Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-20 Yuya Urano, Shingo Oda, Koichi Tsuneyama, Tsuyoshi Yokoi
Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters such as bile salt export pump (Bsep) and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify these mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that among the three GPR40 agonists, TAK-875, AMG-837 and TUG-770, only TAK-875 induced acute liver injury in mice. The comparison of transcriptome profiles of TAK-875-exposed liver with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. In conclusion, by a comprehensive transcriptomic analysis of GPR40 agonists, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.
Inhibition of microRNA-30d attenuates the apoptosis and extracellular matrix degradation of degenerative human nucleus pulposus cells by up-regulating SOX9 Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-19 Junlin Lv, Siyuan Li, Tingting Wan, Yimeng Yang, Yali Cheng, Rongliang Xue
Tissue oxidative damage mediates impairment on phosphotransfer network during thymol intake: Effects on hepatic and renal bioenergetics Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-19 Matheus D. Baldissera, Carine F. Souza, Antônio Francisco Igor M. De Matos, Bernardo Baldisserotto, Aleksandro S. da Silva, Silvia G. Monteiro
Recent evidences demonstrated that ingestion of several monoterpenes cause hepatic and renal damage due to impairment on mitochondrial energy production, eliciting a collapse on adenosine triphosphate (ATP) synthesis and consequently impairment on bioenergetic homeostasis. Thus, the aim of this study was to evaluate whether phosphotransfer network, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), can be a pathway to explain hepatic and renal bioenergetics homeostasis impairment due to thymol ingestion. Daily intake of thymol (40 mg/kg) significantly cause a decreased kidney weight and relative kidney weight compared to control group. The same dose of thymol inhibited renal cytosolic and mitochondrial CK activity as well as renal PK activity compared to control group. Finally, thymol (40 mg/kg) elicited a significant increase on renal reactive oxygen species and lipid damage levels, as well as an inhibition on antioxidant capacity against peroxyl radicals and non-protein thiol levels, which did not occur liver. Doses of 10 and 20 mg/kg of thymol administered orally for 30 consecutive days non-changed these variables. Based on these evidence, the data supported that intake of a high dose of thymol severely inhibits cytosolic and mitochondrial CK activity, a crucial enzyme to maintain cellular energy homeostasis. Moreover, high dietary thymol intake impaired communication between CK isoenzymes, which inhibits the attempts to regenerate ATP or to facilitate the CK/PCr shuttle to improve the intracellular ATP utilization and consumption. Moreover, the inhibition of renal CK and PK activities appears to be mediated by the renal oxidation of lipids and thiol groups, as well as by the reduction of the renal antioxidant capacity.
Oridonin prevents epithelial-mesenchymal transition and TGF-β1-induced epithelial-mesenchymal transition by inhibiting TGF-β1/Smad2/3 in osteosarcoma Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-19 Yang Sun, Xiubo Jiang, Ying Lu, Jianwei Zhu, Lisha Yu, Bo Ma, Qi Zhang
Osteosarcoma is the most common primary bone tumor with highly invasive characteristic and low long-term survival. Recently, epithelial-mesenchymal transition (EMT) is reported as a key event in cancer invasion and metastasis. Oridonin, a bioactive diterpenoid, has been proved to possess anti-cancer effects. However, the effect of oridonin on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the underlying mechanism of oridonin on EMT and metastasis of osteosarcoma. We found that oridonin inhibited migration and invasion of MG-63 and 143B cells. Moreover, oridonin increased the protein expression of E-cadherin and decreased that of N-cadherin and Vimentin. Oridonin upregulated the transcription of E-cadherin and downregulated N-cadherin and Vimentin. Oridonin inhibited the protein and mRNA levels of Snail and Slug. Furthermore, oridonin inhibited TGF-β-induced phosphorylation of Smad 2/3, prevented Smad dimer translocation into the nucleus. Finally, we established metastatic models of osteosarcoma 143B cells, and found that oridonin inhibited lung metastasis in vivo. Oridonin increased the protein expression of E-cadherin and reduced N-cadherin and Vimentin. Oridonin inhibited the protein expression of Snail and Slug as well as Smad 2/3 activation. In conclusion, our study demonstrated that oridonin inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma.
A review of biological and pharmacological activities of Baccharis trimera Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-18 Ana Carolina Silveira Rabelo, Daniela Caldeira Costa
GADD45β-I attenuates oxidative stress and apoptosis via Sirt3-mediated inhibition of ER stress in osteoarthritis chondrocytes Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-17 Zhi Zhang, Meng Li, Xing Ma, Shuang-Li Zhou, Zhi-Wei Ren, Yu-Sheng Qiu
Osteoarthritis (OA) is one of the most characterized joint diseases associated with chondrocyte apoptosis. JNK plays an important role in apoptosis in many pathological conditions, but systemic inhibition of JNK was shown to result in detrimental side effects. MAPK kinase 7 (MKK7) is a direct upstream kinase that regulates JNK and has been shown to activate JNK specifically under toxic conditions. In this study, we investigated the effect of GADD45β-I, a cell-permeable inhibitor targeted for MKK7, on IL-1β-induced cytotoxicity in rat chondrocytes. The results showed that IL-1β exposure resulted in toxicity in a dose-dependent manner, which was nullified by endoplasmic reticulum (ER) stress inhibitors. GADD45β-I significantly preserved cell survival, inhibited oxidative injury and reduced apoptosis after IL-1β treatment. ER stress in chondrocytes was attenuated by GADD45β-I, as evidenced by reduced levels of GRP78 and CHOP, as well as decreased caspase-12 cleavage. In addition, GADD45β-I increased the enzymatic activities of mitochondrial antioxidant enzymes, including IDH2, GSH-Px and SOD2. GADD45β-I significantly upregulated the expression of Sirt3 and attenuated IL-1β-induced acetylation of SOD2. Furthermore, GADD45β-I-induced inhibition of ER stress and protection in chondrocytes were partially reversed by knockdown of Sirt3. In conclusion, our data indicated that GADD45β-I protected chondrocytes against IL-1β through Sirt3-mediated inhibition of ER stress. Targeting MKK7 might be an ideal therapeutic strategy for reducing chondrocyte apoptosis in OA.
The roles of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated proteins (MRPs/ABCCs) in the excretion of cycloicaritin-3-O-glucoronide in UGT1A1-overexpressing HeLa cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-17 Shishi Li, Jinjin Xu, Zhihong Yao, Liufang Hu, Zifei Qin, Hao Gao, Kristopher W. Krausz, Frank J. Gonzalez, Xinsheng Yao
Effects of methylglyoxal on RANKL-induced osteoclast differentiation in RAW264.7 cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-12 Kwang Sik Suh, Suk Chon, Woon-Won Jung, Eun Mi Choi
Methylglyoxal (MG) is a reactive dicarbonyl compound produced by glycolytic processing, which has been identified as a precursor of advanced glycation end products. Elevated MG levels in patients with diabetes are believed to contribute to diabetic complications, including bone defects. The objective of this study was to evaluate the effect of MG on RANKL-induced osteoclast differentiation in RAW264.7 cells, a murine macrophage cell line. RAW264.7 cells were cultured in medium containing 50 ng/mL RANKL and different concentrations of MG. Tartrate-resistant acid phosphatase (TRAP) activity and osteoclast bone resorbing activity were assessed and changes in intracellular calcium concentration, mitochondrial mass, mitochondrial membrane potential, and glyoxalase I level were examined. In addition, real-time RT-PCR assay was used to analyse osteoclast-associated genes. MG markedly inhibited RANKL-induced TRAP activity. MG treatment resulted in a significant decrease in intracellular calcium concentration, mitochondrial mass, mitochondrial membrane potential, and glyoxalase I level during osteoclastogenesis. In addition, MG increased the formation of mitochondrial superoxide. Quantitative reverse transcriptase-polymerase chain reaction revealed increased expression of the TRAF6, GAB2, ERK1, c-Fos, NFATc1, CLCN7, and OSTM1 genes, decreased expression of TCIRG and carbonic anhydrase II, and unchanged expression of cathepsin K and MMP-9 upon MG treatment. MG had no effect on the bone resorbing activity of osteoclasts. Our findings indicate that MG inhibits TRAP and glyoxalase I activity and impairs mitochondrial function in osteoclasts. Further validation of the underlying pathway is necessary.
Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in Guinea pigs Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-12 Marloes JA. Joosen, Steven D. Klaassen, Elwin Verheij, Tomas van Groningen, Alex S. Cornelissen, Mario H. Skiadopoulos, Laura Cochrane, Jeff D. Shearer
The efficacy and pharmacokinetics of the aqueous co-formulation contents of the TROBIGARD™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels.Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect.At both sarin challenge doses, 54 μg/kg and 84 μg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals.Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans.
4′-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-09-12 Dongdong Sun, Feng Zhang, Jie Qian, Weixing Shen, Huisen Fan, Jiani Tan, Liu Li, Changliang Xu, Ye Yang, Haibo Cheng
Different roles of Nrf2 and NFKB in the antioxidant imbalance produced by esculetin or quercetin on NB4 leukemia cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-30 Virginia Rubio, Ana I. García-Pérez, Angel Herráez, José C. Diez
Esculetin (6,7-dihydrocoumarin) and the flavonoid quercetin (3,5,7,3′,4′ pentahydroxyflavone) are compounds that could change the balance of redox homeostasis. NB4 leukemia cells were treated with 25 μM quercetin for 24 h and with esculetin at either 100 or 500 μM for different times. Quercetin increased the levels of pro-inflammatory NFkB p65 in the nucleus correspondingly reducing them in the cytosol. The levels of NFkB p65 decreased in the nucleus at high esculetin concentration treatments for long times (19 h), concomitantly increasing the levels of anti-inflammatory NFkB p50 in the nucleus. This could suggest formation of inhibitory p50 homodimers possibly related with anti-inflammatory response. Lipoxygenase expression was reduced either by esculetin or quercetin. A significant increase of Nrf2 in the nucleus of NB4 cells treated with 100 μM esculetin for 19 h was observed. Quercetin increased the levels of Nrf2 in the cytosol reducing them in the nucleus. Superoxide dismutase expression increased in NB4 cells treated with esculetin in contrast with quercetin. All these data support a relevant differential role for NFkB and Nrf2 in anti-inflammatory and redox response when apoptosis was induced by esculetin or quercetin in human leukemia NB4 cells.
Development of a magnetic nano-graphene oxide Carrier for improved glioma-targeted drug delivery and imaging: In vitro and in vivo evaluations Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-28 Sakine Shirvalilou, Samideh Khoei, Sepideh Khoee, Nida Jamali Raoufi, Mohammad Reza Karimi, Ali Shakeri-Zadeh
Influence of 6-aminonicotinamide (6AN) on Leishmania promastigotes evaluated by metabolomics: Beyond the pentose phosphate pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-29 Shawgi Hago Almugadam, Alessandro Trentini, Martina Maritati, Carlo Contini, Gianluca Rugna, Tiziana Bellini, Maria Cristina Manfrinato, Franco Dallocchio, Stefania Hanau
6-Aminonicotinamide (6AN) is an antimetabolite used to inhibit the NADPH-producing pentose phosphate pathway (PPP) in many cellular systems, making them more susceptible to oxidative stress. It is converted by a NAD(P)+ glycohydrolase to 6-aminoNAD and 6-aminoNADP, causing the accumulation of PPP intermediates, due to their inability to participate in redox reactions. Some parasites like Plasmodium falciparum and Coccidia are highly sensitive but not all cell types showed a strong responsiveness to 6AN, probably due to the different targeted pathway. For instance, in bacteria the main target is the Preiss-Handler salvage pathway for NAD+ biosynthesis. We were interested in testing 6AN on the kinetoplastid protozoan Leishmania as another model to clarify the mechanisms of action of 6AN, by using metabolomics. Leishmania promastigotes, the life-cycle stage residing in the sandfly, demonstrated a three order of magnitude higher EC50 (mM) compared to P. falciparum and mammalian cells (μM), although pre-treatment with 100 μM 6AN prior to sub-lethal oxidative challenge induced a supra-additive cell kill in L. infantum. By metabolomics, we did not detect 6ANAD/P suggesting that NAD+ glycohydrolases in Leishmania may not be highly efficient in catalysing transglycosidation as happens in other microorganisms. Contrariwise to the reported effect on 6AN-treated cancer cells, we did not detect 6-phosphogluconate (6 PG) accumulation, indicating that 6ANADP cannot bind with high affinity to the PPP enzyme 6 PG dehydrogenase. By contrast, 6AN caused a profound phosphoribosylpyrophosphate (PRPP) decrease and nucleobases accumulation confirming that PPP is somehow affected. More importantly, we found a decrease in nicotinate production, evidencing the interference with the Preiss-Handler salvage pathway for NAD+ biosynthesis, most probably by inhibiting the reaction catalysed by nicotinamidase. Therefore, our combined data from Leishmania strains, though confirming the interference with PPP, also showed that 6AN impairs the Preiss-Handler pathway, underlining the importance to develop compounds targeting this last route.
β-eudesmol inhibits thymic stromal lymphopoietin through blockade of caspase-1/NF-κB signal cascade in allergic rhinitis murine model Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-24 Phil-Dong Moon, Na-Ra Han, Jin Soo Lee, Hee-Yun Kim, Sungwei Hong, Hyeong-Jin Kim, Min-Sun Yoo, Hyung-Min Kim, Hyun-Ja Jeong
Allergic rhinitis (AR) is a global health problem because of its steadily increasing incidence and prevalence that currently affects about 30% of people worldwide. β-eudesmol has various beneficial effects, including anti-cancer and anti-allergic activities. However, the effects of β-eudesmol on AR have not yet been clarified; thus, we investigated the effects of β-eudesmol in an ovalbumin-induced AR animal model using enzyme-linked immunosorbent assay, histamine assay, Western blotting, and hematoxylin and eosin staining methods. β-eudesmol reduced the nasal rubs score and levels of histamine and immunoglobulin E in serum of AR mouse. In addition, the levels of thymic stromal lymphopoietin, interleukin-1β, tumor necrosis factor-α, and macrophage inflammatory protein-2 were down-regulated and infiltration of eosinophils and the level of intercellular adhesion molecule-1 were inhibited by β-eudesmol administration. β-eudesmol administration also reduced active caspase-1 and nuclear factor-κB DNA binding activity in nasal mucosa tissues of AR mice. Taken together, these results indicate that β-eudesmol would be effective for the treatment of allergic and inflammatory diseases, such as AR.
Deoxypodophyllotoxin in Anthriscus sylvestris alleviates fat accumulation in the liver via AMP-activated protein kinase, impeding SREBP-1c signal Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-24 Kwang-Youn Kim, Kwang-Il Park, Seul Gi Lee, Su Youn Baek, Eun Hye Lee, Sang Chan Kim, Sang-Hun Kim, Sul-Gi Park, Sun-Nyoung Yu, Tae Woo Oh, Joung-Hee Kim, Keuk-Jun Kim, Soon-Cheol Ahn, Young Woo Kim
Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan in Anthriscus sylvestris known as cow parsley or wild chervil, and has been reported to have inhibitory effects against several pathological processes including cancer, inflammation and infection. Here, we report the effects of DPT in the fatty liver induced by high fat diet in vivo as well as its regulatory mechanism related with the transcription factor for lipogenic genes such as sterol regulatory element binding protein-1c (SREBP-1c) in vitro. C57BL/6 mice were fed high fat diet for 10 weeks and also orally administrated with DPT for additional 4 weeks. 5 and 10 mg/kg of DPT decreased lipid accumulation in the liver induced by high fat diet, as indicated by histological parameters such as Oil Red O staining and hematoxylin & eosin as well as the contents of hepatic triglyceride and cholesterol. In hepatocytes, DPT inhibited the liver X receptor α-mediated SREBP-1c induction and expression of the lipogenic genes, including fatty acid synthase, acetyl-CoA carboxylase and stearoyl-CoA desaturase-1. Moreover, DPT induced AMP-activated protein kinase (AMPK) activation, which has been known to inhibit the expression of SREBP-1c in hepatocyte. Also this compound restored the dysregulation of AMPK and SREBP-1c induced by high fat diet in mice. In conclusion, we demonstrated that DPT significantly inhibited fatty liver by adjusting lipid metabolism coordinated with AMPK activation and SREBP-1c inhibition.
Role of glutathione S-transferases in detoxification of a polycyclic aromatic hydrocarbon, methylcholanthrene Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-23 Sreenivasulu Dasari, Muni Swamy Ganjayi, Prabhakar Yellanurkonda, Sreenivasulu Basha, Balaji Meriga
Erucic acid, a component of Lorenzo's oil and PPAR-δ ligand modifies C6 glioma growth and toxicity of doxorubicin. Experimental data and a comprehensive literature analysis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-22 Meric A. Altinoz, Ayhan Bilir, İlhan Elmaci
BackgroundPPAR-δ is a transcription factor which has crucial roles in stimulating oligodendroglial differentiation and myelination and its activation was also shown to differentiate malignant C6 glioma cells into oligodendrocytes.ObjectiveOne of the ligands of PPAR-δ is erucic acid (EA), an edible omega-9 fatty acid consumed more by Asian populations and exists highly in Chinese womens milk. There exist epidemiological evidence that pediatric brain tumor incidence is among the lowest in the Chinese population. EA is also an ingredient of Lorenzo's oil used against adrenoleukodystrophy, a pediatric demyelinating disease. EA was inappropriately assumed as a strong cardiotoxin based on Spanish oil syndrome, caused by toxic-aniline dye refined rapeseed oil. In this study, we studied whether EA is capable to block growth of C6 glioma cells and modify cardiotoxicity of doxorubicin.Materials and methodsWe studied effects of EA on the 3-dimensional appearance of the adherent cells, soft agar colony formation and S-phase in the 3-dimensional spheroids in C6 glioma cell cultures. We also investigated the effects of EA on hepatic and cardiac toxicity of doxorubicin.ResultsEA decreased in vitro growth of C6 glioma cells at therapeutically achievable concentrations. EA effects were more prominent in 3D-assays (soft agar colonies and spheroids) and induced cell fusions in monolayer cultures. EA decreased S-phase inhibitory potency of doxorubicin (DOX), yet augmented its efficacy to induce a senescent morphology (as assessed by scanning electron microscopy) in monolayer and to increase iNOS and eNOS expression in spheroids. In our study, EA reduced DOX-induced necrosis in mice heart and liver and induced healthier morphology of heart mitochondria (as assessed by transmission electron microscopy); yet intercalated disks (ID) were more disturbed with DOX + EA.ConclusionsBoth the antitumor and cardiac effects of EA may associate with the cell-to-cell contact mechanisms. Combining systemic EA with intrathecal DOX-chemotherapy via Ommaya reservoirs may reduce DOX concentrations in systemic circulation, hinder toxic interactions with EA and induce selective kill of glioma cells.
Tussilagone, a major active component in Tussilago farfara, ameliorates inflammatory responses in dextran sulphate sodium-induced murine colitis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-22 Hye Jin Cheon, Sang-Hyeon Nam, Jin-Kyung Kim
Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Current IBD treatments are associated with poor tolerability and insufficient therapeutic efficacy, prompting the need for alternative therapeutic approaches. Recent advances suggest promising interventions based on a number of phytochemicals. Herein, we explored the beneficial effects of tussilagone, a major component of Tussilago farfara, in mice subjected to acute colitis induced by dextran sulfate sodium (DSS). Treatment with tussilagone resulted in a significant protective effect against DSS-induced acute colitis in mice via amelioration of weight loss, and attenuation of colonic inflammatory damage. Additionally, the expression of tumor necrosis factor-α and interleukin-6 and the activity of myeloperoxidase in colonic tissues were significantly reduced in tussilagone-treated mice. Furthermore, immunohistochemical analysis revealed that tussilagone treatment reduced the numbers of nuclear factor-kappa B (NF-κB) and increased the numbers of nuclear factor erythroid 2-related factor 2 (Nrf2) in nuclei of colonic tissues. Taken together, tussilagone treatment attenuated DSS-induced colitis in mice through inhibiting the activation of NF-κB and inducing Nrf2 pathways, indicating that tussilagone is a potent therapeutic candidate for treatment of intestinal inflammation.
Antioxidant and anti-inflammatory activities of berberine attenuate hepatic fibrosis induced by thioacetamide injection in rats Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-21 Laila Ahmed Eissa, Hany Ibrahim Kenawy, Amro El-Karef, Nehal Mohsen Elsherbiny, Kholoud Alaa El-Mihi
Berberine (BBR) is an isoquinoline alkaloid extracted from the roots, rhizomes and stems of coptis. Liver fibrosis is a worldwide health problem with no established therapy until now. The aim of our study is to investigate the efficacy of BBR on hepatic fibrosis induced in rats and to uncover other mechanisms. Rats were injected with thioacetamide (TAA) (200 mg/kg, i.p) twice per week for 6 weeks to induce fibrosis. Treated group were gavaged with BBR (50 mg/kg/day, p.o) simultaneously with TAA injection. Hepatic antioxidant enzymes (catalase, SOD, GPx) were assessed in hepatic homogenate. Their activities were attenuated by TAA injection and elevated by BBR administration. Additionally, serum IL-6 and mRNA levels of IL-1β, IL-6, IL-10 and IFN-γ were evaluated as inflammatory markers. Our results showed that BBR suppressed the inflammation induced by TAA injection. Tissue expression of α-SMA (marker of activated HSCs), TGF-β1 and fibronectin were measured by immunohistochemistry as well as mRNA expressions of TGF-β1 and fibronectin were quantified as fibrotic markers. The collagen deposition in hepatic tissues was assessed by Masson's trichome staining. BBR significantly alleviated TGF-β1 production, decreased collagen and fibronectin deposition and consequently attenuated hepatic fibrogenesis. Akt pathway controls cell survival, proliferation, migration and adhesion. The relative phosphorylation of Akt was determined in hepatic homogenates that was increased with TAA injection and decreased by BBR treatment. Inhibition of Akt pathway has been linked to the intrinsic pathway of apoptosis. Caspase-3, caspase-9, Bcl-2 and Bax were quantified as apoptotic markers using qPCR and also caspase-3 by immunohistochemistry. BBR-treated rats showed an increase in the expression of apoptotic markers. Moreover, BBR-treated rats showed restoration of normal liver lobular architecture as shown by H&E staining. In conclusion, BBR is a potential therapeutic candidate for liver fibrosis owing to its antioxidant and anti-inflammatory activities.
Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-20 Nagah E. Edrees, Azza A.A. Galal, Aliaa R. Abdel Monaem, Rasha R. Beheiry, Mohamed M.M. Metwally
Colistin is an effective antibiotic against multidrug-resistant (MDR) gram-negative bacterial infections; however, nephrotoxic and neurotoxic effects are fundamental dose-limiting factors for this treatment. This study was conducted to assess the potential protective effects of curcumin, a phenolic constituent of turmeric, against colistin-induced nephrotoxicity and neurotoxicity, and the possible mechanisms underlying any effect. Twenty-four adult male albino rats were randomly classified into 4 equal groups; the control group (orally received saline solution), the curcumin-treated group (orally administered 200 mg curcumin/kg/day), the colistin-treated group (IP administered 300,000 IU colistin/kg/day) and the concurrent group (orally received 200 mg curcumin/kg/day concurrently with colistin injection); all rats were treated for 6 successive days. Colistin administration significantly increased serum creatinine, urea and uric acid levels as well as brain gamma butyric acid (GABA) concentrations. In renal and brain tissues, colistin significantly increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and caspase-3 expression levels. In addition, colistin significantly decreased catalase (CAT), glutathione (GSH), and B-cell lymphoma 2 (Bcl-2) expressions. Curcumin administration in colistin-treated rats partially restored each of these altered biochemical, antioxidant, inflammatory and apoptotic markers. Histopathological changes in renal and brain tissues were also alleviated by curcumin co-treatment. Our study reveals a critical role of oxidative damage, inflammation and apoptosis in colistin-induced nephrotoxicity and neurotoxicity and showed that they were markedly ameliorated by curcumin co-administration. Therefore, curcumin could represent a promising agent for prevention of colistin-induced nephrotoxicity and neurotoxicity.
Enhanced cytotoxic effects of arsenite in combination with anthocyanidin compound, delphinidin, against a human leukemia cell line, HL-60 Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-17 Yuta Yoshino, Bo Yuan, Saki Okusumi, Reiji Aoyama, Ryo Murota, Hidetomo Kikuchi, Norio Takagi, Hiroo Toyoda
BENC-511, a novel PI3K inhibitor, suppresses metastasis of non-small cell lung cancer cells by modulating β-catenin/ZEB1 regulatory loop Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-17 Qianyun Zhang, Lichun Zhou, Yanhui Guan, Yanna Cheng, Xiuzhen Han
Sodium fluoride causes oxidative stress and apoptosis in cementoblasts Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Jing Ni, Yiming Li, Wu Zhang, Rong shu, Zhe Zhong
Objectives Toothpaste with fluoride concentration up to 5000 ppm are recommended to the patients who are susceptible to root caries; however, the effects of fluoride on cementoblasts have received less attention. Methods The OCCM-30 cells were exposed to 0,0.5, 5, 10 mM NaF respectively. A TUNEL (TdT-mediated dUTP-biotin nick end labeling) assay kit was used to detect the DNA fragmentation. Hoechst staining was used to determine changes of nuclear morphology. Real-time quantitative RT-PCR and Western blotting were performed to investigate the mRNA and protein expression of caspase-3,-8,-9, cleaved Poly (ADP-ribose) polymerase (PARP) and Fas-ligand (Fas-L), a ligand of death receptor. CA-DCF-DA [5 (6)-Carboxy-2′,7′-dichlorofluorescein diacetate] was used to measure the generation of reactive oxygen species (ROS) in OCCM-30 cells after the NaF stimulation. Results The results showed apoptotic morphological changes and DNA fragmentation in OCCM-30 cells exposed to high concentration of NaF. 10 mM NaF induced the expression of cleaved caspase-3,-8,-9 and cleaved Poly (ADP-ribose) polymerase (PARP). The mRNA expression of the Fas-L was also increased in cells exposed to 5 mM NaF. Furthermore, 10 mM NaF stimulation resulted in a significant generation of ROS in the OCCM-30 cells. Conclusions Our research demonstrated that apoptosis is activated by NaF in OCCM-30 cells through both of the extrinsic death receptor-dependent and oxidative stress-related intrinsic apoptotic pathway. Clinical significance More consideration should be given about the fluoride concentration and the frequency of dental products when used to prevent the root caries for patients with gingival recession.
Hyperoside suppresses tumor necrosis factor α-mediated vascular inflammatory responses by downregulating mitogen-activated protein kinases and nuclear factor-κB signaling Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Seon-A. Jang, Dae Won Park, Eun Hwa Shon, Sung Ryul Lee, Se Chan Kang
NOL8, the binding protein for beta-catenin, promoted the growth and migration of prostate cancer cells Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Shuo Gu, Peijin Hou, Kun Liu, Xiaobing Niu, Bingjian Wei, Fei Mao, Zongyuan Xu
Overactivation of beta-catenin/TCF signaling in prostate cancer is very common. However, how the beta-catenin/TCF complex is regulated in the nucleus remains largely unknown. In this study, we have shown that NOL8, a binding protein of beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. NOL8 is up-regulated in the prostate cancer, and promoted the growth, migration and colony formation of cancer cells. Knocking down the expression of NOL8 inhibited the growth, migration and colony formation of prostate cancer cells. The molecular mechanism study demonstrated that NOL8 promoted the migration and colony formation of cancer cells by activating beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of NOL8 in prostate cancer and suggested that NOL8 might be an important therapeutic target for prostate cancer.
Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Bin Sun, Changxian Dong, Hongzhao Lei, Yubin Gong, Miaomiao Li, Yuanfang Zhang, Hongyu Zhang, Longlong Sun
Infantile hemangioma (IH) is one of the most common benign vascular tumors of infancy. Propranolol has been recently introduced for the treatment of IH. However, the mechanism of protective effect has not been fully understood. In this study, hemangioma-derived endothelial cells (HemECs) were isolated and treated with propranolol. The cell viability was measured by MTT assay, and the cell cycle arrest was detected using flow cytometry. Cell invasion was determined using transwell assay. The expressions of matrix metalloproteinase (MMP)-2, MMP-9, Delta-like 4 (DLL4), Notch1, Akt, p-Akt, and vascular endothelial growth factor (VEGF) were detected using western blot. HemECs were incubated with recombinant human DLL4 (rhDLL4) to investigate the role of DLL4/Notch1 in the effect of propranolol. The results showed that propranolol inhibited cell viability of HemECs in a time-dependent manner. Propranolol suppressed cell proliferation of HemECs by arresting cell progression at G0/G1 phase. Propranolol inhibited the invasion ability of HemECs and reduced the expression levels of MMP-2 and MMP-9 in HemECs. Besides, propranolol treatment blocked the DLL4/Notch1 and Akt signaling and inhibited VEGF expression in HemECs. Treatment with rhDLL4 activated the Akt signaling and attenuated the effect of propranolol on HemECs. Our data indicated that propranolol inhibited the cell proliferation and invasion of HemECs. The effect was possibly involved in the DLL4/Notch1/Akt signaling pathway.
Oxidative stress caused by TiO2 nanoparticles under UV irradiation is due to UV irradiation not through nanoparticles Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Akihiro Moriyama, Ikuho Yamada, Junko Takahashi, Hitoshi Iwahashi
Currently, nanoparticles are used in various commercial products. One of the most common nanoparticles is titanium dioxide (TiO2). It has a catalytic activity and UV absorption, and generates reactive oxygen species (ROS). This catalytic activity of TiO2 nanoparticles was believed to be capable of killing a wide range of microorganisms. In the environment, the unique properties of TiO2 nanoparticles can be maintained; therefore, the increasing use of TiO2 nanoparticles is raising concerns about their environmental risks. Thus, assessment of the biological and ecological effects of TiO2-NOAAs is necessary. In this study, we assessed the effect of TiO2-NOAAs for S. cerevisiae using DNA microarray. To compare yeast cells under various conditions, six treatment conditions were prepared (1. adsorbed fraction to TiO2-NOAA under UV; 2. non-adsorbed fraction to TiO2-NOAA under UV; 3. adsorbed fraction to TiO2-NOAA without UV; 4. non-adsorbed fraction to TiO2-NOAA without UV; 5. under UV; and 6. untreated control). The result of the DNA microarray analysis, suggested that yeast cells that are adsorbed by TiO2-NOAA under UV irradiation suffer oxidative stress and this stress response was similar to that by only UV irradiation. We concluded that the effect of TiO2-NOAAs on yeast cells under UV irradiation is not caused by TiO2-NOAA but UV irradiation.
Epigenetic silencing of SFRP5 promotes the metastasis and invasion of chondrosarcoma by expression inhibition and Wnt signaling pathway activation Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Wei Sheng, Zhi-Cai Zhang, De-Yao Shi, Bai-Chuan Wang, Qiang Wu, Zeng-Wu Shao, Shu-Hua Yang, Tong-Chuan He, Jian-Xiang Liu
Backgroud/aims Abnormal activation of the Wnt/β-catenin signaling, which may be antagonized by the members of secreted frizzled-related proteins family (SFRPs), is implicated in tumor occurrence and development. However, the function of SFRP5 relating to Wnt/β-catenin pathway in chondrosarcoma is not clear yet. This study was undertaken to investigate the potential role of SFRP5 promoter methylation in chondrosarcoma metastasis and invasion through activating canonical Wnt signaling pathway. Methods and results The results demonstrated that SFRP5 promoter was hypermethylated and SFRP5 expression was significantly reduced in chondrosarcoma cell lines at the mRNA and protein levels. The canonical Wnt/β-catenin signaling was observably activated with β-catenin stabilization by dephosphorylation and translocation into the nulcear. 5-Aza-2′-deoxycytidine (5-Aza-dC), the DNA methyltransferase inhibitor, significantly inhibited the proliferation of chondrosarcoma cells by cell cycle arrest through repressing the methylation of SFRP5 and promoting its expression. Both 5-Aza-dC treatment and SFRP5 overexpression could significantly inhibited the metastasis and invasion of chondrosarcoma cells by inactivating Wnt/β-catenin signaling pathway and promoting chondrosarcoma cells mesenchymal-epithelial transition (MET). 5-Aza-dC also inhibited the xenograft growth and lung metastasis of chondrosarcoma cells in vivo via suppressing SFRP5 promotor methylation, inactivating Wnt/β-catenin pathway and inducing epithelial markers expression. Conclusion All of our results revealed the epigenetic silencing of SFRP5 by promoter methylation plays pivotal roles in chondrosarcoma development and metastasis through SFRP5/Wnt/β-catenin signaling axis. Modulation of their levels may serve as potential targets and diagnostic tools for novel therapeutic strategies of chondrosarcoma.
Effects of Δ9-tetrahydrocannabinol on irinotecan-induced clinical effects in rats Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-18 Ljerka Prester, Anja Mikolić, Andreja Jurič, Nino Fuchs, Marijana Neuberg, Ana Lucić Vrdoljak, Irena Brčić Karačonji
Because of the great interest for research on the potential use of cannabis preparations as co-medication for alleviation of toxic effects in cancer management, we investigated the influence of Δ9-tetrahydrocannabinol (Δ9-THC) to modulate irinotecan (CPT-11)-induced toxicity. Male Wistar rats were treated either with a single irinotecan intraperitoneal dose, 100 mg/kg body-weight (b.w.), or with irinotecan in combination with THC (7 mg/kg b. w., p. o., administered repeatedly for 1, 3 and 7 days). Serial blood samples were obtained up to seven days after dosing and were analyzed for complete blood count and biochemical parameters (liver enzymes, creatinine, inflammatory markers, and lipid status). Serial urine samples were collected in the first 24 h to monitor the time-course of THC metabolite 11-nor-9-carboxy-Δ9-THC (THC-COOH) excretion with concomitant irinotecan treatment or without. Both irinotecan and irinotecan + Δ9-THC administration caused moderate leukopenia but a greater decrease in leukocyte count was observed in the irinotecan + Δ9-THC treated compared to the single irinotecan suggesting higher cytotoxic effects in combined treatment. Irinotecan treatment induced elevation of aspartate aminotransferase (AST) in rats without diarrheal symptoms and without an increase in circulating pro-inflammatory mediators. Interestingly, the elevation of AST was not observed in the irinotecan + Δ9-THC group. The median creatinine-corrected urinary THC-COOH concentration was higher in the irinotecan + THC group compared to the THC-only group in a time-dependent manner, suggesting a possible early interaction between cannabinoids and irinotecan. Further studies are needed to investigate the role of cannabinoids particularly on hematological toxicity, irinotecan metabolism and their role as a possible modifiable factor among irinotecan-treated hosts.
Antitumor activity of BJ-1207, a 6-amino-2,4,5-trimethylpyridin-3-ol derivative, in human lung cancer Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-17 Jaya Gautam, Suhrid Banskota, Prakash Chaudhary, Sadan Dahal, Dong-Guk Kim, Han-eol Kang, Iyn-Hyang Lee, Tae-gyu Nam, Byeong-Seon Jeong, Jung-Ae Kim
Enhanced expression of NADPH oxidase (NOX) and the subsequent production of reactive oxygen species (ROS) are associated with lung cancer. In the present study, fifty 6-amino-2,4,5-trimethylpyridin-3-ol derivatives were screened for anticancer activity by targeting NOX2-derived ROS. The compounds suppressed ROS production and decreased cancer cell viability (R2 = 0.79). Among the derivatives, the compound coded BJ-1207, which contained a 4-(hydroxydiphenylmethyl)piperidine moiety, exhibited the most effective anticancer activity against A549 lung cancer cell line and eight other cancer cell lines, including H1299, MCF-7, MDA-MB-231, HT-29, SW620, Mia PaCa-2, PANC-1, and U937. BJ-1207 also showed significantly lower inhibitory effects on kinase insert domain receptor (KDR) and c-KIT tyrosine kinase but higher inhibitory activity on NOX than those of sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor. In addition, BJ-1207-induced inhibition of RTK-downstream signaling pathways, such as ROS production, and expression of target genes, such as stem cell factor and transforming growth factor-α, were similar to those induced by sunitinib. In the xenograft chick tumor model, BJ-1207 inhibited lung tumor growth to a similar or much greater extent than that of sunitinib or cisplatin, respectively. Overall, the present study showed that BJ-1207, a vitamin B6-derived 2,4,5-trimethylpyridin-3-ol compound with azacyclonol moiety at C (6)-position of the pyridine ring, inhibited NOX activity and that it is a promising lead compound for developing anticancer drugs against lung cancer.
Pattern differences between newborn and adult rats in cisplatin-induced hepatorenal toxicity Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-17 Bruna Cruz Weber Fulco, Juliano Ten Kathen Jung, Pietro Maria Chagas, Caroline Brandão Quines, Cristina Wayne Nogueira, Gilson Rogério Zeni
Although cisplatin (CIS) has been associated with serious adverse effects, such as hepatotoxicity and nephrotoxicity in adult rats, there is few reports on its use in newborn rats. The aim of this study was to evaluate acute toxic effects of CIS in newborn rats. Adult and newborn Wistar rats received CIS by the i. p. route, at the dose of 5 or 10 mg/kg. After 24 h of treatment, blood, kidney, and liver were excised from the animals and parameters of renal and hepatic functions, oxidative stress markers were determined. Acute administration of CIS caused an increase of AST activity and urea levels, suggesting hepatorenal toxicity in newborn and adult rats. However, the pattern and intensity of damage was different between ages and tissues. Newborn rats showed more pronouncedly oxidative stress damage, characterized by an increase in reactive species and protein carbonyl levels, lower NPSH content and highest inhibition in δ-ALA-D and CAT activities. Besides that, it was observed a faster molecular response in protein levels involved with apoptosis and oxidative stress response; whereas in the beginning the damage was less severe in the kidney than in the liver of adult rats. Thus, the present study shows that there are body response differences between adult and newborn rats to CIS acute exposure being that newborn rats are more susceptible than adults.
Selenothymidine protects against biochemical and behavioral alterations induced by ICV-STZ model of dementia in mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-16 Gustavo Roberto Thomé, Vitor Antunes Oliveira, Maria Rosa Chitolina Schetinger, Rogério Aquino Saraiva, Diego Souza, Oscar Endrigo Dorneles Rodrigues, João Batista Teixeira Rocha, Rafael Porto Ineu, Maria Ester Pereira
The present study evaluated the neuroprotective effects of one selenium-containing AZT derivative compound (S1073) in memory and learning impairment caused by Intracerebroventricular-streptozotocin (ICV-STZ). ICV-STZ in mice causes impairment of energy metabolism with oxidative damage and cholinergic dysfunction, and provides a relevant model for sporadic dementia of Alzheimer's type (AD). Acetylcolinesterase (AChE), Catalase (CAT), dichlorofluorescein oxidation (DCFH), TBARS and thiol content were measured. Swiss adult mice were pre-treated with S1073 [1 mmol/kg] (i.p.) and after 30 min of the injection received a bilateral dose of STZ [11.3 μmol/l]. After 8 days' STZ injection, we performed the behavioral experiments (Beaker test, Open field and Morris water maze task). ICV-STZ caused significant learning and memory impairments, which were significantly improved by S1073 pre-treatment. A significant increase in cerebral DFCH, TBARS levels and AChE activity and a disturbance in the memory and learning were observed in ICV-STZ injected animals. S1073 significantly ameliorated all alterations induced by ICV-STZ in mice. All these findings support the neuroprotective role of S1073 in mice model of Alzheimer's dementia-type induced by ICV-STZ, which may be associated with its antioxidant activity and/or with its inhibitory effect in brain AChE. In fact, in silico analysis indicated that S1073 may be an inhibitor of AChE.
Small benzothiazole molecule induces apoptosis and prevents metastasis through DNA interaction and c-MYC gene supression in diffuse-type gastric adenocarcinoma cell line Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-11 Felipe Pantoja Mesquita, Laine Celestino Pinto, Bruno Moreira Soares, Adrhyann Jullyanne de Sousa Portilho, Emerson Lucena da Silva, Ingryd Nayara de Farias Ramos, André Salim Khayat, Caroline Aquino Moreira-Nunes, Mirna Marques Bezerra, Eliza de Lucas Chazin, Thatyana Rocha Alves Vasconcelos, Rommel Mario Rodríguez Burbano, Maria Elisabete Amaral de Moraes, Raquel Carvalho Montenegro
Chemo-resistance has been reported as a relevant barrier for the efficiency of gastric cancer treatment. Therefore, the development of effective and safe drugs for cancer chemotherapy is still a challenge. The purpose of this study was to evaluate the anticancer potential of (E)-2-((2-(benzo[d]thiazo-2-yl)hydrazono)methyl)-4-nitrophenol) (AFN01) against gastric cancer cell lines. Our results showed promising anticancer activity against gastric cancer cells ACP-02 (IC50 = 1.0 μM) and mild activity against other cell lines including non-malignant gastric cell MNP-01 (IC50 = 3.4 μM). This compound significantly induced S phase cell cycle arrest, prevented cell migration and triggered apoptosis in a concentration-dependent manner. Moreover, AFN01 was significantly more genotoxic against tumoral cell ACP-02, when compared to non-malignant cells, such as MNP-01 and healthy peripheral mononuclear blood cells. AFN01 also synergistically interacts with doxorubicin suppressing cell proliferation and c-MYC gene expression in gastric cancer cell line model, with remarkable c-MYC overexpression. Although further pre-clinical and clinical studies are required to explore its safety and efficiency, AFN01 may represent a promising lead anticancer agent for the treatment of gastric cancer.
Protective effects of apigenin against 3-MCPD-induced renal injury in rat Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-11 Yujie Zhong, Chengni Jin, Xiaorui Wang, Xuan Li, Jiahui Han, Wei Xue, Peng Wu, Xiaoli Peng, Xiaodong Xia
Apigenin (API) is a kind of important flavonoid present in temperate and tropical fruit and vegetables, especially the celery. It exerts anticancer, anti-bacterial, anti-viral, anti-inflammatory, anti-oxidation properties. In the present study, the mechanism of protective action of apigenin on 3-chloro-1, 2-propanediol (3-MCPD)-induced renal injury was investigated in rat. Sprague-Dawley (SD) rats were divided into five groups: control group (ultrapure water treated), CMC group (sodium carboxymethylcellulose treated), 3-MCPD treatment group (30 mg/kg body weight/day), 3-MCPD plus API co-treatment group (20, 40 mg/kg body weight/day). The results showed that API significantly reduced renal function markers, serum creatinine and urea nitrogen content. Besides, the renal tissue lesion in 3-MCPD treatment group was restored by API to some extent. We indicated that API exerted renoprotective effect by modulating oxidative phosphorylation especially up-regulated the expressions of ATP6 and ATP8, re-establishing mitochondrial membrane potential (MMP), relieving the increase of Bax/Bcl2 ratio, reducing cytochrome c release, thus inhibiting the activation of Caspase 9 and Caspase 3. In conclusion, apigenin possesses excellent protective effect against 3-MCPD-induced renal injury by modulating mitochondria dependent Caspase cascade pathway.
Novel organic salts based on quinoline derivatives: The in vitro activity trigger apoptosis inhibiting autophagy in Leishmania spp Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-09 Stephane Lima Calixto, Nícolas Glanzmann, Michele Maria Xavier Silveira, Juliana da Trindade Granato, Kezia Katiani Gorza Scopel, Thiago Torres de Aguiar, Renato Augusto DaMatta, Gilson Costa Macedo, Adilson David da Silva, Elaine Soares Coimbra
Leishmaniases are infectious diseases, caused by protozoa of the Leishmania genus. These drugs present high toxicity, long-term administration, many adverse effects and are expensive, besides the identification of resistant parasites. In this work, the antileishmanial activity of quinoline derivative salts (QDS) was evaluated, as well as the toxicity on mammalian cells and the mechanism of action of the most promising compound. Among the compound tested, only the compound QDS3 showed activity against promastigotes and amastigotes of Leishmania spp., being more active against the intracellular amastigotes of L. amazonensis-GFP (IC50 of 5.48 μM). This value is very close to the one observed for miltefosine (IC50 of 4.05 μM), used as control drug. Furthermore, the compound QDS3 exhibited a selective effect, being 40.35 times more toxic to the amastigote form than to the host cell. Additionally, promastigotes of L. amazonensis treated with this compound exhibited characteristics of cells in the process of apoptosis such as mitochondrial membrane depolarization, mitochondrial swelling, increase of ROS production, phosphatidylserine externalization, reduced and rounded shape, and cell cycle alteration. The integrity of the plasma membrane remained unaltered, excluding necrosis in treated promastigotes. The compound QDS3 inhibited the formation of autophagic vacuoles, which may have contributed to parasite death by preventing autophagic mechanisms in the removal of damaged organelles, intensifying the damage caused by the treatment, highlighting the antileishmanial effect of this compound. In addition, treatment with QDS3 induced increased ROS levels in L. amazonensis-infected macrophages, but not in uninfected host cell. These data reinforce that the induction of oxidative stress is one of the main toxic effects caused by the treatment with the compound QDS3 in L. amazonensis, causing irreversible damage and triggering a selective death of intracellular parasites. Data shown here confirm the biological activity of quinoline derivatives and encourage future in vivo studies with this compound in the murine model.
Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-04 Kyungbo Kim, Jianzhuang Yao, Zhenyu Jin, Fang Zheng, Chang-Guo Zhan
The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-04 Panfeng Feng, Lei Zhao, Fengfeng Guo, Bo Zhang, Li Fang, Ge Zhan, Xueqi Xu, Qing Fang, Zhaoguang Liang, Baoxin Li
Metabolism of most endogenous and exogenous compounds is usually produced by the oxidation of cytochrome P450. Due to drug-drug interactions caused by the inhibition or induction of cytochrome P450 enzymes, changes in drug metabolism are the major causes of drug toxicity, CYP3A4 is one of the key isozymes, and involved in the metabolism of over 60% of clinical drugs. Human ether-a-go-go related genes (hERG) potassium channel is the most important target of many drugs and plays an important role in cardiac repolarization. Blockade of this channel may lead to long QT syndrome (LQTS), leading to sudden cardiac death. Therefore, it is necessary to evaluate the inhibitory properties of drugs on cytochrome P450 enzymes and hERG channel. We primarily evaluate the safety of berberine in combination with statins. Based on these findings, berberine in combination with statins has a greater inhibitory effect on CYP3A4 activity and CYP3A4 protein and mRNA expression than berberine alone. Simvastatin and atorvastatin reduce hERG current by accelerating channel inactivation. At the same time, the inhibitory effect of berberine and statin combination increased on hERG current by reducing the time constant of inactivation than the single drug alone. These results indicate that berberine in combination with statins can increase cardiotoxicity by inhibiting CYP3A4 and hERG channel.
Exposure to ayahuasca induces to developmental and behavioral alterations on early life stages of zebrafish Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-08-04 Thayres S. Andrade, Rhaul de Oliveira, Muriel Lopes, Marcus Vinicius Von Zuben, Cesar Koppe Grisolia, Inês Domingues, Eloisa Dutra Caldas, Aline Pic-Taylor
Ayahuasca is a psychoactive concoction prepared from the plants Banisteriopsis caapi and Psychotria viridis which are used ancestrally by Amazonian Indian populations and more recently, by Christian religious groups in Brazil and other countries. The aims of the present study were to identify the effects of ayahuasca on zebrafish embryo development and neurobehavior. Toxicity and developmental endpoints for zebrafish embryos were assessed from 0 to 1000 mg/L over 96 h of exposure. The effects on locomotor activity of zebrafish larvae were assessed using a video tracking system (ZebraBox) from 0 to 20 mg/L and after 120 and 144 h of exposure. The LC50 of ayahuasca in zebrafish was determined as 236.3 mg/L. Ayahuasca exposure caused significant developmental anomalies in zebrafish embryos, mainly at the highest concentration tested, including hatching delay, loss of equilibrium, edema and the accumulation of red blood cells. Embryo behavior was also significantly affected, with decreased locomotor activity at the highest concentration tested. These results are in accordance with data obtained in mammal studies highlighting the possible risks of uncontrolled use of ayahuasca. Further research employing more specific behavior analysis could provide additional data on both therapeutic benefits and possible toxicological risk of ayahuasca.
Flubendazole and mebendazole impair migration and epithelial to mesenchymal transition in oral cell lines Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-31 Věra Králová, Veronika Hanušová, Kateřina Caltová, Petr Špaček, Martina Hochmalová, Lenka Skálová, Emil Rudolf
Benzimidazole anthelmintics flubendazole and mebendazole are microtubule-targeting drugs that showed considerable anti-cancer activity in different preclinical models. In this study, the effects of flubendazole and mebendazole on proliferation, migration and cadherin switching were studied in a panel of oral cell lines in vitro. Both compounds reduced the viability of the PE/CA-PJ15 and H376 oral squamous carcinoma cells and of the premalignant oral keratinocytes DOK with the IC50 values in the range of 0.19–0.26 μM. Normal oral keratinocytes and normal gingival fibroblasts were less sensitive to the treatment. Flubendazole and mebendazole also reduced the migration of the PE/CA-PJ15 cell in concentrations that had no anti-migratory effects on the normal gingival fibroblasts. Levels of the focal adhesion kinase FAK, Rho-A and Rac1 GTPases and the Rho guanine nucleotide exchange factor GEF-H1 were decreased in both PE/CA-PJ15 cells and gingival fibroblasts following treatment. Both drugs also interfered with cadherin switching in the model of TGF-β-induced epithelial to mesenchymal transition (EMT) in the DOK cell line. Levels of N-cadherin were reduced in the TGF-β induced cells co-treated with flubendazol and mebendazole in very low concentration (50 nM). These results suggest direct effects of both benzimidazoles on selected processes of EMT in oral cell lines such as cadherin switching as well as cellular migration.
Global metabolomics approach in in vitro and in vivo models reveals hepatic glutathione depletion induced by amorphous silica nanoparticles Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-29 Nivedita Chatterjee, Jaeseong Jeong, Dahye Yoon, Suhkmann Kim, Jinhee Choi
The present study aimed to investigate the mechanisms involved in amorphous silica nanoparticles (aSiNPs)-mediated hepatotoxicity through the evaluation of changes in global metabolomics in in vitro and in vivo systems. 1H NMR-based non-targeted global metabolomics and biochemical approaches were conducted in an aSiNPs-treated human hepatoma cell line (HepG2) and in ICR mice liver. The non-targeted NMR-based metabolomic analysis, followed by pathway analysis, revealed the perturbation of glutathione metabolism and the depletion of the glutathione pool after aSiNPs treatment in both in vitro (HepG2 cells) and in vivo systems. The total glutathione level, glutathione-S-transferase enzyme activity, and antioxidant gene expression strongly corroborated the metabolomic analysis results. The in vitro results were further supported by the in vivo data, specifically for metabolites profiling (Pearson Correlation coefficient is 0.462 (p = 0.026)). Furthermore, the depletion of glutathione, the formation of NADPH oxidase-mediated reactive oxygen species, and oxidative stress were evident in aSiNPs-treated HepG2 cells. Overall, the suppression of glutathione metabolism and oxidative stress are among the principal causes of aSiNPs-mediated hepatotoxicity.
Thermal Co-reduction engineered silver nanoparticles induce oxidative cell damage in human colon cancer cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-27 Nandita Dasgupta, Shivendu Ranjan, Debasish Mishra, Chidambaram Ramalingam
Hispidulin inhibits adipogenesis in 3T3-L1 adipocytes through PPARγ pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-25 Seul Gi Lee, Jin Soo Kim, Kyoungjin Min, Taeg Kyu Kwon, Ju-Ock Nam
Cirsimarin, a flavone glucoside from the aerial part of Cirsium japonicum var. ussuriense (Regel) Kitam. ex Ohwi, suppresses the JAK/STAT and IRF-3 signaling pathway in LPS-stimulated RAW 264.7 macrophages Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-25 Hee-Soo Han, Ji-Sun Shin, Seung-Bin Lee, Jong Cheol Park, Kyung-Tae Lee
Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-25 Xinrui Zhang, Mengya Wang, Shanshan Teng, Di Wang, Xin Li, Xiaofeng Wang, Weiwei Liao, Di Wang
A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3′-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase -3, -8, and -9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage.
Effect of homocysteine on pregnancy: A systematic review Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-24 Andrey N. Gaiday, Akylbek B. Tussupkaliyev, Saule K. Bermagambetova, Sagira S. Zhumagulova, Leyla K. Sarsembayeva, Moldir B. Dossimbetova, Zhanibek Zh Daribay
Research purpose was to put together the available pieces of present scientific data and to close the gap in the knowledge of Hcy levels in pregnancy and its association with some pregnancy complications. Scientific data were taken from research papers published between January 1990 and December 2017, and found on the Internet (PubMed, ClinicalKey and Embase databases) by the following tags entered in English, Russian, French and German languages: pregnancy, homocysteine, pregnancy complications, pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. The review showed that Hcy levels range in uncomplicated pregnancy. Upon that, Hcy level tends to decrease during the second and third trimesters. Some studies have revealed a link between polymorphism and abortion. Sufficient data were obtained indicating the relationship between HHcy and PE. Placental abruption was also associated with high Hcy levels increasing the risk 5.3-fold, but still there are data not supporting the hypothesis that Hcy levels correlate with placental abruption.
Effects of isopulegol in acute nociception in mice: Possible involvement of muscarinic receptors, opioid system and l-arginine/NO/cGMP pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-24 Deyna Francélia Andrade Próspero, Antonio Carlos Reis Filho, Celyane Alves Piauilino, Everton Moraes Lopes, Damião Pergentino de Sousa, Fernanda Regina de Castro Almeida
Previous studies have shown that isopulegol has anxiolytic, anticonvulsant, gastro-protective and antioxidant activities in rodents, but until now there are no studies showing activity of isopulegol in animal models of nociception and inflammation. The objective of this study was to evaluate the antinociceptive effect of isopulegol and to propose possible mechanisms involved in its effects observed in mice. Groups of male and female Swiss mice (20–35 g, n = 5–8) were used in this test under the authorization of Ethics Committee on Animal Experimentation (CEEA/UFPI N° 82/2014). In order to evaluate the antinociceptive activity of isopulegol, nociception was induced using formalin test, capsaicin and glutamate in hind paw licking model, followed by the investigation of the involvement of opioid mechanisms, K + ATP channels, muscarinic, L arginine-nitric oxide and cGMP. The oral administration of isopulegol showed antinociceptive effect in both phases of the formalin test at doses from 0.78 to 25 mg/kg (first phase) and 1.56–25 mg/kg (second phase) and also produced significant results before capsaicin test at doses from 1.56 to 12.5 mg/kg and glutamate test at doses from 3.12 to 6.25 mg/kg with a dose-dependent effect. The antinociception activity of isopulegol was inhibited in the presence of naloxone (2 mg / kg, ip), glibenclamide (3 mg/kg, ip), atropine (1 mg/kg, ip), l-arginine (600 mg/kg, ip) and methylene blue (20 mg/kg, ip). The results suggested that acute antinociceptive action of opioid isopulegol seems to be related to the K + ATP channels system, through the involvement of muscarinic receptors, inhibiting nitric oxide and cGMP.
Dietary hydrogenated vegetable fat exacerbates the activation of kynurenine pathway caused by peripheral lipopolysaccharide immune challenge in aged mice Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-24 Marcelo Gomes de Gomes, Leandro Cattelan Souza, Silvana Peterini Boeira, André Rossito Goes, Lucian Del Fabbro, Carlos Borges Filho, Franciele Donato, Robson Luiz Puntel, Cristiano Ricardo Jesse
In vitro meningeal permeation of MnFe2O4 nanoparticles Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-24 Marcella Mauro, Matteo Crosera, Massimo Bovenzi, Gianpiero Adami, Elena Baracchini, Giovanni Maina, Francesca Larese Filon
MnFe2O4 nanoparticles (NPs) are commonly produced in some occupational settings and may reach high concentration in activities such as arc-welding or ferroalloy metallurgy. Manganese is an essential cofactor in enzyme activities but it has been demonstrated that long-term exposure to excessive levels can lead to “manganism”, a neurodegenerative disease resembling Parkinson features. Inhaled NPs deposit partially in pharynx and nasopharynx and may reach the central nervous system through the olfactory nerve, which is completely enveloped by the meningeal membranes throughout its course from the nasal cavity to the olfactory bulb or through the trigeminal nerves. This study investigated in vitro the transmeningeal absorption of 50 nm MnFe2O4NPs, using excised porcine meninges mounted on Franz diffusion cells. We tested two donor solutions: the first containing MnFe2O4NPs (2.0 g/L) and the second obtained by the ultrafiltration of the first one, in order to test only the NPs water soluble fraction. Each experiment was carried separately for 4 h. Results showed that no Mn flux permeation through the meninges occurred, since only trace of the metal was found in receivers solutions of cells exposed to MnFeNPs (5.5 ± 2.2 ng/cm2), ultrafiltered solution (3.5 ± 1.5 ng/cm2) and blank cells. (2.1 ± 0.6 ng/cm2) (mean and SE). Differences did not reach the statistical significance. Our study shows – for the first time - that MnFe2O4NPs penetrate the meningeal membrane in a negligible amount, thus making unlikely the hypothesis of a transcellular and paracellular absorption through the olfactory nerve but not excluding the hypothesis of an active intraneuronal absorption.
Toxicological Status of Nanoparticles: What We Know and What We Don't Know Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-23 Wided N. Missaoui, Robert D. Arnold, Brian S. Cummings
The field of nanotechnology has grown exponentially during the last few decades, due in part to the use of nanoparticles in many manufacturing processes, as well as their potential as clinical agents for treatment of diseases and for drug delivery. This has created several new avenues by which humans can be exposed to nanoparticles. Unfortunately, investigations assessing the toxicological impacts of nanoparticles (i.e. nanotoxicity), as well as their possible risks to human health and the environment, have not kept pace with the rapid rise in their use. This has created a gap-in-knowledge and a substantial need for more reserach. Studies are needed to help complete our understanding of the mechanisms of toxicity of nanoparticles, as well as the mechanisms mediating their distribution and accumulation in cells and tissues and their elimination from the body. This review summarizes our knowledge on nanoparticles, including their various applications, routes of exposure, their potential toxicity and risks to human health.
Interaction of STAT3 and RelB modulates MMP-1 in colon cancer Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-21 Xue-Feng Jiang, Lei Ding, Yuan Tian, Ning Han, Zhi-Qi Li
Background MMP-1 (Matrix metalloproteinase-1) promotes carcinogenesis and distant metastasis in different cancers. Regulation of MMP-1 could occur at multiple levels: epigenetically, post-transcriptionally, or post-translationally. An increasing body of evidence supports that the cytoplasmic transcription factor STAT3 (signal transducer and activator of transcription 3) is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and also facilitates metastasis. In addition, STAT3 has been found to regulate nuclear activity pro-inflammatory transcriptional factor, NF-κB signaling, especially, the alternative one (RelB/p100) by directly interacting with them Method and Results In this proof of concept study, we tested the hypothesis that STAT3 interacts with RelB to promote tumor invasion by positively regulating MMP-1 in colon cancer. We found that RelB and STAT3 were constitutively localized in the nucleus of colon cancer in surgically-resected specimens with use of Western blot analysis, which was further confirmed by immunofluorescence (IF) staining in colon carcinoma cell line HT29. We further observed that STAT3/RelB knockdown resulted in reduced MMP-1. Our results from chromatin immunoprecipitation studies further established that association between RelB and MMP-1 promoter decreased when STAT3 was depleted, and conversely, STAT3 association with MMP-1 decreased with the knockdown of RelB. Conclusion These results suggest that STAT3 and ReB constitute a minimal activator complex for positive regulation of MMP-1 in colon cancer
Therapeutic applications of cannabinoids Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-21 Bharath Kumar Velmurugan
The psychoactive properties of cannabinoids are well known and there has been a continuous controversy regarding the usage of these compounds for therapeutic purposes all over the world. Their use for medical and research purposes are restricted in various countries. However, their utility as medications should not be overshadowed by their negative physiological activities. This review article is focused on the therapeutic potential and applications of phytocannabinoids and endocannabinoids. It highlights their mode of action, overall effects on physiology, various in vitro and in vivo studies that have been done so far and the extent to which these compounds can be useful in different disease conditions such as cancer, Alzheimer's disease, multiple sclerosis, pain, inflammation, glaucoma and many others. Thus, this work is an attempt to make the readers understand the positive implications of these compounds and indicates the significant developments that can occur upon utilizing cannabinoids as therapeutic agents.
Thermo- and pH dual responsive polymeric micelles and nanoparticles Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-20 Rahul S. Kalhapure, Jwala Renukuntla
A new generation of the more effective polymeric micelle and nanoparticle drug delivery systems evolved due to the emergence of stimuli-responsive polymers. Among various stimuli, pH and temperature are most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive polymeric micelles and nanoparticles for controlled and enhanced drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and decrease in extracellular pH around the tumor site. Fabrication of dual responsive polymeric micelles and nanoparticles has been possible for drug delivery and imaging purposes; due to advancement in the synthesis of non-toxic dual pH- and thermo-responsive polymers. Adequately designed polymeric micelles and nanoparticles sensitive to both pH and temperature can achieve better targeting and treatment. These systems can be very efficient due to their ability to wisely distinguish between pathological and healthy tissues. Our review manuscript's primary focus is on pH- and thermo-dual responsive polymeric nanoparticles and micelles for application in precision drug delivery.
Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-κB/NLRP3 inflammasome pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-19 Zhiqiang Sun, Yali Ma, Fang Chen, Shiying Wang, Baoping Chen, Jun Shi
Inflammatory response is important for the development and progression of diabetic nephropathy (DN). Artesunate (ART), an antimalarial drug, possesses anti-inflammatory effect and exhibits protective effect on chronic kidney diseases. However, the effect of ART on DN is unknown. The aim of the present study was to evaluate the effect and the molecular mechanism of ART on DN in an in vitro model. The rat mesangial cell line, HBZY-1, was induced by high glucose (HG; 30 mM D-glucose) in the presence or absence of ART (15 and 30 μg/ml) and incubated for 24 h. We found that HG induced the proliferation of HBZY-1 cells, while treatment with ART inhibited the cell proliferation. Treatment with ART inhibited HG-induced inflammatory cytokines production and expression of extracellular matrix (ECM). Besides, HG induced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inhibited the superoxide dismutase (SOD) activity of HBZY-1 cells, and the effects were attenuated by ART treatment. ART decreased HG-induced the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), nuclear factor κB (NF-κB) p-p65, and nod-like receptor protein 3 (NLRP3). Inhibition of the TLR4/NF-κB pathway suppressed NLRP3 inflammasome in HBZY-1 cells. In conclusion, ART exhibited protective effect on HG-induced HBZY-1 cells by inhibiting the inflammatory response, oxidative stress and ECM accumulation. The TLR4/NF-κB/NLRP3 inflammasome pathway was involved in the protective effect of ART. The results suggested that ART might be a potential therapy agent for the DN treatment.
Evaluation of lipid peroxidation and the level of some elements in rat erythrocytes during separate and combined vanadium and magnesium administration Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-18 Agnieszka Ścibior, Agnieszka Adamczyk, Dorota Gołębiowska, Joanna Kurus
The impact of vanadium (V) and magnesium (Mg) as sodium metavanadate (SMV, 0.125 mg V/ml) and magnesium sulfate (MS, 0.06 mg Mg/ml) on lipid peroxidation (LPO) and selected elements in the rat erythrocytes (RBCs) was investigated. Relationships between some indices determined in RBC were also studied. SMV alone (Group II) elevated the malondialdehyde level (MDARBC) (by 95% and 60%), compared with the control (Group I) and MS-supplemented rats (Group III), respectively, reduced the concentration of CuRBC (by 23.5%), in comparison with Group I, but did not change the levels of NaRBC, KRBC, and CaRBC, whereas MS alone (Group III) only reduced the CuRBC concentration (by 22%), compared with Group I. The SMV + MS combination (Group IV) reduced and elevated the CuRBC (by 24%) and CaRBC (by 111%) concentrations, respectively, in comparison with Groups I and III, and these changes were induced by the V-Mg antagonistic and synergistic interaction, respectively. The combined SMV + MS effect also enhanced the MDARBC level, compared with Groups I (by 79%) and III (by 47%) and slightly limited its concentration, compared with Group II, which, in turn, resulted from the distinct trend toward the V-Mg antagonistic interaction. We can conclude that V (as SMV) is able to stimulate LPO in rat RBCs and that V-Mg interactive effects are involved in changes in CuRBC, CaRBC, and MDARBC. Further studies are needed to elucidate the exact mechanisms of the V-Mg antagonistic/synergistic interactions and to provide insight into the biochemical mechanisms of changes in rats suffering from anemia , characterized by a disrupted antioxidant barrier in RBCs  and an intensified free radical process in these cells.
Tumor-promoting and pro-angiogenic effects of roxarsone via VEGFR2/PLCγ/PKC signaling Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-17 Yanhua Pang, Kai Wang, Yujing Wang, Zhongri Chenlin, Weiwei Lei, Yumei Zhang
Roxarsone is an organoarsenic feed additive used in livestock and poultry production that is released into the environment, where it poses a risk to human health. It is known to have a tumor-promoting effect that is brought about by pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and it receptors (VEGFR). However, little information is available about the other signaling molecules that could be involved. This study aims to investigate the role of PLCγ/PKC signaling in roxarsone-induced angiogenesis in a mouse B16-F10 melanoma xenograft model and rat vascular endothelial cells (ECs). Results showed treatment with 5 mg/kg and 25 mg/kg roxarsone resulted in an obvious increase in the weight and volume of B16-F10 xenografts and PLCγ/PKC phosphorylation in a dose-dependent manner in C57BL/6 mice. SU5416, a VEGFR2 inhibitor, significantly attenuated the tumor growth induced by roxarsone. Further, 1.0 μmol/L roxarsone treatment in rat ECs was observed to significantly increase the optical density rate in the MTT assay, the number of BrdU-positive cells in the proliferation assay, the migration distance in the scratch test, and the number of meshes formed in the tube formation assay. In addition, treatment with 1.0 μmol/L roxarsone was associated with significantly higher phosphorylation of PLCγ/PKC than the control treatment. U73122, a PLCγ inhibitor, was found significantly to combat the effects of 1.0 μmol/L roxarsone on the ECs. Roxarsone is capable of promoting the growth of mouse B16-F10 xenografts and tube formation in vascular ECs. Moreover, VEGFR2/PLCγ/PKC signaling may play a regulatory role in in vivo and in vitro roxarsone-induced angiogenesis.
Antitumor activity of a molecularly imprinted nanopreparation of 5-flurouracil against Ehrlich's carcinoma solid tumors grown in mice: Comparison to free 5-flurouracil Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-04-17 Ahmed R. Gardouh, Bassant M. Barakat, Mona K.E. Qushawy, Amany Y. El-kazzaz, Manal M. Sami, Sawsan A. Zaitone
Recently, nanotechnology has received great attention in war against cancer. The present study investigated the antitumor efficacy of molecularly imprinted nanopreparation of 5-fluorouracil (nano-5-FU) against Ehrlich ascites carcinoma (EAC) solid tumors grown in mice. Tumor cells were transplanted into female albino mice. Mice were allocated into 5 groups; Group 1: control EAC bearing mice. Groups 2&3: EAC-bearing mice treated orally with 5-FU (5 and 10 mg/kg) twice weekly. Groups 4&5: EAC bearing mice treated with nano-5-FU (5 and 10 mg/kg) twice weekly. Treatment with nano-5-FU showed higher antitumor effect compared to free 5-FU as indicated by enhanced apoptosis and reduction in tumor weight. Additionally, lower number of mitotic figures and greater area for necrosis were observed in the tumor specimens alongside with a decline in the number of intratumoral proliferating nuclei in comparison to free 5-FU. Furthermore, the results showed a significant down-regulation in tumoral expression of caspase-3 and vascular endothelial growth factor. Together, these results further support the potential of using nanotechnology to enhance anticancer efficacy of 5-FU.
Potential of siRNA-albumin complex against cancer Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-04-27 Na Liu, Yan-Hua Qi, Chuan-Tao Cheng, Wen Bin Yang, Anshoo Malhotra, Qi Zhou
RNA interference is a highly specific as well as efficient technology for gene therapy application in molecular oncology. The present study was planned to develop an efficient and stable tumor selective delivery mechanism for siRNA gene therapy for the purpose of both diagnosis as well as therapy. We have used 20 Male wistar rats for the formation of colon cancer model and utilized albumin as carrier molecule for the delivery of siRNA against vascular endothelial growth factor receptor 2 (VEGF R2). The study results confirmed efficient delivery of siRNA at tumor site as confirmed by tagging of siRNA-albumin complex with 99mTC. Moreover, the expression of VEGF also showed decline after efficient delivery of siRNA at tumor site. The study concluded that albumin is an efficient molecule for the efficient delivery of siRNA at tumor sites.
Red disperse dyes (DR 60, DR 73 and DR 78) at environmentally realistic concentrations impact biochemical profile of early life stages of zebrafish (Danio rerio) Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-10 Gabriela Meireles, Michiel A. Daam, Ana Letícia Madeira Sanches, Maria V.B. Zanoni, Amadeu M.V.M. Soares, Carlos Gravato, Danielle P. de Oliveira
Dyes have been used for more than twenty thousand years in textile, pharmaceutical, food, cosmetic, and photographic industries, among others. Despite their importance in these applications, dyes can be toxic and resistant to many degradation processes used in wastewater treatment plants. Although a large number of dyes have been released in the environments in high amounts, studies into the environmental toxicity of these substances are still scarce. The aim of this study was to evaluate the potential toxic effects of textile dyes Disperse Red 60, Disperse Red 73 and Disperse Red 78 in zebrafish early life stages. To this end, biochemical biomarkers were selected to evaluate non-enzimatic antioxidant (Total Glutathione), antioxidant enzymes (Glutathione S-transferase and Catalase), oxidative stress (lipid peroxidation), neurotransmission (acetylcholinesterase) and energetic metabolism parameters (energy available and energy consumed) after 96 h exposure to these dyes. Our results demonstrated that these disperse dyes induce biochemical alterations in zebrafish embryos at environmental realistic concentrations and that the discharge of these disperse dyes into water bodies should be carefully evaluated. The selected biomarkers were sensitive as early-warning endpoints of disperse dyes toxicity on zebrafish embryos. Implications for risk assessment and indications for future research are discussed.
New insights into TGF-β/Smad signaling in tissue fibrosis Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-11 He-He Hu, Dan-Qian Chen, Yan-Ni Wang, Ya-Long Feng, Gang Cao, Nosratola D. Vaziri, Ying-Yong Zhao
Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.
New chalcone derivative exhibits antiproliferative potential by inducing G2/M cell cycle arrest, mitochondrial-mediated apoptosis and modulation of MAPK signalling pathway Chem. Biol. Interact. (IF 3.296) Pub Date : 2018-07-06 Peter Takac, Martin Kello, Martina Bago Pilatova, Zuzana Kudlickova, Maria Vilkova, Pavlina Slepcikova, Peter Petik, Jan Mojzis
In the present study, we investigated antiproliferative activity of seven newly synthesized chalcone derivatives. Among tested compounds, (2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one (1C) was the most potent with IC50 = 4.1 μmol/L in human colorectal HCT116 cells and was selected for further studies. Inhibition of cell proliferation was associated with cell cycle arrest in G2/M phase and dysregulation of α, α1 and β5 tubulins. Moreover, 1C caused disruption of the mitochondrial membrane potential and increased number of cells with sub G0/G1 DNA content which is considered as marker of apoptosis. Apoptosis was confirmed by annexin V/PI and AO/PI staining. Furthermore, we found increased concentration of cytochrome c, Smac/Diablo and increased caspase-3 and caspase-9 activity, cleavage of PARP as well as activation of DNA repair mechanisms in 1C-treated HCT116 cancer cells. Moreover this chalcone derivative up-regulated proapoptotic Bax expression and down-regulated antiapoptotic Bcl-2 and Bcl-xL expression. Additionally, 1C treatment led to modulation of MAPKs and Akt signalling pathways.In conclusion, our data showed ability of 1C to suppress cancel cell growth and provide the rationale for further in vivo study.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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