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Nimbolide induces apoptosis in human nasopharyngeal cancer cells

Chien SY, Hsu CH, Lin CC, Chuang YC, Lo YS, Hsi YT, et al.

Environ Toxicol, 2017 Aug;32(8):2085-2092.
PMID: 28383207 DOI: 10.1002/tox.22423

Nasopharyngeal carcinoma (NPC), a tumor arising from epithelial cells that cover the surface and line the nasopharynx, is a rare malignancy worldwide but is prevalent in certain geographical areas, such as Southern Asia (Taiwan, Hong Kong, Singapore, Malaysia, and Southern China) and North Africa. Despite advances in diagnostic techniques and improvements in treatment modalities, the prognosis of NPC remains poor. Therefore, an effective chemotherapy regimen that enhances tumor sensitivity to chemotherapeutics is urgently required. Nimbolide, derived from Azadirachta indica, has a wide range of beneficial effects, including anti-inflammatory and anticancer properties. The present study evaluated the antitumor activity of nimbolide in NPC cells and its underlying mechanisms. Our results revealed that the treatment of HONE-1 cells with nimbolide potently inhibited cell viability. Moreover, nimbolide led to cell cycle arrest, which subsequently activated caspase-3, -8, and -9 and poly (ADP-ribose) polymerase to induce cell apoptosis. Moreover, nimbolide induced Bik, Bax, and t-Bid expression in HONE-1 cells. The results indicated that nimbolide induces apoptosis through the modulation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways. Nimbolide induces apoptosis in human NPC cells and is a potential chemopreventive agent against NPC proliferation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2085-2092, 2017.
Chemical evaluation and cytotoxic mechanism investigation of Clinacanthus nutans extract in lymphoma SUP-T1 cells

Lu MC, Li TY, Hsieh YC, Hsieh PC, Chu YL

Environ Toxicol, 2018 Dec;33(12):1229-1236.
PMID: 30188005 DOI: 10.1002/tox.22629

Clinacanthus nutans has been used as herbal medicine with antidiabetic, blood pressure lowering, and diuretic properties in Singapore, Thailand, and Malaysia. The in vitro cellular study showed the chloroform extract possessed significant cytotoxicity against leukemia K562 and lymphoma Raji cells. The clinical study reported that administration of plant could treat or prevent relapse in 12 cancer patients. However, detailed mechanism of the anticancer effects and chemical profiles are not thoroughly studied. The chemical study did show that the acetone extract (MHA) exerted the highest antiproliferative effect on human leukemia MOLT-4 cells and lymphoma SUP-T1 cells in dose-dependent cytotoxicity. We found that the use of MHA increased apoptosis by 4.28%-43.65% and caused disruption of mitochondrial membrane potential (MMP) by 11.79%-26.93%, increased reactive oxygen species (ROS) by 19.54% and increased calcium ion by 233.83%, as demonstrated by annexin-V/PI, JC-1, H2 DCFDA, and Flou-3 staining assays, respectively. MHA-induced ER stress was confirmed by increase expression of CHOP and IRE-1α with western blotting assay. In conclusion, we identified good bioactivity in Clinacanthus nutans and recognize its potential effect on cancer therapy, but further research is needed to determine the use of the plant.
4-chloro-1,2-phenylenediamine induces apoptosis in Mardin-Darby canine kidney cells via activation of caspases

Onn LC, Ching CS, Lian TY, Foon LV, Chew Hee N, Moi CS

Environ Toxicol, 2014 Jun;29(6):655-64.
PMID: 22778066 DOI: 10.1002/tox.21792

4-Chloro-1,2-phenylenediamine (4-Cl-o-PD) is a halogenated aromatic diamine that was used as a precursor for manufacturing permanent hair dyes. Despite its well-documented mutagenic and carcinogenic effects in a number of in vitro and in vivo models, its cytotoxicity and mode of action have not received similar attention. Here, we investigated the effect of 4-Cl-o-PD on Mardin-Darby canine kidney cells. It induced apoptosis and the evidence suggests its initiation by reactive oxygen species (ROS). The results of various assays used show a dose-dependent (i) decrease in cell viability, (ii) increase in cells at sub-G1 phase and the G0/G1 phase arrested in cell cycle, (iii) increase in intracellular ROS accompanied by depletion of glutathione, and (iv) that apoptotic cell death probably involves activation of both intrinsic and extrinsic pathways.
Analysis of endosulfan and its metabolites in rat plasma and selected tissue samples by gas chromatography-mass spectrometry

Chan MP, Mohd MA

Environ Toxicol, 2005 Feb;20(1):45-52.
PMID: 15712329

A method has been developed for the determination of trace levels of alpha-endosulfan, beta-endosulfan, endosulfan sulfate, and endosulfan diol in rat plasma and tissue samples. Endosulfan and its metabolites in the plasma samples were extracted with solid-phase extraction Chromabond-end-capped C18 cartridges and analyzed by a Shimadzu QP-5050A gas chromatograph-mass spectrometer (GCMS) with quadrupole detector in selected-ion-monitoring mode. The analysis of endosulfan and its metabolites in liver and kidney samples involved solvent extraction, Florisil solid-phase-extraction cleanup, and quantitation by GCMS. Recovery experiments for the plasma and tissue samples were conducted over concentration ranges of 10-100 ng mL(-1) and 100-1000 ng mL(-1), respectively. The method was applied to the analysis of trace levels of endosulfan and its metabolites in plasma and tissue samples collected from an animal study. Trace levels of alpha-endosulfan and beta-endosulfan in the ranges of undetectable to 3.11 microg g(-1) and undetectable to 1.19 microg g(-1), respectively, were detected in the kidney samples, whereas trace levels of endosulfan sulfate in the range of 0.02-0.22 microg g(-1) were detected in the liver samples of rats. Neither endosulfan nor its metabolites was detected in any of the plasma samples.
The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides

Singh S, Prakash A, Kaur S, Ming LC, Mani V, Majeed AB

Environ Toxicol, 2016 Aug;31(8):1017-26.
PMID: 25864908 DOI: 10.1002/tox.22111

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.
para-Phenylenediamine induces apoptosis through activation of reactive oxygen species-mediated mitochondrial pathway, and inhibition of the NF-κB, mTOR, and Wnt pathways in human urothelial cells

Reena K, Ng KY, Koh RY, Gnanajothy P, Chye SM

Environ Toxicol, 2017 Jan;32(1):265-277.
PMID: 26784575 DOI: 10.1002/tox.22233

para-Phenylenediamine (PPD) has long been used in two-thirds of permanent oxidative hair dye formulations. Epidemiological studies and in vivo studies have shown that hair dye is a suspected carcinogen of bladder cancer. However, the toxicity effects of PPD to human bladder remains elusive. In this study, the effects of PPD and its involvement in the apoptosis pathways in human urothelial cells (UROtsa) was investigated. It was demonstrated that PPD decreased cell viability and increased the number of sub-G1 hypodiploid cells in UROtsa cells. Cell death due to apoptosis was detected using Annexin V binding assay. Further analysis showed PPD generated reactive oxygen species (ROS), induced mitochondrial dysfunction through the loss of mitochondrial membrane potential and increased caspase-3 level in UROtsa cells. Western blot analysis of PPD-treated UROtsa cells showed down-regulation of phosphorylated proteins from NF-κB, mTOR, and Wnt pathways. In conclusion, PPD induced apoptosis via activation of ROS-mediated mitochondrial pathway, and possibly through inhibition of NF-κB, mTOR, and Wnt pathways. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 265-277, 2017.
Sesame indicum, a nutritional supplement, elicits antiamnesic effect via cholinergic pathway in scopolamine intoxicated mice

Chidambaram SB, Pandian A, Sekar S, Haridass S, Vijayan R, Thiyagarajan LK, et al.

Environ Toxicol, 2016 Dec;31(12):1955-1963.
PMID: 26434561 DOI: 10.1002/tox.22196

PURPOSE: Present study was undertaken to evaluate the antiamnesic effect of Sesamum indicum (S. indicum) seeds (standardized for sesamin, a lignan, content) in scopolamine, a muscarinic antagonist intoxicated mice.
METHODS: Male Swiss albino mice (18-22 g bw) were pretreated with methanolic extract of sesame seeds (MSSE) (100 and 200 mg/kg/day, p.o) for a period of 14 days. Scopolamine (0.3 mg/kg, i.p.) was injected on day 14, 45 ± 10 min after MSSE administration. Antiamnesic effect of MSSE was evaluated using step-down latency (SDL) on passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. To unravel the mechanism of action, we examined the effects of MSSE on the genes such as acetyl cholinesterase (AChE), muscarinic receptor M1 subtype (mAChRM1 ), and brain derived neurotrophic factor (BDNF) expression within hippocampus of experimental mice. Further, its effects on bax and bcl-2 were also evaluated. Histopathological examination of hippocampal CA1 region was performed using cresyl violet staining.
RESULTS: MSSE treatment produced a significant and dose dependent increase in step down latency in passive avoidance test and decrease in transfer latency in elevated plus maze in scopolamine intoxicated injected mice. MSSE down-regulated AChE and mAChRM1 and up-regulated BDNF mRNA expression. Further, it significantly down-regulated the bax and caspase 3 and up-regulated bcl-2 expression in scopolamine intoxicated mice brains. Mice treated with MSSE showed increased neuronal counts in hippocampal CA1 region when compared with scopolamine-vehicle treated mice.
CONCLUSION: Sesame seeds have the ability to interact with cholinergic components involved in memory function/restoration and also an interesting candidate to be considered for future cognitive research. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1955-1963, 2016.
Apoptosis induced by para-phenylenediamine involves formation of ROS and activation of p38 and JNK in chang liver cells

Chye SM, Tiong YL, Yip WK, Koh RY, Len YW, Seow HF, et al.

Environ Toxicol, 2014 Sep;29(9):981-90.
PMID: 23172806 DOI: 10.1002/tox.21828

para-Phenylenediamine (p-PD) is a suspected carcinogen, but it has been widely used as a component in permanent hair dyes. In this study, the mechanism of p-PD-induced cell death in normal Chang liver cells was investigated. The results demonstrated that p-PD decreased cell viability in a dose-dependent manner. Cell death via apoptosis was confirmed by enhanced DNA damage and increased cell number in the sub-G1 phase of the cell cycle, using Hoechst 33258 dye staining and flow cytometry analysis. Apoptosis via reactive oxygen species generation was detected by the dichlorofluorescin diacetate staining method. Mitogen-activated protein kinase (MAPK) activation was assessed by western blot analysis and revealed that p-PD activated not only stress-activated protein kinase (SAPK)/c-Jun N-terminal kinases (JNK) and p38 MAPK but also extracellular signal-regulated kinase (ERK). Cytotoxicity and apoptosis induced by p-PD were markedly enhanced by ERK activation and selectively inhibited by ERK inhibitor PD98059, thus indicating a negative role of ERK. In contrast, inhibition of p38 MAPK activity with the p38-specific inhibitor SB203580 moderately inhibited cytotoxicity and apoptosis induction by p-PD. Similarly, SP600125, an inhibitor of SAPK/JNK, moderately inhibited cytotoxicity and apoptosis induced by p-PD, thus implying that p38 MAPK and SAPK/JNK had a partial role in p-PD-induced apoptosis. Western blot analysis revealed that p-PD significantly increased phosphorylation of p38 and SAPK/JNK and decreased phosphorylation of ERK. In conclusion, the results demonstrated that SAPK/JNK and p38 cooperatively participate in apoptosis induced by p-PD and that a decreased ERK signal contributes to growth inhibition or apoptosis.
Combinatorial effect of genistein and female sex-steroids on uterine fluid volume and secretion rate and aquaporin (AQP)-1, 2, 5, and 7 expression in the uterus in rats

Chinigarzadeh A, Muniandy S, Salleh N

Environ Toxicol, 2017 Mar;32(3):832-844.
PMID: 27235753 DOI: 10.1002/tox.22283

We hypothesized that genistein can interfere with the regulation of uterine fluid volume, secretion rate and expression of aquaporin in the uterus by female sex-steroids, i.e., estrogen and progesterone. Therefore, the aims of this study were to investigate changes in these parameters in the presence of genistein and female sex-steroids.
METHODS: Female Sprague-Dawley rats were ovariectomized and received 3-days estradiol-17β benzoate (E2) plus genistein (25, 50, or 100 mg kg(-1) day(-1) ) or 3-days E2 followed by 3-days E2 plus progesterone with genistein (25, 50, or 100 mg kg(-1) day(-1) ). A day after last treatment, uterine fluid secretion rate was determined by in vivo uterine perfusion with rats under anesthesia. Animals were sacrificed and uteri were harvested and subjected for histological analyses. Luminal/outer uterine circumference was determined and distribution of AQP-1, 2, 5, and 7 in endometrium was visualized by immunofluorescence. Expression of AQP-1, 2, 5, and 7 proteins and mRNAs were determined by Western blotting and Real-time PCR respectively.
RESULTS: Combined treatment of E2 with high dose genistein (50 and 100 mg kg(-1) day(-1) ) resulted in significant decrease in uterine fluid volume, secretion rate and expression of AQP-1, 2, 5, and 7 proteins and mRNAs in uterus (p
In vivo hepatoprotective effect of Morinda elliptica stem extract against liver fibrosis induced by thioacetamide

Bradosty SW, Hamad SW, Agha NFS, Shaikh FK, Qadir Nanakali NM, Aziz PY, et al.

Environ Toxicol, 2021 Dec;36(12):2404-2413.
PMID: 34436826 DOI: 10.1002/tox.23353

Morinda elliptica L. (Rubiaceae) is a phytomedicinal herb, used to treat gastrointestinal complications in Peninsular Malaysia. The study evaluates the in vivo hepatoprotective activity of ethanolic extract of M. elliptica stem in thioacetamide (TAA) induced liver fibrosis in male Sprague Drawly rats. Thirty adult rats were divided into five groups of six rats each. Rats of the normal control group received intraperitoneal injections (i. p.) of vehicle 10% Tween-20, 5 ml/kg, and hepatotoxic group 200 mg/kg TAA three times per week respectively. Three supplementary groups were treated with TAA plus daily oral silymarin (50 mg/kg) or M. elliptica (250 or 500 mg/kg). After 8 weeks of treatment, all rats were sacrificed. Liver fibrosis was assessed by gross macroscopic and microscopic tissue analysis, histopathological, and biochemical analysis. The livers of the TAA treated group showed uniform coarse granules, hepatocytic necrosis with lymphocytes infiltration. Contrary, the livers of M. elliptica treated groups (250 and 500 mg/kg) were much smoother and the cell damage was much lesser. The livers of M. elliptica treated groups rats showed elevated activity of SOD and CAT with a significant decrease in MDA level at p
Acacia catechu seed extract provokes cytotoxicity via apoptosis by intrinsic pathway in HepG2 cells

Thangavelu L, Geetha RV, Devaraj E, Dua K, Chellappan DK, Balusamy SR

Environ Toxicol, 2022 Mar;37(3):446-456.
PMID: 34800081 DOI: 10.1002/tox.23411

Acacia catechu Willd (Fabaceae) is a thorny tree widely distributed in India and commonly used as traditional Ayurvedic medicine for various ailments. The current study evaluates the cytotoxic potentials of A. catechu ethanolic seed extract (ACSE) in HepG2 cells, a human hepatocellular carcinoma cell line. The HepG2 cells were treated with 0.1, 0.3, 1, 3, 10, 30, 100, 300 and 1000 μg/ml of ACSE and the cytotoxic effect was evaluated by MTT and lactate dehydrogenase (LDH) leakage assays. The IC50 of ACSE was found at 77.04 μg/ml and therefore, further studies were carried out with the concentrations of 35 and 70 μg/ml. The intracellular reactive oxygen species (ROS) generation and apoptosis-related morphological changes were evaluated. Gene expressions of Bax, Bcl-2, cytochrome C (Cyt-c), caspases-9 and 3 were analyzed by qPCR. The ACSE treatments caused LDH leakage was associated with an increased ROS generation. The increased ROS generation was associated with the downregulation of intracellular antioxidant enzyme superoxide dismutase and reduced glutathione content. AO/EB and PI staining also confirmed chromatin condensation and apoptosis. The flow cytometric analysis showed an accumulation of HepG2 cells at sub G0/G1 (apoptotic) phase upon ACSE treatments. The ACSE induced cytotoxicity and oxidative stress were related to increased apoptotic marker gene expressions such as Bax, Cyt-c, caspase-9 and 3, and decreased anti-apoptotic marker Bcl-2. The current finding suggests that ACSE has apoptosis-inducing potential via the mitochondrial pathway in HepG2 cells.
Demethylnobiletin ameliorates cerebral ischemia-reperfusion injury in rats through Nrf2/HO-1 signaling pathway

Huang D, Awad ACA, Tang C, Chen Y

Environ Toxicol, 2024 Mar;39(3):1335-1349.
PMID: 37955318 DOI: 10.1002/tox.24036

BACKGROUND: Demethylnobiletin (DN), with a variety of biological activities, is a polymethoxy-flavanone (PMF) found in citrus. In the present study, we explored the biological activities and potential mechanism of DN to improve cerebral ischemia reperfusion injury (CIRI) in rats, and identified DN as a novel neuroprotective agent for patients with ischemic brain injury.
METHODS: Rat CIRI models were established via middle cerebral artery occlusion (MCAO). Primary nerve cells were isolated and cultured in fetal rat cerebral cortex in vitro, and oxygen-glucose deprivation/reperfusion (OGD/R) models of primary nerve cells were induced. After intervention with DN with different concentrations in MCAO rats and OGD/R nerve cells, 2,3,5-triphenyltetrazolium chloride staining was used to quantify cerebral infarction size in CIRI rats. Modified neurological severity score was utilized to assess neurological performance. Histopathologic staining and live/dead cell-viability staining was used to observe apoptosis. Levels of glutathione (GSH), superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA) in tissues and cells were detected using commercial kits. DN level in serum and cerebrospinal fluid of MCAO rats were measured by liquid chromatography tandem mass spectrometry. In addition, expression levels of proteins like Kelch like ECH associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nfr2) and heme oxygenase 1 (HO-1) in the Nrf2/HO-1 pathway, and apoptosis-related proteins like Cleaved caspase-3, BCL-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) were determined by Western blot and immunofluorescence.
RESULTS: DN can significantly enhance neurological function recovery by reducing cerebral infarction size and weakening neurocytes apoptosis in MCAO rats. It was further found that DN could improve oxidative stress (OS) injury of nerve cells by bringing down MDA and ROS levels and increasing SOD and GSH levels. Notably, DN exerts its pharmacological influences through entering blood-brain barrier. Mechanically, DN can reduce Keap1 expression while activate Nrf2 and HO-1 expression in neurocytes.
CONCLUSIONS: The protective effect of DN on neurocytes have been demonstrated in both in vitro and in vivo circumstances. It deserves to be developed as a potential neuroprotective agent through regulating the Nrf2/HO-1 signaling pathway to ameliorate neurocytes impairment caused by OS.

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