-fat diet. Alleviated oxidative stress and endothelial dysfunction were involved in these benefits. This could represent a novel approach to prevent cardiovascular diseases.
Taurine attenuates OTA-promoted PCV2 replication through blocking ROS-dependent autophagy via inhibiting AMPK/mTOR signaling pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-14 Nianhui Zhai, Hong Wang, Ying Chen, Hu Li, Korolchuk Viktor, Kehe Huang, Xingxiang Chen
MicroRNA-148b-3p is involved in regulating hypoxia/reoxygenation-induced injury of cardiomyocytes in vitro through modulating SIRT7/p53 signaling Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-09 Meng Sun, Mengen Zhai, Nan Zhang, Rui Wang, Hongliang Liang, Qinghua Han, Yongping Jia, Liqin Jiao
Toxicity of lupane derivatives on anionic membrane models, isolated rat mitochondria and selected human cell lines: Role of terminal alkyl chains Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-04 Filipa S. Carvalho, Catarina M. Morais, Jon Holy, Dmytro Krasutsky, Sergiy V. Yemets, Pavel A. Krasutsky, António J. Moreno, Amália S. Jurado, Paulo J. Oliveira, Teresa L. Serafim
Triterpenoids have multiple biological properties, although little information is available regarding their toxicity. The present study evaluates the toxicity of two new synthetic lupane derivatives using distinct biological models including synthetic lipids membranes, isolated liver and heart mitochondria fractions, and cell lines in culture. The two novel triterpenoids caused perturbations in the organization of synthetic lipid bilayers, leading to changes in membrane fluidity. Inhibition of cell proliferation and mitochondrial and nuclear morphological alterations were also identified. Inhibition of mitochondrial oxygen consumption, transmembrane electric potential depolarization and induction of the mitochondrial permeability transition pore was observed, although effects on isolated mitochondrial fractions were tissue-dependent (e.g. liver vs. heart). The size and length of hydrocarbon chains in the two molecules appear to be determinant for the degree of interaction with mitochondria, especially in the whole cell environment, where more barriers for diffusion exist. The results suggest that the positively charged triterpenoids target mitochondria and disrupt bioenergetics.
NEAT1 contributes to the CSC-like traits of A549/CDDP cells via activating Wnt signaling pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-03 Pan Jiang, Hai Xu, Chuyue Xu, Aochang Chen, Lijun Chen, Ming Zhou, Ijaz ul Haq, Xiaoyue Wu, Zahula Mariyam, Qing Feng
Long non-coding RNAs (lncRNAs) have been identified to exert crucial roles in tumorigenesis and can serve as novel biomarkers for cancer therapy including lung cancer. Cisplatin is a first-line chemotherapeutic agent in non-small cell lung cancer (NSCLC), but the therapeutic effect is unsatisfactory, partly due to drug resistance. Emerging evidence showed that chemo-resistance is associated with acquisition of cancer stem cell (CSC)-like properties. Cisplatin resistance remains a major obstacle in the treatment of lung cancer, and its mechanism is still not fully elucidated. Meanwhile, CSCs have been involved in tumor metastasis, tumor recurrence and chemotherapy resistance. So far, the mechanism of nuclear enriched abundant transcript 1 (NEAT1) in modulating CSCs in lung cancer remains barely known. Therefore, we aimed to explore the correlation between NEAT1 and cancer stem cells in lung cancer. In our current study, we observed that CSC-like traits were much more enriched in cisplatin-resistant A549/CDDP cells. In addition, NEAT1 was obviously up-regulated in A549/CDDP cells compared with parental A549 cells. Knockdown of NEAT1 decreased the CSC-like properties of A549/CDDP cells through inhibiting tumor cell sphere volume, repressing CSC-like biomarkers levels and restraining CD44 positive cell ratios. Oppositely, overexpression of NEAT1 enhanced the stemness respectively. Moreover, it has been reported that Wnt pathway is implicated in many vital cellular functions including cancer stem cells. Here, it was exhibited that Wnt signal pathway was inactivated by knockdown of NEAT1 whereas activated by NEAT1 overexpression in A549/CDDP cells. Taken these together, it was indicated that NEAT1 could exert a novel biological role in NSCLC chemo-resistance.
Phloretin cytoprotection and toxicity Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-10-01 Brian C. Geohagen, Boris Korsharskyy, Amaresh Vydyanatha, Lars Nordstroem, Richard M. LoPachin
Phloretin (Phl) is a dihydrochalcone flavonoid with significant cytoprotective properties; e.g., free radical trapping, electrophile scavenging. Based on this, it has been suggested that Phl might be useful in the treatment of pathogenic processes and prevention of drug toxicities. Therefore, we determined the ability of Phl to provide route- and dose-dependent hepatoprotection in a mouse model of acetaminophen (APAP) overdose. Intraperitoneal (i.p.) administration of Phl produced a bimodal effect; i.e., the highest dose (2.40 mmol/kg) did not prevent APAP-induced lethality, whereas lower doses (0.2–0.4 mmol/kg) afforded modest hepatoprotection. When given alone, the highest i.p. Phl dose was lethal within 24 h, whereas the lower doses were not toxic. Oral Phl (0.40–2.40 mmol/kg) did not prevent APAP-induced hepatotoxicity. The highest oral dose given alone (2.4 mmol/kg) produced 64% lethality, whereas lower doses were not lethal. This toxicity profile was reflected in a study using APAP-exposed isolated mouse hepatocytes, which showed that the Phl pharmacophores, 1,3,5-trihydroxyacetophenone (PG) and 2′,4′,6′-trihydroxyacetophenone (THA) where protective. Corroborative cell free studies showed that polyphenol protectants prevented glutathione loss mediated by the APAP metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Thus, in spite of possesing cytoprotective attributes, Phl was generally toxic in our APAP models. These and earlier findings suggest that Phl is not a candidate for drug design. In contrast, we have found that the enol-forming pharmacophores, THA and PG, are potential platforms for pharmacotherapeutic development.
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