Gut microbiota in neurological diseases: Melatonin plays an important regulatory role.

Melatonin is a highly conserved molecule produced in the human pineal gland as a hormone. It is known for its essential biological effects, such as antioxidant activity, circadian rhythm regulator, and immunomodulatory effects. The gut is one of the primary known sources of melatonin. The gut microbiota helps produce melatonin from tryptophan, and melatonin has been shown to have a beneficial effect on gut barrier function and microbial population. Dysbiosis of the intestinal microbiota is associated with bacterial imbalance and decreased beneficial microbial metabolites, including melatonin. In this way, low melatonin levels may be related to several human diseases. Melatonin has shown both preventive and therapeutic effects against various conditions, including neurological diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review was aimed to discuss the role of melatonin in the body, and to describe the possible relationship between gut microbiota and melatonin production, as well as the potential therapeutic effects of melatonin on neurological diseases.

The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions.

The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.

Safety assessment of the Quercus brantii gall hydroalcoholic extract: Single and repeated oral dose toxicity studies.

Objectives: Quercus brantii galls (QBGs) are well-known in Iranian traditional medicine for treating various diseases. The aim of study was to assess the acute and repeated oral toxicity of the hydroalcoholic extract of QBG in female rats. Materials and Methods: The ethanolic extract of QBG was administered in rats by gavage in both acute and repeated dose models. In the acute section of the study, a single oral dose of 2000 mg/kg was administered to female rat which were observed for physical symptoms and behavioral changes for 14 days. In the repeated dose toxicity study, the QBG extract (50, 500, and 1000 mg/kg/day) was administered for a period of 28 days to rats. On 28th day of experiment, blood sampling of animals was done for hematological and biochemical analysis and then sacrificed for histopathological examination of the harvested tissues (liver, heart, kidney, lung, spleen, stomach, ovary and uterus). Results: A single oral administration of the QBG extract (2000 mg/kg) did not produce mortality or significant behavioral changes during 14 days of observation. In repeated oral toxicity models, the extract significantly increased (P<0.05) the levels of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thyroid-stimulating hormone (TSH) and significantly decreased the levels of triiodothyronine (T3) and thyroxin (T4) in 500 and 1000 mg/kg dosage. The histopathological studies showed the absence of toxic effects of QBG (50 mg/kg dosage) and revealed evidence of microscopic lesions in the liver, kidney, stomach, heart, spleen, lung, uterus, and ovary in the 500- and 1000-mg/kg groups. Conclusion: The results indicate that the oral acute toxicity of QBG extract was of a low order with LD50 being more than 2000 mg/kg in rats. In addition, slight tissue damage was observed in some tissues in the 500 and 1000 mg/kg groups. It was found that prolonged use at higher doses i.e. 500 mg/kg/day of QBG extract should be avoided.

Inhibition of GSK_3ß by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer's Disease Using Computational Drug Design Methods.

The inhibition of glycogen synthase kinase-3ß (GSK-3ß) activity prevents tau hyperphosphorylation and binds it to the microtubule network. Therefore, a GSK-3ß inhibitor may be a recommended drug for Alzheimer's treatment. In silico methods are currently considered as one of the fastest and most cost-effective available alternatives for drug/design discovery in the field of treatment. In this study, computational drug design was conducted to introduce compounds that play an effective role in inhibiting the GSK-3ß enzyme by molecular docking and molecular dynamics simulation. The iridoid glycosides of the common snowberry (Symphoricarpos albus), including loganin, secologanin, and loganetin, are compounds that have an effect on improving memory and cognitive impairment and the results of which on Alzheimer's have been studied as well. In this study, in the molecular docking phase, loganin was considered a more potent inhibitor of this protein by establishing a hydrogen bond with the ATP-binding site of GSK-3ß protein and the most negative binding energy to secologanin and loganetin. Moreover, by molecular dynamics simulation of these ligands and GSK-3ß protein, all structures were found to be stable during the simulation. In addition, the protein structure represented no change and remained stable by binding ligands to GSK-3ß protein. Furthermore, loganin and loganetin have higher binding free energy than secologanin; thus, these compounds could effectively bind to the active site of GSK-3ß protein. Hence, loganin and loganetin as iridoid glycosides can be effective in Alzheimer's prevention and treatment, and thus, further in vitro and in vivo studies can focus on these iridoid glycosides as an alternative treatment.

Identification of common key regulators in rat hepatocyte cell lines under exposure of different pesticides.

Pesticides exposure can have harmful effects on human health. The liver is the most common organ of pesticides toxicity due to its major metabolic activity. The molecular mechanism of pesticides effect is complex and is controlled by gene regulatory networks. All components of regulatory networks are controlled by transcription factors and other regulatory elements. Therefore, identification of key regulators through system biology approaches and high-throughput techniques can help to provide comprehensive insights into molecular mechanisms of the pesticide effect. In the current study, a microarray data-set was used to potentially identify molecular mechanisms that regulate gene expression profile of rat hepatocyte cell lines in response to pesticides exposure. Results showed that the number of differentially expressed genes (DEGs) and differentially expressed transcription factors (DE-TFs) were dramatically different among pesticides tested. Results also revealed 205 common DEGs and 11 DE-TFs among pesticides tested. Additionally, we found that six DE-TFs (CREB1, CTNNB1, PPARG, SP1, SRF and STAT3) had the highest number of interactions with other DEGs and acted as the key regulatory genes. The results of this study revealed regulator genes that have the key functions in response to pesticides toxicity in rat liver, which can provide the basis for future studies. Furthermore, these regulatory genes can be used as toxicity biomarkers to improve diagnosis and prognosis.

Mechanistic Approach for Thioridazine-Induced Hepatotoxicity and Potential Benefits of Melatonin and/or Coenzyme Q10 on Freshly Isolated Rat Hepatocytes.

Thioridazine (TZ) is used mainly in the treatment of schizophrenia. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. In this context, we examined the cytotoxic mechanisms of TZ on freshly isolated rat hepatocytes to better understanding of the pathogenesis of TZ-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. The level of parameters such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosomal membrane integrity and cellular glutathione (GSH) content in TZ-treated and non-treated hepatocytes were determined and the mentioned markers were assessed in the presence of Coenzyme Q10 and/or melatonin. Results showed that TZ caused an increase in ROS formation as well as induction of LPO and GSH depletion. Moreover, mitochondria and lysosomes seem to be targets of TZ-induced toxicity. The administration of Coenzyme Q10 and/or melatonin efficiently decreased the rate of ROS formation, LPO and improved cell viability, MMP, GSH level and lysosome membrane integrity. This study proposes the possible protective role of Coenzyme Q10 and/or melatonin against TZ-induced cellular injury probably through their radical scavenging properties and their effects on mitochondria and lysosomes.

Protective Roles of N-acetyl Cysteine and/or Taurine against Sumatriptan-Induced Hepatotoxicity.

Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening. Results: It was revealed that liver toxicity induced by sumatriptan in in freshly isolated parenchymal hepatocytes is dose-dependent. Sumatriptan caused significant free radical generation followed by lipid peroxide formation, mitochondrial injury as well as lysosomal damage. Moreover, sumatriptan reduced cellular glutathione content. Taurine and N-acetyl cysteine were able to protect hepatocytes against sumatriptan-induced harmful effects. Conclusion: It is concluded that sumatriptan causes oxidative stress in hepatocytes and the decreased hepatocytes glutathione has a key role in the sumatriptan-induced harmful effects. Also, N-acetyl cysteine and/or taurine could be used as treatments in sumatriptan-induced side effects.

A Review of Molecular Mechanisms Involved in Toxicity of Nanoparticles.

In recent decades, the use of nanomaterials has received much attention in industrial and medical fields. However, some reports have mentioned adverse effects of these materials on the biological systems and cellular components. There are several major mechanisms for cytotoxicity of nanoparticles (NPs) such as physicochemical properties, contamination with toxic element, fibrous structure, high surface charge and radical species generation. In this review, a brief key mechanisms involved in toxic effect of NPs are given, followed by the in vitro toxicity assays of NPs and prooxidant effects of several NPs such as carbon nanotubes, titanium dioxide NPs, quantum dots, gold NPs and silver NPs.