Arsenic trioxide inhibits the response of primary human B cells to influenza virus A in vitro.

Arsenic compounds are common environmental toxicants worldwide and particularly enriched in the Northeast and the Southwestern United States, the Alps, and Bangladesh. Exposure to arsenic is linked with various detrimental health outcomes, including cancer, cognitive decline, and kidney damage. Our group has previously shown that arsenic trioxide alters T cell cytokine production. In the current study, we demonstrate that exposure to arsenic compounds alters B cell function in an in vitro influenza model. Human peripheral blood mononuclear cells (PBMCs) were isolated from blood and cultured with arsenic trioxide (As3O2) and subsequently challenged with Influenza A virus. B cells showed decreased expression of CD267, surface IgG and CD80 when treated with As3O2. Taken together, the data suggest that As3O2 affects the activation and surface antibody expression of human peripheral B cells. Overall, this suggests that As3O2 exposure could cause impaired humoral immunity.

Febuxostat alleviates Arsenic Trioxide-Induced renal injury in Rats: Insights on the crosstalk between NLRP3/TLR4, Sirt-1/NF-κB/TGF-ß signaling Pathways, and miR-23b-3p, miR-181a-5b expression.

Febuxostat (FBX), a xanthine oxidase inhibitor, is known to improve renal function and can show promise as a therapeutic agent for preventing drug-induced nephrotoxicity. This study aimed to explore the protective effect of FBX in preventing renal damage caused by arsenic trioxide (ATO) toxicity and uncover the underlying mechanisms. The researchers examined how FBX (10 mg/kg, orally) affected ATO-induced kidney injury (5 mg/kg, intraperitoneally) in rats. Kidney function and toxicity parameters in serum and oxidative stress biomarkers and inflammatory cytokine levels in renal tissue were measured. H&E staining was used to detect histopathological changes in the kidney. Network the molecular mechanisms of FBX in improving kidney injury were investigated using Western blotting and PCR techniques. The findings showed that FBX improved kidney function by inhibiting the pathological changes seen in H&E staining, decreasing levels of probed kidney function and toxicity measures in serum and tissue, and exhibiting antioxidant and anti-inflammatory effects. FBX decreased MDA, MPO, TNF-α, IL-1ß, IL-6, COX-II, and NADPH oxidase levels, while increased GSH, GPx, SOD, and IL-10 levels. FBX also reduced the expression of NLRP3, ASC, TLR4, and micro-RNA 181a-5b while increased the expression of IKBα, Sirt-1, and micro-RNA 23b-3p, according to Western blotting and PCR results. In conclusion, FBX can play a vital role in reducing kidney injury in cases of ATO-induced nephrotoxicity, though more clinical research needs to be conducted.

Mitochondrial Toxicity of Organic Arsenicals.

Arsenic is either notorious toxicant or miracle cure for acute promyelocytic leukemia and several other diseases. It interacts with mitochondria directly or indirectly, by interacting with mitochondrial enzymes, such as respiratory chain complexes and tricarboxylic acid cycle proteins, or affecting mitochondrial homeostasis via ROS or mitochondrial outer membrane permeabilization. Given the ubiquitous presence of mitochondria and indispensable role in cellular metabolism, arsenical-mitochondrial interactions may manifest clinical importance by revealing mechanism of disease curation, preventing severe side effects, and foreseeing potential health issues. Here, we described the interaction between isolated mitochondria and arsenicals.

Low-dose arsenic trioxide enhances membrane-GLUT1 expression and glucose uptake via AKT activation to support L-02 cell aberrant proliferation.

Long term low dose exposure of arsenic has been reported to lead various cells proliferation and malignant transformation. GLUT1, as the key transporter of glucose, has been reported to have association with rapid proliferation of various cells or tumor cells. In our study, we found that low dose exposure to arsenic trioxide (0.1µmol/L As2O3) could induce an increase in glucose uptake and promote cell viability and DNA synthesis. And, 2-DG, a non-metabolized glucose analog, significantly decreased the glucose uptake and cell proliferation of 0.1µmol/L As2O3 treated L-02 cells. However, 4 mmol/L 2-DG was co-utilized with equal dose glucose had no significant effect on the cell proliferation of 0.1µmol/L As2O3 treated L-02 cells. Further studies showed that exposure to 0.1µmol/L As2O3 could promote the expression of GLUT1 on plasma membrane. Inhibition of GLUT1 expression by 5µmol/L BAY-876 significantly decreased the abilities of glucose uptake and cell proliferation in As2O3-treated L-02 cells. Moreover, 0.1µmol/L As2O3 induced the AKT activation indicated by increased the phospho-AKT (Ser473 and Thr308). Knockdown AKT by shRNA or inhibited AKT activation by LY294002 was followed by significantly decreased glucose uptake, GLUT1 plasma membrane expression and cell proliferation in As2O3-treated L-02 cells. All in all, these results demonstrated that arsenic trioxide-induced AKT activation contributed to the cells proliferation through upregulating expression of GLUT1 on plasma membrane that enhanced glucose uptake.

Honokiol attenuate the arsenic trioxide-induced cardiotoxicity by reducing the myocardial apoptosis.

Despite advantages of arsenic trioxide (ATO) in oncological practice, its clinical applications have been hampered by severe cardiotoxicity. The general mechanism of ATO-induced cardiotoxicity has been attributed to its damage to mitochondria, resulting in cardiac remodeling. Honokiol (HKL) is a naturally occurring compound derived from Magnolia bark. Previous studies have demonstrated that HKL exerts cardio-protective effects on ischemia/reperfusion (I/R) or chemical-induced cardiotoxicity by counteracting the toxic effects on mitochondria. The present study was conducted to investigate whether HKL pretreatment protects against ATO-induced cardiac oxidative damage and cell death. For the in vitro study, we evaluated the effects of ATO and/or Honokiol on reactive oxygen species (ROS) production and apoptosis induction in primary cultured cardiomyocytes; for the in vivo study, BALB/c mice were administrated with ATO and/or HKL for a period of 4 weeks, myocardial apoptosis, cardiac function, and cardiac remodeling (cardiac hypertrophy and cardiac fibrosis) were assessed at the end of administration. Our results demonstrated Honokiol pretreatment alleviated the ATO-induced boost in ROS concentration and the following apoptosis induction in primary cultured cardiomyocytes. In the mouse model, Honokiol pretreatment ameliorated ATO-induced myocardial apoptosis, cardiac dysfunction, and cardiac remodeling. Collectively, these results indicated that Honokiol provide a protection against ATO-induced cardiotoxicity by reducing mitochondrial damage. In addition, given that Honokiol has shown considerable suppressive effects on leukemia cells, our data also imply that ATO and Honokiol combination may possibly be a superior avenue in leukemia therapy.

Arsenic trioxide-induced cardiotoxicity triggers ferroptosis in cardiomyoblast cells.

Arsenic trioxide (ATO) has been found to be effective in acute promyelocytic leukemia. However, ATO-induced severe cardiotoxicity limits its clinical application. To date, the mechanisms of ATO-induced cardiotoxicity remain unclear. It is hypothesized that ferroptosis may trigger ATO-induced cardiotoxicity; however, this has not yet been investigated. To clarify this hypothesis, rat cardiomyocyte H9c2 cells were treated with ATO with or without ferrostain-1 (Fer-1). The results indicated that ATO exposure induced H9c2 cell death and apoptosis, and the ferroptosis inhibitor Fer-1, administered for 24 h before ATO exposure, suppressed ATO-induced cell death, and apoptosis, as determined by Annexin V-APC/7-AAD apoptosis assay. Furthermore, Fer-1 displayed a cardioprotective effect through inhibiting the ATO-induced production of intracellular reactive oxygen species, improving the ATO-induced loss of the mitochondrial membrane potential, alleviating hyperactive endoplasmic reticulum stress, and alleviating the ATO-induced impairment in autophagy in H9c2 cells. Overall, the cardioprotective effect of Fer-1 against ATO-induced cell injury implies that ATO may trigger ferroptosis to induce cardiotoxicity. These findings lay the foundation for exploring the potential value of ferroptosis inhibitors against ATO-induced cardiotoxicity in the future.

Functional and structural phenotyping of cardiomyocytes in the 3D organization of embryoid bodies exposed to arsenic trioxide.

Chronic exposure to environmental pollutants threatens human health. Arsenic, a world-wide diffused toxicant, is associated to cardiac pathology in the adult and to congenital heart defects in the foetus. Poorly known are its effects on perinatal cardiomyocytes. Here, bioinformatic image-analysis tools were coupled with cellular and molecular analyses to obtain functional and structural quantitative metrics of the impairment induced by 0.1, 0.5 or 1.0 µM arsenic trioxide exposure on the perinatal-like cardiomyocyte component of mouse embryoid bodies, within their 3D complex cell organization. With this approach, we quantified alterations to the (a) beating activity; (b) sarcomere organization (texture, edge, repetitiveness, height and width of the Z bands); (c) cardiomyocyte size and shape; (d) volume occupied by cardiomyocytes within the EBs. Sarcomere organization and cell morphology impairment are paralleled by differential expression of sarcomeric α-actin and Tropomyosin proteins and of acta2, myh6 and myh7 genes. Also, significant increase of Cx40, Cx43 and Cx45 connexin genes and of Cx43 protein expression profiles is paralleled by large Cx43 immunofluorescence signals. These results provide new insights into the role of arsenic in impairing cytoskeletal components of perinatal-like cardiomyocytes which, in turn, affect cell size, shape and beating capacity.

Resveratrol protects against inorganic arsenic-induced oxidative damage and cytoarchitectural alterations in female mouse hippocampus.

Prolonged inorganic arsenic (iAs) exposure is widely associated with brain damage particularly in the hippocampus via oxidative and apoptotic pathways. Resveratrol (RES) has gained considerable attention because of its benefits to human health. However, its neuroprotective potential against iAs-induced toxicity in CA1 region of hippocampus remains unexplored. Therefore, we investigated the neuroprotective efficacy of RES against arsenic trioxide (As2O3)-induced adverse effects on neuronal morphology, apoptotic markers and oxidative stress parameters in mouse CA1 region (hippocampus). Adult female Swiss albino mice of reproductive maturity were orally exposed to either As2O3 (2 and 4 mg/kg bw) alone or in combination with RES (40 mg/kg bw) for a period of 45 days. After animal sacrifice on day 46, the perfusion fixed brain samples were used for the observation of neuronal morphology and studying the morphometric features. While the freshly dissected hippocampi were processed for biochemical estimation of oxidative stress markers and western blotting of apoptosis-associated proteins. Chronic iAs exposure led to significant decrease in Stratum Pyramidale layer thickness along with reduction in cell density and area of Pyramidal neurons in contrast to the controls. Biochemical analysis showed reduced hippocampal GSH content but no change in total nitrite (NO) levels following iAs exposure. Western blotting showed apparent changes in the expression levels of Bax and Bcl-2 proteins following iAs exposure, however the change was statistically insignificant. Contrastingly, iAs +RES co-treatment exhibited substantial reversal in morphological and biochemical observations. Together, these findings provide preliminary evidence of neuroprotective role of RES on structural and biochemical alterations pertaining to mouse hippocampus following chronic iAs exposure.

Enhanced GRP78 protein expression via the IRE1α/ASK1/p38 MAPK pathway during As2O3-induced endoplasmic reticulum stress in BEAS-2B cells.

Inorganic arsenic is widely present in the environment. Exposure to moderate to high concentrations of arsenic from drinking water or air can cause various cancers and multisystem dysfunction. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) stress sensor of unfolded protein response (UPR) under stress conditions and it enhances cell survival. The aim of this study is to investigate molecular mechanisms of arsenic-induced GRP78 expression in BEAS-2B cells model. We found that GRP78 protein expression was enhanced, while the level of GRP78 mRNA expression did not change under arsenic trioxide (As2O3)-induced ER stress condition in BEAS-2B cells. Cycloheximide, a protein synthesis inhibitor, completely inhibited As2O3-induced GRP78 protein expression. GRP78 mRNA expression was inhibited by actinomycin-D (Act-D). However, GRP78 protein expression was upregulated in the presence of Act-D under As2O3-induced ER stress condition. These data indicated that the upregulation of GRP78 protein under As2O3-induced UPR condition was possibly due to the increased biosynthesis of GRP78 protein. Moreover, both inositol-requiring enzyme 1α (IRE1α) RNase and kinase inhibitor KIRA6 and IRE1α kinase inhibitor APY29 completely inhibited As2O3-induced GRP78 protein expression and phosphorylation of JNK, ERK and p38 MAPK. Activation of apoptotic signaling kinase 1 (ASK1) is a downstream effector of IRE1α kinase. ASK1 inhibitor selonsertib and p38 MAPK inhibitor SB203580 partially inhibited As2O3-induced GRP78 protein expression, respectively. Our results suggested that As2O3 enhanced GRP78 protein expression in BEAS-2B cells via IRE1α kinase/ASK1/p38 MAPK signaling pathway. To our knowledge, this is the first report on illuminating the related mechanisms of increased GRP78 protein expression in As2O3-induced ER stress condition through a novel IRE1α pathway.

Evaluación hepática en pacientes con leucemia promielocítica tratados con el protocolo LPM-TOA / Hepatic evaluation in patients with promyelocytic leukemia treated with the LPM-TOA protocol

Introducción: Con el protocolo LPM-TOA para el tratamiento de la leucemia promielocítica se obtienen excelentes resultados, se prolonga la sobrevida global y es posible la curación de los enfermos. En la de inducción a la remisión se utilizan dos drogas, una antraciclina y trióxido de arsénico, y en la consolidación los enfermos reciben de nuevo una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad hepática tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó estudio longitudinal prospectivo que incluyó20 pacientes tratados con dicho protocolo, todos con más de dos años de haberlo suspendido. Se revisaron las historias clínicas para evaluar mediante los valores iniciales y evolutivos de las enzimas hepáticas, la función hepática inicial y evolutiva. Se determinó el índice de Ritis para predecir evolución a la cronicidad de existir daño hepático. Resultados: Hombres y mujeres se presentaron con la misma frecuencia y la media para la edad del sexo masculino fue 36,39 y para el femenino 39, con desviación estándar de ±14,02 y ±9,43, respectivamente. La variedad morfológica más frecuente fue la hipergranular, el promedio del índice de Ritis fue de solo 1,006 con desviación estándar de 0,745. Conclusiones: No hubo evidencias clínica ni enzimática de toxicidad hepática tardía en los pacientes estudiados(AU)

Introduction: With the LPM-TOA protocol for the treatment of acute promyelocytic leukemia, excellent results are obtained, overall survival is prolonged and the patients are cured, in the induction to remission two drugs are used, an anthracycline and arsenic trioxide, and in consolidation the patients again receive a high dose of arsenic. Objective: To assess late liver toxicity in patients with promyelocytic leukemia treated according to the PML-TOA protocol. Methods: A prospective longitudinal study was carried out that included 20 patients treated with this protocol, all with more than two years of having suspended treatment. The clinical histories were reviewed and by means of the initial and evolutionary values of liver enzymes, the initial and evolutionary liver function was evaluated and the Ritis index was determined to predict evolution to chronicity if there is liver damage. Results: Men and women presented with the same frequency and the mean age for males was 36.39 and for females it was 39, with a standard deviation of ± 14.02 and ± 9.43 respectively. The most frequent morphological variety was hypergranular, the average Ritis index was only 1.006 with a standard deviation of 0.745. Conclusions: There was no clinical or enzymatic evidence of late liver toxicity in the patients studied(AU)

Investigation of the ameliorative effects of baicalin against arsenic trioxide-induced cardiac toxicity in mice.

Baicalin (BA), a kind of flavonoids compound, comes from Scutellaria baicalensis Georgi (a kind of perennial herb) and has beneficial effects on the cardiovascular system through anti-oxidant, anti-inflammation, and anti-apoptosis actions. However, the therapeutic effects and latent mechanisms of BA on arsenic trioxide (ATO)-induced cardiac toxicity has not been reported. The present research was performed to explore the effects and mechanisms of BA on ATO-induced heart toxicity. Male Kunming mice were treated with ATO (7.5 mg/kg) to induce cardiac toxicity. After the mice received ATO, BA (50 and 100 mg/kg) was administered for estimating its cardioprotective effects. Statistical data demonstrated that BA treatment alleviated electrocardiogram abnormalities and pathological injury caused by ATO. BA could also lead to recovery of CK and LDH activities to normal range and cause a decrease in MDA levels and ROS generation, augmentation of SOD, CAT, and GSH activities. We also found that BA caused a reduction in the expression of proinflammatory cytokines, such as TNF-α and IL-6. Moreover, BA attenuated ATO-induced apoptosis by promoting the expression of Bcl-2 and suppressing the expression of Bax and caspase-3. TUNEL test result demonstrated BA caused impediment of ATO-induced apoptosis. Furthermore, BA treatment suppressed the high expression of TLR4, NF-κB and P-NF-κB caused by ATO. In conclusion, these results indicate that BA may alleviate ATO-induced cardiac toxicity by restraining oxidative stress, apoptosis, and inflammation, and its mechanism would be associated with the inhibition of the TLR4/NF-κB signaling pathway.

Arsenic trioxide induces expression of BCL-2 expression via NF-κB and p38 MAPK signaling pathways in BEAS-2B cells during apoptosis.

Inorganic arsenic compounds are environmental toxicants that are widely distributed in air, water, and food. B-cell lymphoma 2 (BCL-2) is an oncogene having anti-apoptotic function. In this study, we clarify that BCL-2, as a pro-apoptotic factor, participates in As2O3-induced apoptosis in BEAS-2B cells. Specifically, As2O3 stimulated the expression of BCL-2 mRNA and protein in a dose-dependent manner which was highly accumulated in the nucleus of BEAS-2B cell together with chromatin condensation and DNA fragmentation during apoptosis. Mechanistically, the process described above is mediated through the NF-κB and p38 MAPK signaling pathways, which can be abated by corresponding inhibitors, such as BAY11-7082 and SB203580, respectively. Additionally, BAY11-7082, actinomycin D, and cycloheximide have inhibitory effects on As2O3-induced expression of BCL-2 mRNA and protein, and restore the cell viability of BEAS-2B cells. Suppression of BCL-2 protein activation by ABT-199 also restored viability of BEAS-2B cell in As2O3-induced apoptosis. Furthermore, As2O3 increased the level of BCL-2 phosphorylation. These results suggest that in BEAS-2B cells, As2O3-induced apoptosis is mainly dominated by BCL-2 upregulation, nuclear localization and phosphorylation. The study presented here provides a novel insight into the molecular mechanism of BCL-2-induced apoptosis.

Arsenic and antimony co-induced nephrotoxicity via autophagy and pyroptosis through ROS-mediated pathway in vivo and in vitro.

Arsenic (As) and antimony (Sb) are commonly accumulated environmental pollutants that often coexist in nature and cause serious widespread biological toxicity. To investigate the nephrotoxicity induced by As and Sb in detail, we explored the mechanism by which As and Sb cotreatment induced autophagy and pyroptosis in vivo and in vitro. In this study, mice were treated with 4 mg/kg arsenic trioxide (ATO) or/and 15 mg/kg antimony trichloride (SbCl3) by intragastric intubation for 60 days. TCMK-1 cells were treated with ATO (12.5 µM), SbCl3 (25 µM) or a combination of As and Sb for 24 h. The results of the in vivo experiment demonstrated that As or/and Sb exposure could induce histopathological changes in the kidneys, and increase the levels of biochemical indicators of nephrotoxicity. In addition, As and Sb can co-induce oxidative stress, which further activate autophagy and pyroptosis. In an in vitro experiment, As and/or Sb coexposure increased ROS generation and decreased MMP. Moreover, the results of related molecular experiments further confirmed that As and Sb coactivated autophagy and pyroptosis. In conclusion, our results indicated that As and Sb co-exposure could cause autophagy and pyroptosis via the ROS pathway, and these two metals might have a synergistic effect on nephrotoxicity.

Riboflavin recovery of spermatogenic dysfunction via a dual inhibition of oxidative changes and regulation of the PINK1-mediated pathway in arsenic-injured rat model.

Arsenic trioxide (As2O3) poisoning and associated potential lesions are of a global concern. Inversely, riboflavin (vitamin B2, VB2) as a component of flavoproteins could play a vital role in the spermatogenic enzymatic reactions. Thus, this research aimed to explore potential beneficial roles of VB2 during As2O3-injured-toxicity. Rats were randomly allocated into 4 groups (n=8/group) and challenged as follows (for 30 days continuously): Group 1 received normal saline; Group 2 was treated with 3 mg As2O3/L; Group 3 received 40 mg VB2/L; Group 4 received 3 mg As2O3/L + 40 mg VB2/L. Both As2O3 and VB2 were dissolved in deionized water. Malondialdehyde (MDA), Glutathione Peroxidase (GSH-Px), Superoxide dismutase (SOD), and Catalase (CAT) were assessed for the oxidative profile, while TAS (Total Antioxidative Status) levels were evaluated for the antioxidant system, in both serum and testicular tissue. P<0.05 was considered statistically significant. The results show that As2O3 significantly decreased the body weight, testicular weight and testis volume, semen quality and testicular cell count (p<0.05). Furthermore, MDA content in the testicular tissue of the As2O3 group rats was significantly higher in comparison to the vehicle group (p<0.05). Likewise, TAS and the activities of GSH-Px, CAT and SOD were reduced (p<0.05) when compared to the control. As(2)O(3) induced testicular damage and seminiferous tubular atrophy. Monodansylcadaverine assays mirrored the histopathology observations. Meanwhile, As2O3 upregulated the expression of mitophagy-related genes including PINK1, Parkin, USP8, LC3-I, Fis1 and Mfn2. The p38 gene, responsible to stress stimuli, was also upregulated by As2O3 administration. Meanwhile, exposure to VB2 led to a significant decrease of the expression levels of mitophagy related genes. Our study revealed that VB2 supplementation protected testicular structures against As2O3-induced injury via a dual inhibition of oxidative changes and a regulation of the PINK1-mediated pathway.

Protective effects of curcumin on ATO-induced nephrotoxicity in ducks in relation to suppressed autophagy, apoptosis and dyslipidemia by regulating oxidative stress.

Arsenic trioxide (ATO) has been known as common environmental pollution, and is deemed to a threat to global public health. Curcumin (Cur) is a phytoconstituent, which has been demonstrated to have antioxidant effects. In the current experiment, we investigated the efficacy of Cur against ATO-induced kidney injury and explored the potential molecular mechanisms that have not yet been fully elucidated in ducks. The results showed that treatment with Cur attenuated ATO-induced body weight loss, reduced the content of ATO in the kidney, and improved ATO-induced kidney pathological damage. Cur also remarkably alleviated the ascent of ATO-induced MDA level and activated the Nrf2 pathway. Using the TEM, we found Cur relieved mitochondrial swelling, autolysosomes generating and nuclear damage. Simultaneously, Cur was found that it not only significantly reduced autophagy-related mRNA and protein levels (mTOR, LC3-Ⅰ, LC3-Ⅱ, Atg-5, Beclin1, Pink1 and Parkin) and but also decreased apoptosis-related mRNA and protein expression levels (cleaved caspase-3, Cytc, p53 and Bax). Furthermore, through nontargeted metabolomics analysis, we observed that lipid metabolism balance was disordered by ATO exposure, while Cur administration alleviated the disturbance of lipid metabolism. These results showed ATO could induce autophagy and apoptosis by overproducing ROS in the kidney of ducks, and Cur might relieve excessive autophagy, apoptosis and disturbance of lipid metabolism by regulating oxidative stress. Collectively, our findings explicate the potential therapeutic value of Cur as a new strategy to a variety of disorders caused by ATO exposure.

Phloretin Alleviates Arsenic Trioxide-Induced Apoptosis of H9c2 Cardiomyoblasts via Downregulation in Ca2+/Calcineurin/NFATc Pathway and Inflammatory Cytokine Release.

Arsenic trioxide (ATO) is among the first-line chemotherapeutic drugs for treating acute promyelocytic leukemia patients, but its clinical use is hampered due to cardiotoxicity. The present investigation unveils the mechanism underlying ATO-induced oxidative stress that promotes calcineurin (a ubiquitous Ca2+/calmodulin-dependent serine/threonine phosphatase expressed only during sustained Ca2+ elevation) expression, inflammatory cytokine release and apoptosis in H9c2 cardiomyoblasts, and its possible modulation with phloretin (PHL, an antioxidant polyphenol present in apple peel). ATO caused Ca2+ overload resulting in elevated expression of calcineurin and its downstream transcriptional effector NFATc causing the release of cytokines such as IL-2, IL-6, MCP-1, IFN-γ, and TNF-α in H9c2 cardiomyoblast. There was a visible increase in the nuclear fraction of NF-κB and ROS-mediated apoptotic cell death. The expression levels of cardiac-specific genes (troponin, desmin, and caveolin-3) and genes of the apoptotic signaling pathway (BCL-2, BAX, IGF1, AKT, ERK1, -2, RAF1, and JNK) in response to ATO and PHL were studied. The putative binding mode and the potential ligand-target interactions of PHL with calcineurin using docking software (Autodock and iGEMDOCKv2) showed the high binding affinity of PHL to calcineurin. PHL co-treatment significantly reduced Ca2+ influx and normalized the expression of calcineurin, NFATc, NF-κB, and other cytokines. PHL co-treatment resulted in activation of BCL-2, IGF1, AKT, RAF1, ERK1, and ERK2 and inhibition of BAX and JNK. Overall, these results revealed that PHL has a protective effect against ATO-induced apoptosis and we propose calcineurin as a druggable target for the interaction of PHL in ATO cardiotoxicity in H9c2 cells.

Effect of lycopene on As2O3 induced oxidative stress in SH-SY5Y cells.

It is known that oxidative stress may cause neuronal injury and several experimental models showed that As2O3 exposure causes oxidative stress. Lycopene, a carotenoid, has been shown to have protective effect in neurological disease models due to antioxidant activity, but its effect on As2O3-induced neurotoxicity is not identified yet. The aim of this study is to investigate the effects of lycopene on As2O3-induced neuronal damage and the related mechanisms. Cell viability was determined by the MTT assay. Lycopene was administrated with different concentrations (2, 4, 6 and 8 µM) one hour before 2 µM As2O3 exposure in SH-SY5Y human neuroblastoma cells. The anti-oxidant effect of lycopene was determined by measuring superoxide dismutase (SOD), catalase (CAT) hydrogen peroxide (H2O2), malondialdehyde (MDA), total antioxidant status (TAS) and total oxidant status (TOS). MTT results and LDH cytotoxicity analyses showed that pretreatment with 8 µM lycopene significantly improved the toxicity due to As2O3 exposure in SH­SY5Y neuroblastoma cells. Pretreatment with lycopene significantly increased the activities of anti­oxidative enzymes as well as total antioxidant status and decreased total oxidative status in As2O3 exposed cells. The results of this study indicate that lycopene may be a potent neuroprotective against oxidative stress and could be used to prevent neuronal injury or death in several neurological diseases.

Evaluation of toxic effects induced by arsenic trioxide or/and antimony on autophagy and apoptosis in testis of adult mice.

Arsenic trioxide (ATO) and antimony (Sb) are well-known ubiquitous environmental contaminants and cause unpromising male reproductive effects in target and non-target exposed organisms. The main objective of this study was to investigate the effects of ATO or/and Sb on process of autophagy, apoptosis, and reproductive organ in adult mice. For this reason, a total of 32 adult mice were randomly divided into different groups like control group, ATO-treated group, Sb-treated group, and combined group. The duration of current experimental trial was 2 months. Various adverse effects of ATO or/and Sb on sperm parameters, oxidative stress, autophagy, and apoptosis were determined in testis of mice. Results indicated that parameters of sperm quality for organ coefficient, sperm count, ratio of sperm survival, testosterone level, and germ cells were significantly decreased, while malformation rate and vacuolization significantly increased in mice exposed to different treatments. Furthermore, the status of antioxidant index of T-AOC, SOD, and MsrB1 levels was reduced, while MDA increased significantly in ATO + Sb group. Results on TEM investigation determined that the autophagosomes, autolysosome, nuclear pyknosis, and chromatin condensation were prominent ailments, and the levels of autophagy and pro-apoptosis indictors including Beclin1, Atg-5, LC3B/LC3A, caspase-8, cytc, cleaved caspase-3, p53, and Bax were up-regulated in treated group, while the content of an anti-apoptosis maker (Bcl-2) was down-regulated. In conclusion, the results of our experiment suggested that abnormal process of autophagy and apoptosis was triggered by arsenic and antimony, and intensity of toxic effects increased in combined treatments of ATO and Sb.

The effect of aflibercept and arsenic trioxide on the proliferation, migration and apoptosis of oral squamous cell carcinoma in vitro.

Aflibercept and arsenic trioxide drugs apply a cytotoxic effect on some human cancer cell lines. However, no more study has followed the effects of both drugs, especially arsenic trioxide, on oral squamous cell carcinoma (OCC). We used three OCC lines as a model to show the effect of these drugs on the genetically complex disease and investigate its targeted therapy. In this study, three human OCC cell lines were used from different patients. We treated cell lines with both medications to detect the effect and relevant molecular basis. First, methyl thiazolyl tetrazolium (MTT) assay was performed to detect the cytotoxicity effect and cell growth. Second, flow cytometry, gene and protein expression were performed to evaluate the anti-angiogenic effect on OCC lines. Next apoptosis was analyzed by flow cytometry. Finally, clonogenesis capacity and cell migration were assessed by colony formation assay and wound healing, respectively. Aflibercept had no cytotoxic effect on the three OCC cell lines but decreased cell growth rate. Arsenic trioxide had a significant cytotoxic effect on three cell lines. Our results demonstrated that both drugs significantly decreased endoglin, VEGFA, and VEGFB expression. In addition, Migration and colony formation assays confirmed that these drugs have significant anti-proliferative and anti-migration effect on oral carcinoma cells. These results revealed that both medications might be a potential drug for the management of oral cancer patients.

Acute promyelocytic leukemia drug - arsenic trioxide in the presence of eugenol shows differential action on leukemia cells (HL-60) and cardiomyocytes (H9c2) - inference from NMR study.

The increased concern of cardiovascular dysfunction by cancer therapeutics has led to more effective treatment strategies. Arsenic trioxide (As2O3) is a potential chemotherapeutic agent for acute promyelocytic leukemia (APL), but the effectiveness is affected by potential cardiotoxicity. Researchers have been trying to find out novel modalities to manage the adverse effects of As2O3. In our study, the antioxidant molecule eugenol showed protective action against the destructive impact of As2O3 on cardiomyocytes (H9c2) without compromising the anti-cancer property As2O3 on leukemia cells (HL-60). We have studied the interaction between arsenic and eugenol in physiological and acidic pH to understand the molecular mechanism of differential action of As2O3 in the presence of eugenol using NMR spectroscopy. The study observed that at physiological pH, arsenic and eugenol interact to form an inactive product, positively affecting H9c2 cardiomyocytes. Still, there is no such interaction in acidic pH evidenced by the useful anti-cancer property of As2O3. The result concludes that the antioxidant molecule eugenol is an efficient protective agent against the adverse effect of As2O3 on cardiomyocytes.