Melatonin attenuates liver injury in arsenic-treated rats: The potential role of the Nrf2/HO-1, apoptosis, and miR-34a/Sirt1/autophagy pathways.

Arsenic is a toxic metalloid found in the environment in different organic and inorganic forms. Molecular mechanisms implicated in arsenic hepatotoxicity are complex but include oxidative stress, apoptosis, and autophagy. The current study focused on the potential protective capacity of melatonin against arsenic-induced hepatotoxicity. Thirty-six male Wistar rats were allocated into control, arsenic (15 mg/kg; orally), arsenic (15 mg/kg) plus melatonin (10, 20, and 30 mg/kg; intraperitoneally), and melatonin alone (30 mg/kg) groups for 28 days. After the treatment period, the serum sample was separated to measure liver enzymes (AST and ALT). The liver tissue was removed and then histological alterations, oxidative stress markers, antioxidant capacity, the levels of Nrf2 and HO-1, apoptosis (Bcl-2, survivin, Mcl1, Bax, and caspase-3), and autophagy (Sirt1, Beclin-1, and LC3 II/I ratio) proteins, as well as the expression level of miR-34a, were evaluated on this tissue. Arsenic exposure resulted in the enhancement of serum AST, ALT, and substantial histological damage in the liver. Increased levels of malondialdehyde, a lipid peroxidation marker, and decreased levels of physiological antioxidants including glutathione, superoxide dismutase, and catalase were indicators of arsenic-induced oxidative damage. The levels of Nrf2, HO-1, and antiapoptotic proteins diminished, while proapoptotic and autophagy proteins were elevated in the arsenic group concomitant with a low level of hepatic miR-34a. The co-treatment of melatonin and arsenic reversed the changes caused by arsenic. These findings showed that melatonin reduced the hepatic damage induced by arsenic due to its antioxidant and antiapoptotic properties as well as its regulatory effect on the miR-34a/Sirt1/autophagy pathway.

The protective effects of curcumin against cigarette smoke-induced toxicity: A comprehensive review.

Cigarette smoking (CS) is a crucial modifiable risk of developing several human diseases and cancers. It causes lung, bladder, breast, and esophageal cancers, respiratory disorders, as well as cardiovascular and metabolic diseases. Because of these adverse health effects, continual efforts to decrease the prevalence and toxicity of CS are imperative. Until the past decades, the impacts of natural compounds have been under investigation on the harmful effects of CS. Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant that belongs to the Zingiberaceae family, is the main source of curcumin. This review is an attempt to find out the current knowledge on CS's harmful effects and protective potential of curcumin in the pulmonary, liver, brain, gastrointestinal, and testis organs. According to the present review, simultaneous consumption of curcumin and CS can attenuate CS toxicities including chronic obstructive pulmonary disease, gastrointestinal toxicity, metabolic diseases, testis injury, and neurotoxicity. Moreover, curcumin suppresses carcinogenesis in the skin, liver, lungs, breast, colon, and stomach. Curcumin mediates these protective effects through antioxidant, anti-inflammatory, anti-apoptotic, and anti-carcinogenicity properties.

The blockade of transient receptor potential ankyrin 1 (TRPA1) protects against PTZ-induced seizure.

Treatment of epilepsy remains a major problem as some epileptic patients do not respond to the current therapeutics. Transient receptor potential ankyrin 1 (TRPA1) belongs to the TRP channels and has diverse physiological functions in the body. Considering its physiological properties, we aimed to evaluate its role in two experimental models of epilepsy, including pentylenetetrazol (PTZ)-induced acute seizure and PTZ-evoked kindling. Furthermore, the TRPA1 protein levels were assessed in the cerebral cortex, hippocampus, and cerebellum after seizure induction. Three groups of Wistar rats received acute intraperitoneal injection of pentylenetetrazol (PTZ, 85 mg/kg). The groups received intraventricular injections of vehicle (dimethyl sulfoxide, Tween 80, and sterile 0.9% saline), valproate (30 µg/rat), or HC030031 (TRPA1 antagonist, 14 µg/rat) before PTZ injection. In the PTZ-induced kindling model, PTZ was administrated 35 mg/kg every other day for 24 days. PTZ gradually provoked seizure-related behaviors. After experiments, the TRPA1 levels in the brain were assessed using western blot. The results showed that HC030031 reduced the median of seizure scores and S5 duration while increasing S2 and S5 latencies in acute and kindling models. The anticonvulsant effect of HC030031 was comparable with valproate as a standard anticonvulsant drug. Furthermore, induction of seizure, either acute or kindling, enhanced TRPA1 levels in the cerebral cortex, hippocampus, and cerebellum that were prevented by HC030031 or valproate administration. The results of this study showed that HC030031 as a TRPA1 receptor antagonist promoted a significant anticonvulsant effect comparable with valproate. Both drugs prevented TRPA1 upregulation during seizures. These findings imply that TRPA1 is a potential target in treating epilepsy.

The effect of melatonin on benzo(a)pyrene-induced renal toxicity in mice.

Benzo(a)pyrene is a ubiquitous environmental contaminant, which could induce renal injury. It is reported that melatonin has a protective effect against multiple organ injuries by regulating oxidative stress, apoptosis, and autophagy. The aim of this study was to estimate the melatonin effects on benzo(a)pyrene renal toxicity in mice and the possible molecular mechanisms involved in this model. Thirty male mice were allocated to five groups and treated with benzo(a)pyrene (75 mg/kg, oral gavage) and/or melatonin (10 and 20 mg/kg, intraperitoneally). The oxidative stress factors were evaluated in renal tissue. The levels of apoptotic (the Bax/Bcl-2 ratio and caspase-3) and autophagic (the LC3 II/I, Beclin-1, and Sirt1) proteins were examined using Western blot. Following the administration of benzo(a)pyrene, malondialdehyde, caspase-3 and the Bax/Bcl-2 ratio increased in renal tissue, while Sirt1, Beclin-1, and the LC3 II/I ratio diminished. Interestingly, the co-administration of 20 mg/kg melatonin along with benzo(a)pyrene reduced the oxidative stress markers, apoptotic and autophagic proteins. Collectively, melatonin exhibited a protective effect against benzo(a)pyrene-induced renal injury through the suppression of oxidative stress and apoptosis and the inhibition of Sirt1/autophagy pathway.

Effects of alpha lipoic acid on metabolic syndrome: A comprehensive review.

Metabolic syndrome (MetS) is a multifactorial disease with medical conditions such as hypertension, diabetes, obesity, dyslipidemia, and insulin resistance. Alpha-lipoic acid (α-LA) possesses various pharmacological effects, including antidiabetic, antiobesity, hypotensive, and hypolipidemia actions. It exhibits reactive oxygen species scavenger properties against oxidation and age-related inflammation and refines MetS components. Also, α-LA activates the 5' adenosine monophosphate-activated protein kinase and inhibits the NFκb. It can decrease cholesterol biosynthesis, fatty acid ß-oxidation, and vascular stiffness. α-LA decreases lipogenesis, cholesterol biosynthesis, low-density lipoprotein and very low-density lipoprotein levels, and atherosclerosis. Moreover, α-LA increases insulin secretion, glucose transport, and insulin sensitivity. These changes occur via PI3K/Akt activation. On the other hand, α-LA treats central obesity by increasing adiponectin levels and mitochondrial biogenesis and can reduce food intake mainly by SIRT1 stimulation. In this review, the most relevant articles have been discussed to determine the effects of α-LA on different components of MetS with a special focus on different molecular mechanisms behind these effects. This review exhibits the potential properties of α-LA in managing MetS; however, high-quality studies are needed to confirm the clinical efficacy of α-LA.

Quetiapine attenuates the acquisition of morphine-induced conditioned place preference and reduces ERK phosphorylation in the hippocampus and cerebral cortex.

Background: Quetiapine is an atypical antipsychotic that antagonizes dopamine and serotonin receptors. It has been suggested that quetiapine can be used to treat substance use disorders, including opioid use disorder. Opioids modulate dopaminergic functions associated with conditioned reinforcement and these effects can be measured via the conditioned place preference (CPP) paradigm. Opioids' unconditioned effects are regulated by several proteins, including extracellular signal-regulated kinase (ERK) and cAMP-responsive element-binding (CREB).Objective: To assess the effect of quetiapine on morphine-induced CPP and motor activity levels, and on the levels of ERK and CREB proteins in the hippocampus and cerebral cortex.Methods: 42 male rats were exposed to a CPP protocol, in which they underwent a conditioning paradigm with saline, quetiapine (40 mg/kg), morphine (10 mg/kg), morphine plus quetiapine (10, 20, or 40 mg/kg), or morphine plus memantine (7.5 mg/kg, a positive control drug) (n = 6 per group). The rats were tested for CPP and exploratory activity. Levels of ERK and CREB proteins in the hippocampus and cerebral cortex were also measured.Results: Quetiapine co-administered with morphine inhibited morphine-induced CPP [F (6, 70) = 11.67, p < .001] and morphine's effects on motor activity (p < .001). Morphine enhanced ERK phosphorylation in the hippocampus (p < .001) and cerebral cortex (p < .001), an effect inhibited by quetiapine.Conclusion: Quetiapine attenuates morphine-induced CPP and locomotion and these effects are associated with a reduction of ERK phosphorylation in the hippocampus and cerebral cortex. These results suggest that quetiapine should be further explored as a potential treatment for opioid use disorder.

The genus Glycyrrhiza (Fabaceae family) and its active constituents as protective agents against natural or chemical toxicities.

Licorice is the dried roots and rhizomes of various species of the genus Glycyrrhiza (Fabaceae) that have been used in folk medicine from ancient times. Many important research projects have established several beneficial effects for this medicinal herb, including antiinflammatory, antimicrobial, antiviral, antiprotozoal, antioxidant, antihyperglycemic, antihyperlipidemic, hepatoprotective, and neuroprotective. Licorice contains important bioactive components, such as glycyrrhizin (glycyrrhizic, glycyrrhizinic acid), liquiritigenin, liquiritin, and glycyrrhetinic acid. The protective effects of licorice and its main chemical components against toxins and toxicants in several organs including the brain, heart, liver, kidney, and lung have been shown. In this comprehensive review article, the protective effects of these constituents against natural, industrial, environmental, and chemical toxicities with attention on the cellular and molecular mechanism are introduced. Also, it has been revealed that this plant and its main compounds can inhibit the toxicity of different toxins by the antioxidant, antiinflammatory, and anti-apoptotic properties as well as the modulation of Inhibitor of kappaB kinase (IKK), Extracellular signal-regulated protein kinase1/2 (ERK1/2), p38, inducible nitric oxide synthase, and nuclear factor-κB (NF-κB) signaling pathways. More high-quality investigations in both experimental and clinical studies need to firmly establish the efficacy of licorice and its main constituents against toxic agents.

Evaluation of the effect of thymoquinone in d-galactose-induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length.

D-galactose (d-gal) induces aging and memory impairment via oxidative stress and neuroinflammation pathways. This study evaluated the neuroprotective activity of thymoquinone (TQ) against d-gal. d-gal (400 mg/kg, SC), d-gal plus TQ (2.5, 5, 10 mg/kg, i.p.), and TQ alone (2.5 and 10 mg/kg) for 8 weeks were administered to rats. The effect of TQ on learning and memory were studied using the Morris water maze test. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the hippocampus. The levels of MAPKs (p-ERK/ERK, p-P38/P38), cAMP response elements binding (p-CREB/CREB), advanced glycation end products (AGEs), inflammatory markers (TNFα, IL-1ß), glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. Telomere length was evaluated using real-time PCR. Memory and learning impairment, MDA enhancement, GSH reduction, and neuroinflammation via increasing the TNFα, IL-1ß, and GFAP contents were observed in d-gal group. TQ with d-gal, improved memory impairment, reduced oxidative stress, and alleviated neuroinflammation. The elevated level of AGEs decreased by TQ compared to d-gal. No changes were observed in the levels of p-ERK/ERK, p-CREB/CREB, p-P38/P38, BDNF, and telomere length following administration of d-gal or TQ plus d-gal. TQ improved memory deficits of d-gal through anti-oxidative and anti-inflammatory mechanisms.

An updated review of protective effects of rosemary and its active constituents against natural and chemical toxicities.

Natural and chemical toxic agents cause severe adverse effects on people's health in a variety of exposing ways. Herbal medications have taken into consideration as alternative safe treatments for toxicities. Rosmarinus officinalis also known as rosemary belongs to the Lamiaceae family. Rosemary and its constituents including carnosic acid, rosmarinic acid, and carnosol have a lot of benefits such as anti-inflammatory, antioxidant, anti-mutagenic, anti-bacterial, antiviral, antinociceptive, and neuroprotective activities. In this literate review, we focused on the protective effects of rosemary and its main compounds against natural and chemical toxicities in both in vitro and in vivo studies. The protective effects of rosemary and its components are mostly mediated through different mechanisms such as the inhibition of oxidative stress, reduction of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), cyclooxygenase-2 (COX-2) and nuclear factor ĸB (NF-ĸB) as well as the modulation of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways.

miR-155 influences cell-mediated immunity in Balb/c mice treated with aflatoxin M1.

Aflatoxin M1 (AFM1) is a 4-hydroxylated metabolite of aflatoxin B1 (AFB1). It induces various toxicological effects including immunotoxicity. In the present study, we investigated the effects of AFM1 on immune system and its modulation by MicroRNA (miR)-155. AFM1 was administered intraperitoneally at doses of 25 and 50 µg/kg for 28 days to Balb/c mice and different immune system parameters were analyzed. The levels of miR-155 and targeted proteins were evaluated in isolated T cells from spleens of mice. Spleen weight was reduced in mice exposed to AFM1 compared to negative control. Proliferation of splenocytes in response to phytohemagglutinin-A was reduced in mice exposed to AFM1. IFN-γ was decreased in mice exposed to AFM1, whereas IL-10 was increased. Concentration of IL-4 did not change different in mice exposed to AFM1 compared to negative control. Exposure to AFM1 reduced the expression of miR-155. Significant upregulation of phosphatidylinositol-3, 4, 5-trisphosphate 5-phosphatase 1 (Ship1) and suppressor of cytokine signaling 1 (Socs1) was observed in isolated T cells from spleens of mice treated with AFM1, but the transcription factor Maf (c-MAF) was not affected. These results suggest that miR-155 and targeted proteins might be involved in the immunotoxicity observed in mice exposed to AFM1.

Role of Oxidative Stress, MAPKinase and Apoptosis Pathways in the Protective Effects of Thymoquinone Against Acrylamide-Induced Central Nervous System Toxicity in Rat.

The present study evaluated biochemical endpoints characterizing acrylamide (ACR) neurotoxicity in the cortex of rats, following the possible neuroprotective activity of thymoquinone (TQ), an active constituent of Nigella sativa. ACR (50 mg/kg, intraperitoneal [i.p.]) concurrently with TQ (2.5, 5 and 10 mg/kg, i.p.) for 11 days were administered to rats. As positive control, vitamin E was used. After 11 days of injections, narrow beam test (NBT) was performed. The levels of reduced glutathione (GSH) and malondialdehyde (MDA) were measured and Western blotting was done for mitogen-activated protein kinases (MAPKinases) and apoptosis pathways proteins in the rats' cortex. Additionally, Evans blue assay was done to evaluate the integrity of blood brain barrier (BBB). Administration of ACR significantly induced gait abnormalities. A significant decrease and increase in the levels of GSH and MDA was observed in the cortex of ACR-treated rats, respectively. The elevation in the levels of caspases 3 and 9, glial fibrillary acidic protein (GFAP) content, and Bax/Bcl-2, P-P38/P38 and P-JNK/JNK ratios accompanied by reduction in myelin basic protein (MBP) content and P-ERK/ERK ratio were noticed in the ACR group. TQ (5 mg/kg) improved gait abnormalities, and restored these changes. ACR affected the integrity of BBB while TQ was able to maintain the integrity of this barrier. TQ reversed the alterations in the protein contents of MAP kinase and apoptosis signaling pathways as well as MBP and GFAP contents, induced by ACR. It protected against ACR-mediated neurotoxicity, partly through its antioxidant and antiapoptotic properties.

Melatonin inhibits Benzo(a)pyrene-Induced apoptosis through activation of the Mir-34a/Sirt1/autophagy pathway in mouse liver.

Benzo(a)pyrene (BaP), an important environmental pollutant, is produced as the result of incomplete combustion of organic materials in many industries and food cooking process. It has been purposed that BaP induces hepatotoxicity through oxidative stress and apoptosis. Several studies have shown that melatonin can protect against chemical-induced apoptosis through autophagy pathway. In this study, we assessed the modulating effect of melatonin, a well-known antioxidant, on BaP-induced hepatotoxicity through induction of autophagy. Thirty male mice were treated daily for 28 consecutive days. BaP (75 mg/kg; oral gavage) and melatonin (10 and 20 mg/kg, i.p.) were administered to mice. The liver histopathology and the levels of apoptosis and autophagy proteins as well as the expression of miR-34a were determined. The BaP exposure induced severe liver histological injury and markedly enhanced AST, ALT and MDA level. Also, apoptosis proteins and hepatic miR-34a expression increased. However, the level of Sirt1 and autophagy markers such as LC3 II/I ratio and Beclin-1 reduced. The co-administration of melatonin reversed all changes caused by BaP. In summary, melatonin appears to be effective in BaP-induced hepatotoxicity maybe through the miR-34a/Sirt1/autophagy molecular pathway.

Protective effect of punicalagin, the main polyphenol compound of pomegranate, against acrylamide-induced neurotoxicity and hepatotoxicity in rats.

Acrylamide (ACR) is widely used in industries. Oxidative stress and apoptosis pathways are important mechanisms behind ACR-induced hepatotoxicity and neurotoxicity. Regarding to antioxidant and antiapoptotic properties of punicalagin (PUN), the protective effect of this agent on ACR-induced toxicity in rat was evaluated. Rats were divided into seven groups: control, ACR (50 mg/kg/day, i.p.), PUN (10, 20, and 40 mg/kg/day, i.p.) plus ACR, vitamin E (200 mg/kg, i.p.) plus ACR, and PUN groups. After 11 days, the gait score test was evaluated. Then, the animals were sacrificed and the malondialdehyde (MDA) and glutathione (GSH) contents were determined in the brain and liver tissues. Apoptosis-involved factors and myelin basic protein (MBP) were determined by western blotting. Severe movement disorder, MDA enhancement, and GSH reduction in the brain and liver tissues were observed in ACR-treated animals. The Bax/Bcl2 ratio and caspase-3 levels were enhanced in the tested tissues. ACR elevated the level of aspartate aminotransferases and decreased serum protein and albumin concentration. PUN recovered movement disorders, changed the level of markers which are important in oxidative stress and reduced apoptosis. Also, PUN increased the MBP level which was reduced due to ACR toxicity. PUN can protect against ACR-induced toxicity through antioxidant and antiapoptotic properties.

The protective effect of fasudil against acrylamide-induced cytotoxicity in PC12 cells.

Acrylamide (ACR), a vinyl monomer that has multiple chemical and industrial applications, is a neurotoxic agent in human and animal. Fasudil is a potent Rho-kinase inhibitor which exhibits neuroprotective effects in some neuronal degenerative disorders. In this study, the potential protective effect of Fasudil on ACR-induced cytotoxicity in PC12 cells was evaluated. Our results showed that ACR increased the level of intracellular reactive oxygen species (ROS) and consequently upregulated the Bax/Bcl-2 ratio and significantly elevated the level of caspase-3 and 9 proteins in PC12 cells. Interestingly, pretreatment with Fasudil protected PC12 cells against ACR-induced toxicity mainly through the reduction of ROS production and modulation of proteins which involved in apoptosis pathway. Fasudil down-regulated the Bax/Bcl-2 ratio and the levels of caspase-3 and 9 proteins in cells exposed to ACR. In conclusion, the neuroprotective effect of Fasudil against ACR-induced toxicity in PC12 cells appears to be mediated through inhibition of ROS production and modulation of apoptosis.

Neuroprotective Effects of Thymoquinone in Acrylamide-Induced Peripheral Nervous System Toxicity Through MAPKinase and Apoptosis Pathways in Rat.

Acrylamide (ACR) is extensively used in industrial areas and has been demonstrated to induce neurotoxicity via oxidative stress and apoptosis. In this study, we assessed the probable protective effects of thymoquinone (TQ), an active constituent of Nigella sativa, against ACR-induced neurotoxicity. ACR (50 mg/kg, i.p., for 11 days) and TQ (2.5, 5 and 10 mg/kg, i.p., for 11 days) were administered to rats. On 12th day, gait score was examined and rats were sacrificed. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined in sciatic nerve. Furthermore, western blotting was conducted. The exposure of rats to ACR caused severe gait disabilities. The MDA and GSH contents were increased and decreased, respectively. ACR decreased P-ERK/ERK ratio and myelin basic protein (MBP) content, but significantly increased P-JNK/JNK, P-P38/P38, Bax/Bcl-2 ratios and caspase 3 and 9 levels. Concurrently administration of TQ (5 and 10 mg/kg) with ACR, prevented gait abnormalities and meaningfully reduced MDA and elevated the GSH contents. Furthermore, TQ (5 mg/kg) elevated the P-ERK/ERK ratio and MBP content while reduced the P-JNK/JNK, P-P38/P38 ratios and apoptotic markers. MAP kinase and apoptosis signaling pathways were involved in ACR-induced neurotoxicity in rat sciatic nerve and TQ significantly reduced ACR neurotoxicity. TQ afforded neuroprotection, in part, due to its anti-oxidative stress and anti-apoptotic mechanisms.

Neuroprotective effect of clavulanic acid on trimethyltin (TMT)-induced cytotoxicity in PC12 cells.

Trimethyltin (TMT) is a short-chain trialkyltin with various applications in industry. In addition, it is a known neurotoxin, producing significant and selective neurodegeneration in the limbic system of both human and animals. Recently, effect of clavulanic acid (CA) in nervous system has been mentioned. Therefore, in this study, the role of CA in TMT-induced toxicity in PC12 cells was evaluated. For this study, PC12 cells were cultured and exposed to different concentrations of CA for 24 h. Then, TMT (20 µM) was added to cells. After that, MTT test was performed to assay cytotoxicity. Reactive oxygen species production (ROS) was determined using 2,7-dichlorofluorescein diacetate (DCFH-DA) method. Additionally, the levels of Bax, Bcl-2, caspase-3, CERB and p-CREB proteins were evaluated using Western blot analysis. The exposure of PC12 cells to TMT reduced cell viability, increased intracellular ROS production, elevated Bax/Bcl-2 ratio and enhanced the expression of caspase-3 (Pro and cleaved forms) protein. Pretreatment of cells with CA before TMT, significantly reduced ROS generation, diminished upregulation of proapoptotic Bax protein and attenuated caspase-3 protein expression. In conclusion, CA exhibited significant neuroprotective effects against neurotoxicity of TMT mainly throughout reduction of ROS production and regulation of proteins, which are involved in apoptosis pathway.

Protective effects of Vitis vinifera (grapes) and one of its biologically active constituents, resveratrol, against natural and chemical toxicities: A comprehensive review.

Vitis vinifera (grape) is one of the "most-produced fruit" in the world. Grape seeds are a valuable source of phenolic compounds including resveratrol (RSV). Grape and one of its biologically active constituents, RSV, exert their protective effects against different natural or chemical toxins which could alter physiological homeostasis through a variety of mechanisms. Some of these mechanisms of actions include increase in superoxide dismutase, hemeoxygenase-1, and glutathione peroxidase activities and reduced glutathione content and decrease in malondialdehyde (MDA) levels and activation of the nuclear erythroid2-related factor2/ARE pathway. There are also various reports of the potential use of such compounds in preventing different ailments including cardiovascular diseases, cancer, degenerative diseases, and inflammatory disorders. Therefore, in this review, we have investigated the possible protective effects of grape and one of its biologically active constituents, RSV, on different organs' toxicity induced by natural toxins (such as mycotoxins, lipopolysaccharide, and triptolide) and chemical toxins (such as antitumors, metals, and carbon tetrachloride). There are insufficient clinical trials on this subject, so our review only includes in vivo and in vitro studies. To establish the grape beneficial effects in human intoxication, more clinical trials need to be accomplished.

Design, synthesis and biological evaluation of 7-(aryl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline derivatives as potential Hsp90 inhibitors and anticancer agents.

A new series of quinoline analogues was designed and synthesized as Hsp90 inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines including MCF-7 (human breast cancer cells), DU145 (human prostate cancer cell lines), and A549 (adenocarcinomic human alveolar basal epithelial cells). Some of our compounds (13a-13f) showed significant cytotoxic activity on MCF-7 cells. The most potent anti-proliferative compounds were also tested against Her2, a client protein of Hsp90. Compound 13d that demonstrated the highest antiproliferative activity in the series, was found the most potent one for both Her2 protein degradation and Hsp70 protein induction as well. Molecular modeling studies displayed possible mode of interaction between this compound and N-terminal ATP-binding site of Hsp90.

The effects of polyethylenimine/DNA nanoparticle on transcript levels of apoptosis-related genes.

CONTEXT: Polyethylenimine (PEI) is a cationic polymer commonly used in gene transfer. Although numerous investigations have indicated that PEI can induce apoptosis/necrosis but the mechanism of its cytotoxicity is still poorly understood. OBJECTIVE: The purpose of this study was to investigate the effects of PEI/DNA complexes on the expression of apoptotic genes in human colon adenocarcinoma cells (HT29). METHODS: HT29 cells were exposed to PEI/DNA complex (C/P = 0.8) for 24 h. Then, qRT PCR was used to assess the expression of 26 apoptotic-related genes. RESULT: Analysis of the transcript level of genes revealed that while the expression of anti-apoptotic genes such as Bclx, Bcl2, NFkB, and AIF was not significantly reduced but the expression of pro-apoptotic genes such as Fasl, Bax, TNFR1, DR4, Casp8, and cytochrome C was considerably increased in transfected HT29 cell lines. CONCLUSIONS: Our results showed that PEI could increase the level of pro-apoptotic genes and decrease antiapoptotic genes as a possible mechanism involved in PEI cytotoxicity.

Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats.

Acrylamide (ACR) is a water-soluble monomer which has broad application in different industries and also can form in food during heating process. This monomer is a potent neurotoxic and damages the central and the peripheral nervous system in human and animals. Oxidative stress has been mentioned as an important pathway in ACR neurotoxicity, therefore the purpose of the current study was evaluation of possible effects of linalool which is a naturally enantiomer monoterpene compound. Linalool has shown antioxidant properties in several studies. Male Wistar rats were treated with ACR (50 mg/kg ip) alone or with linalool (12.5, 25, 50 and 100 mg/kg ip) for 11 days. In another 2 groups rats were treated with linalool (12.5 mg/kg ip) 3 days after and before ACR administration. Then behavior index (gait score) was examined for rats. After that, rats were sacrified and molondialdehyde (MDA) as a marker of lipid peroxidation and glutathione (GSH) content were determined in brain tissue. Exposure to ACR led to severe gait abnormalities and treatment with linalool significantly reduced abnormalities. ACR reduced GSH content and increased level of MDA in cerebral cortex. Linalool increased GSH content while decreased ACR-induced lipid peroxidation in rat brain tissue and the best protocols were initiation of supplementation before or simultaneous with ACR administration.