Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer's disease.

Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid plaques, and gradual cognitive decline. Regardless of the advances in understanding AD's pathogenesis and progression, its causes are still contested, and there are currently no efficient therapies for the illness. The post-mortem analyses revealed widespread neuronal loss in multiple brain regions in AD, evidenced by a decrease in neuronal density and correlated with the disease's progression and cognitive deterioration. AD's neurodegeneration is complicated, and different types of neuronal cell death, alone or in combination, play crucial roles in this process. Recently, the involvement of non-apoptotic programmed cell death in the neurodegenerative mechanisms of AD has received a lot of attention. Aberrant activation of necroptosis and ferroptosis, two newly discovered forms of regulated non-apoptotic cell death, is thought to contribute to neuronal cell death in AD. In this review, we first address the main features of necroptosis and ferroptosis, cellular signaling cascades, and the mechanisms involved in AD pathology. Then, we discuss the latest therapies targeting necroptosis and ferroptosis in AD animal/cell models and human research to provide vital information for AD treatment.

Alpha-Pinene Alleviates Motor Activity in Animal Model of Huntington's Disease via Enhancing Antioxidant Capacity.

Huntington's disease (HD) is a progressive, neurodegenerative, and inherited disease. Antioxidants have been shown to be effective in slowing disease progression in animal models of HD and are under investigation in human clinical trials. α-pinene, a member of the monoterpene class, has been shown to exert antioxidant activity. Therefore, this study aimed to investigate the impact of α-pinene on animal model of HD. Thirty-two male Wistar rats received 3-Nitropropionic acid (3-NP) for induction of the disease model or treated with α-pinene + 3-NP in different groups. Motor skill, and biochemical evaluations to detect oxidant/antioxidant markers in rat cortex and striatum were performed in all groups. We found that α-pinene significantly improved 3-NP-induced changes in the body weight, rotarod activity, time taken to cross the narrow beam, and locomotor activity. Biochemical analysis revealed that α-pinene significantly decreased the 3NP-induced elevation in oxidant markers, nitrite, and malondialdehyde in both cortex and striatum. In addition, α-pinene counteracted the 3-NP-induced fall in antioxidant enzymes, including superoxide dismutase, catalase, and glutathione in the cortex and striatum. In conclusion, we found that α-pinene prevented the motor dysfunction induced by 3-NP in the animal model of Huntington's disease. Oxidants-antioxidant balance might be involved in the protective effect of α-pinene.

Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic.

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown. Therefore, this study aims to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated. First, rotenone induced cell toxicity and α-Syn aggregation, with a significant reduction of SUMOylation and autophagy. Boosting SUMOylation prevented α-Syn aggregation, phosphorylation and recovery of autophagy. Moreover, α-Syn 140 and α-Syn 126 were SUMOylated while the other two isoforms, α-Syn 112 and 98 were not and their overexpression showed that were more toxic and induced more α-Syn aggregation. Rotenone increased their toxicity that was not affected by boosting SUMOylation. These results may indicate a role of SUMOylation in modulating α-Syn aggregation, inducing to understanding more about the behavior of α-Syn isoforms.

Syntaxin-1a and SNAP-25 expression level is increased in the blood samples of ischemic stroke patients.

The interest for the discovery of blood biomarkers for several neurological disorders, including Ischemic Stroke (IS), is growing and their identification in blood samples would be revolutionary allowing a fast and better pathology prediction or outcome and to collect information on patient recovery. The increased permeability of the blood-brain barrier, following a brain infarct, allows the detection of brain proteins in the blood flow. In this work, we analyzed the expression levels of two synaptic proteins Syntaxin (STX)-1a and Synaptosomal Associated Protein, 25 kDa (SNAP-25), in Peripheral Blood Mononuclear Cell (PBMC), serum and in Neuronal Derived Extracellular vesicles (NDEs) of IS patients, age and sex matched healthy control (HC) and younger HC (Y-HC). Interestingly, we identified STX-1a protein in the cytoplasm of PBMC and both STX-1a and SNAP-25 expression levels were significantly augmented in all IS patient's blood fractions compared to control subjects. In addition, STX-1a blood levels correlated with the IS clinical scales National Institutes of Health Stroke Scale (NIH-SS) and the modified Barthel Index (BI). These results prompted us to speculate that STX-1a and SNAP-25 hematic fluctuations depict the brain damage after an ischemic attack and that their hematic detection could represent a novel and accessible IS biomarkers.

Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.

Retinal degeneration is the major and principal cause behind many incurable blindness diseases. Several studies indicated the neuroprotective effect of Curcuma longa in eye pathologies, specifically retinopathy. However, the molecular mechanism behind its effect has not been completely elucidated. Using an ex vivo model of retinal degeneration obtained from an ex vivo optic nerve cut (ONC), we demonstrated that Curcuma extract (Cur) exerted a neuroprotective effect. Importantly, Cur was able to modulate apoptosis and MAPK signaling pathway activation and prevent retinal ganglion cell (RGC) loss. Other well-known neuroprotective pharmacological tools, including memantine (Mem), citicoline (Cit), and ginkgolic acid (GA), were used to compare the potential mechanisms of Cur. The antioxidant activity of retinas treated with Cur following optic nerve cut was significantly higher than control, but Cur failed to change the retina glutamate content. Considering the antioxidant effect of Cur and taking advantage of our recent findings on the crosstalk between oxidative stress and post-translational protein modifiers, in particular, small ubiquitin-related modifier (SUMO), we were interested in exploring the effect of Cur on SUMOylation. We found that Cur significantly prevented the increase of protein SUMOylation, confirming our previous in vitro data indicating the cytoprotective effect of curcumin through modulating the oxidative stress and SUMO-JNK axis. Altogether, these results suggest that Curcuma protects the retina from degeneration via antioxidant activity and targets SUMOylation. Therefore, it might be considered for the combination therapy with other neuroprotective agents with different mechanisms in preclinical studies on retinal degeneration.

Topical phenytoin administration accelerates the healing of acetic acid-induced colitis in rats: evaluation of transforming growth factor-beta, platelet-derived growth factor, and vascular endothelial growth factor.

Ulcerative colitis (UC), limited to the colon's innermost lining, has become a global health problem. Immunomodulatory and monoclonal antibodies are used to treat UC despite their side effects and limitations. Phenytoin is used to heal wounds owing to its effects on growth factors, collagen, and extracellular matrix synthesis. This study aimed to evaluate the effect of topical phenytoin administration in UC. Phenytoin was administered in two doses during the treatment. Eighty male Wistar rats (230-280 g) were divided randomly into ten groups of sham, control, hydrocortisone, phenytoin 1%, and 3% groups in 6- or 12-day treatment protocols. The UC model was induced by the administration of acetic acid 4% into the colon. Animals were killed on the 7th and 13th postoperative days. The main outcome measures included body weight loss, microscopic score, and ulcer index measured using specific criteria. Growth factors were measured by western blotting. Results illustrated that body weight loss was reversed in the treatment groups. Ulcer index had decreased on 6- and 12-day treatment protocols. Microscopic scores in 6-day enema treatment significantly decreased compared to the control groups. Transforming growth factor-beta (TGFß) significantly increased in a time-dependent manner and platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) significantly increased in a time- and dose-dependent manner in phenytoin 1% and 3% in the 6- and 12-day protocols. Phenytoin dose- and time-dependently reversed weight loss. In addition, histopathological parameters included microscopic scores, and the ulcer index was decreased through the induction of growth factors TGFß, PDGF, and VEGF and consequently accelerated ulcer healing.

An overview of the therapeutic effects of curcumin in reproductive disorders with a focus on the antiinflammatory and immunomodulatory activities.

Curcumin, the polyphenolic compound obtained from turmeric, has several pharmacological properties. These properties include antioxidant, antimicrobial, anti-angiogenic, anticarcinogenic, antiinflammatory, and immunomodulatory activities. Therefore, the clinical efficacy of this substance has been largely investigated for curing numerous disorders. Based on a growing body of literature, this review aimed to investigate curcumin's molecular and clinical effects on reproduction and related disorders. Curcumin in the female reproductive system attenuates folliculogenesis, promotes apoptosis of oocytes and blastocyst, and decreases embryo implantation and survival. Curcumin at <100 mg concentration shows protective effects against testicular injury. The concentration of >250 mg of curcumin exhibits immobilizing action on sperms, and at 500 mg concentration completely blocks pregnancy. Curcumin inhibits vaginal infections, attenuates the severity of the premenstrual syndrome, ameliorates inflammatory conditions in polycystic ovary syndrome, improves preeclampsia, and prevents ectopic endometrial lesions. Taken together, curcumin, because of the numerous biological activities, low level of toxicity, and lower adverse effects compared to the synthetic drugs, could be considered as a protective agent for preserving the semen quality parameters, a contraceptive, and chemotherapeutic or chemopreventive agent, as well as an appropriate agent for the treatment of female reproductive disorders.

Association between trace elements in cancerous and non-cancerous tissues with the risk of breast cancers in western Iran.

This study aimed to assess the tissue content of essential and toxic metals including lead (Pb), cadmium (Cd), arsenic (As), silver (Ag), aluminum (Al), chromium (Cr), copper (Cu), iron (Fe), selenium (Se), and zinc (Zn) in the breast cancerous tissues compared to the non-cancerous tissue. The biopsy specimens of 63 breast cancers along with 63 adjacent healthy tissues in Kurdistan Province, Iran, were collected from 2019 to 2020 and assayed using ICP-MS (Agilent 7900). The results of the Mann-Whitney test illustrated that the concentration of Pb, Cd, As, Cr, Cu, and Se were significantly elevated in cancerous tissue (p < 0.05), while Zn was the only trace element with higher levels in healthy subjects (p < 0.05). Moreover, weak to moderate correlations between elements were observed in the cancerous group including Al-Cr (r=0.60), As-Cu (r=0.52), and Cu-Se (r=0.56). In contrast, no correlation over 0.50 was found between trace elements in the non-cancerous group. Raw risk differences (RDs) accounted for a significant effect for Pb, Cd, As, Ag, Cr, Se, and Zn on the development of breast cancer. In conclusion, elevated levels of As, Cd, Cu, Pb, and Se may contribute to enhancing the risk of breast cancer.

Oral Administration of Probiotic Enterococcus durans to Ameliorate Experimental Autoimmune Encephalomyelitis in Mice.

Introduction: Probiotics, including lactobacilli, have immunomodulatory activities with promising effects on inflammatory diseases. In this study, we evaluate the effect of Enterococcus durans (Edu) and three various strains of lactobacilli (Lacto-mix), including L. rhamnosus, L. casei, and L. plantarum, to prevent Experimental Autoimmune Encephalomyelitis (EAE) features. Methods: C57BL/6 female mice were inoculated with Myelin Oigodendrocyte Glycoprotein (MOG35-55) in CFA (complete Freund's adjuvant) to induce EAE. Five groups (n=6 in each group) of animals received saline or probiotics by oral gavage with 200 µL of lactobacilli (1.5×108 CFU/mL) for 2 weeks before the immunization and during the test for one month. Results: Histopathological studies showed an increase in infiltration of inflammatory cells and destruction of the myelin membrane in the EAE group but a decrease in inflammatory cells in the probiotic-treated animals. Pro-inflammatory cytokines (Interleukin [IL]-17 and Interferon [IFN]-γ) concentration in the supernatant of the brain and spinal cord tissues showed a significant increase in the EAE compared with the normal saline group (P<0.01). While in the spinal cord tissue, there was a decrease in IL-17 in those animals treated with the Lactomix and Edu + Lacto-mix (P<0.01) and a significant decrease in IFN-γ in those animals that received Edu (P<0.05). Western blot analysis of matrix metalloproteinase-9 and myelin basic protein showed a decrease and increase in treatment and EAE groups, respectively, compared to the normal control group. Conclusion: Our data suggest that probiotic Enterococcus durans and Lacto-mix prevents EAE, but further studies are needed to clarify the exact mechanisms and their application in preclinical and clinical trials. Highlights: Dysfunction of the blood-brain barrier, migration of inflammatory cells into the Central Nervous System (CNS), and an increase in the pro-inflammatory factors, are the hallmarks in the pathogenesis of Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE).The optimal effects of probiotic strains may involve the simultaneous use of more than one strain.Probiotic Enterococcus durans and Lacto-mix have a preventive effect against EAE. Plain Language Summary: Multiple Sclerosis (MS) is a myelin-degenerating autoimmune disease in the central nervous system. Experimental Autoimmune Encephalomyelitis (EAE), due to its similar clinical and pathologic features to MS, is widely used in many model studies of this disease. The microbiome refers to a genomic set of germs (bacteria, arches, fungi, and viruses), a commensal flora that lives in the intestine and niche of humans and other mammals. The microbiome affects the host's physiological system, especially the balance between health and disease. Additionally, the importance of the microbiome is evident in regulating the intestine-brain axis, or the coordination of the digestive and the central nervous system. In this regard, probiotics, including lactobacilli, have antioxidant and anti-inflammatory properties in vitro and in vivo. Probiotic strains have a wide range of health-improvement effects, and a combination of strains with specific properties provides a broader range of antimicrobial spectrum and stronger anti-inflammatory effects. Considering the critical role of probiotics in the immune system, this study aimed to investigate the possible role of Enterococcus durans alone or in combination with Lactobacillus mixture (L. rhamnosus, L. casei, and L. plantarum) on the EAE animal model of MS.

Retinal ganglion cell loss in an ex vivo mouse model of optic nerve cut is prevented by curcumin treatment.

Retinal ganglion cell (RGC) loss is a pathologic feature common to several retinopathies associated to optic nerve damage, leading to visual loss and blindness. Although several scientific efforts have been spent to understand the molecular and cellular changes occurring in retinal degeneration, an effective therapy to counteract the retinal damage is still not available. Here we show that eyeballs, enucleated with the concomitant optic nerve cut (ONC), when kept in PBS for 24 h showed retinal and optic nerve degeneration. Examining retinas and optic nerves at different time points in a temporal window of 24 h, we found a thinning of some retinal layers especially RGC's layer, observing a powerful RGC loss after 24 h correlated with an apoptotic, MAPKs and degradative pathways dysfunctions. Specifically, we detected a time-dependent increase of Caspase-3, -9 and pro-apoptotic marker levels, associated with a strong reduction of BRN3A and NeuN levels. Importantly, a powerful activation of JNK, c-Jun, and ERK signaling (MAPKs) were observed, correlated with a significant augmented SUMO-1 and UBC9 protein levels. The degradation signaling pathways was also altered, causing a significant decrease of ubiquitination level and an increased LC3B activation. Notably, it was also detected an augmented Tau protein level. Curcumin, a powerful antioxidant natural compound, prevented the alterations of apoptotic cascade, MAPKs, and SUMO-1 pathways and the degradation system, preserving the RGC survival and the retinal layer thickness. This ex vivo retinal degeneration model could be a useful method to study, in a short time window, the effect of neuroprotective tools like curcumin that could represent a potential treatment to contrast retinal cell death.

From the environment to the cells: An overview on pivotal factors which affect spreading and infection in COVID-19 pandemic.

Several factors ranging from environmental risks to the genetics of the virus and that of the hosts, affect the spread of COVID-19. The impact of physicochemical variables on virus vitality and spread should be taken into account in experimental and clinical studies. Another avenue to explore is the effect of diet and its interaction with the immune system on SARS-CoV-2 infection and mortality rate. Past year have witnessed extensive studies on virus and pathophysiology of the COVID-19 disease and the cellular mechanisms of virus spreading. However, our knowledge has not reached a level where we plan an efficient therapeutic approach to prevent the virus entry to the cells or decreasing the spreading and morbidity in severe cases of disease. The risk of infection directly correlates with the control of virus spreading via droplets and aerosol transmission, as well as patient immune system response. A key goal in virus restriction and transmission rate is to understand the physicochemical structure of aerosol and droplet formation, and the parameters that affect the droplet-borne and airborne in different environmental conditions. The lifetime of droplets on different surfaces is described based on the contact angle. Hereby, we recommend regular use of high-quality face masks in high temperature and low humidity conditions. However, in humid and cold weather conditions, wearing gloves and frequently hand washing, gain a higher priority. Additionally, social distancing rules should be respected in all aforementioned conditions. We will also discuss different routes of SARS-CoV-2 entry into the cells and how multiple genetic factors play a role in the spread of the virus. Given the role of environmental and nutritional factors, we discuss and recommend some strategies to prevent the disease and protect the population against COVID-19. Since an effective vaccine can prevent the transmission of communicable diseases and abolish pandemics, we added a brief review of candidate SARS-CoV-2 vaccines.

Effect of lobeglitazone on motor function in rat model of Parkinson's disease with diabetes co-morbidity.

Parkinson's disease (PD) and diabetes mellitus share similar pathophysiological characteristics, genetic and environmental factors. It has been reported that people with diabetes mellitus appear to have a remarkable higher incidence of PD than age matched non diabetic individuals. Evidences suggest that use of antidiabetic glitazone is associated with a diminished risk of PD incidence in patients with diabetes. This study examined the effect of lobeglitazone, a member of thiazolidinedione class, in rat model of Parkinson's disease with diabetes co-morbidity. Rats received either rotenone and/or a combination of streptozocin and a high calorie diet for disease induction and they were treated with different doses of lobeglitazone or its vehicle. Behavioral tests comprising rotarod, bar test and rearing test were conducted to evaluate the motor function. Changes in the level tyrosine hydroxylase, TNF-α and NF-κB were analyzed using ELISA. In the same brain regions the possible changes in PPAR-γ receptor level were evaluated. Findings showed that although lobeglitazone tends to reverse the effect of rotenone in animals with diabetes, it was just able to prevent partly the motor defect in rearing test. Furthermore, lobeglitazone (1 mg/kg) reversed, in substantia nigra and striatum, the changes in tyrosine hydroxylase, TNF-α, NF-κB and PPAR-γ receptor content induced by rotenone in rats with diabetic condition. Although other preclinical studies are needed, these findings suggest that lobeglitazone is a promising neuroprotective candidate for clinical trials for PD patients with diabetes co-morbidity.

Cinnamomum zeylanicum extract has antidepressant-like effects by increasing brain-derived neurotrophic factor (BDNF) and its receptor in prefrontal cortex of rats.

OBJECTIVE: Depression is one of the most common mood disorders. Considering the evidence on the effect of Cinnamomum on mood disorders, this study investigatedthe effect of hydroalcoholic extract of Cinnamomum (HEC) in an animal model of depression. MATERIALS AND METHODS: Thirty-two male rats were selected and divided into four groups (n=8) including: control, depressed, and depressed treated with200 and 400 mg/kg HEC. Depression induction protocol was conducted in all groups except for the control group. Sucrose preference test (SPT) and forced swimming test (FST) were done to analyze the depression score. After four weeks, the animals brain cortex was removed and BDNF protein and tyrosine receptor kinase B (TrkB) gene expression levels were determined by ELISA and Real Time PCR, respectively. RESULTS: The results of this study showed that 400 mg/kg of HEC increased the tendency to drink the sucrose solution. Furthermore, immobility time significantly increased in the depressed group compared to the control group while it was attenuated by administration of 400 mg/kg extract on the 28th day versus the depressed group. Also the extract at both doses increased swimming time compared to the depressed group. In addition, an increase in the BDNF protein and TrkB gene expression levels was observed in the prefrontal cortex of the treatment groups. CONCLUSION: We found that HEC ameliorated depression symptoms in rats and these effects were probably due to an increase in BDNF proteins and its receptor, TrkB, gene expressions in the prefrontal cortex.

A Novel Pharmacological Protective Role for Safranal in an Animal Model of Huntington's Disease.

Huntington's disease (HD) is a progressive, neurodegenerative and inherited disease and recent years have witnessed the understanding of the cellular and molecular mechanisms related to HD. Safranal, an organic compound isolated from saffron, has been reported to have anti-apoptotic, anti-inflammatory and antioxidant activity and has studied in chronic and neurodegenerative disease. Therefore, this study was aimed to investigate the effect of safranal on 3-NP induced locomotor activity and biochemical alterations in rats. To this aim, 40 male Wistar rats weighting 250-300 g were divided into 5 groups (n = 8) including sham, 3-NP group (10 mg/kg) as control and treatment groups (3-NP + safranal 0.75, 1.5 and 3 mg/kg) in two weeks duration of treatment. Behavioral/movement assessments in addition to oxidant/antioxidant markers in rat cortex and striatum were evaluated in control and treatment groups. Here, we found that safranal significantly alleviated 3-NP-induced changes of body weight, rotarod activity, number of vacuous chewing movements (VCMs), and locomotor activity. In addition, brain tissue assessments in cortex and striatum revealed that safranal could prevent the elevation of nitrite and malondialdehyde (MDA) levels as well as decrease of superoxide dismutase (SOD), catalase activity and glutathione (GSH) induced by 3-NP. In conclusion our results showed that safranal prevented the motor dysfunction induced by 3-NP in animal model of Huntington's disease. This effect might be due to its modulating effect on oxidants-antioxidant balance.

Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells.

Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.

Hepatoprotective effect of the hydroalcoholic extract of Cichorium intybus in a rat model of obstructive cholestasis.

BACKGROUND AND STUDY AIMS: Obstructive cholestasis increases the levels of oxidants and inflammatory mediators, leading to liver damage. Previous studies have found that Cichorium intybus possesses anti-inflammatory effects. In the present study, the effects of the hydroalcoholic extract of C. intybus leaves were assessed in a rat model of obstructive cholestasis. MATERIAL AND METHODS: Male Wistar rats were randomly divided into five groups (n = 6 rats per group): sham-operated, control [bile duct ligation (BDL) + vehicle)] and BDL + extract treatment (100, 200 and 400 mg/kg/day, i.p.) groups. Rats received treatments for 7 consecutive days. On the eighth day, prothrombin time (PT); serum albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and total and direct bilirubin levels and total antioxidant and paraoxonase activities were measured using colorimetric methods. In addition, tumour necrosis factor-α and nitric oxide (NO) levels were measured using enzyme-linked immunosorbent assay. RESULTS: The hydroalcoholic extract of C. intybus significantly decreased PT and the serum levels of AST, ALT, TNF-α and NO compared with the control group (p < 0.05). On the other hand, the serum albumin levels were increased in the extract-treated groups compared with the control group (p < 0.05). CONCLUSION: The hydroalcoholic extract of C. intybus protects the liver against injury induced by obstructive cholestasis.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Obstacles against the Marketing of Curcumin as a Drug.

Among the extensive public and scientific interest in the use of phytochemicals to prevent or treat human diseases in recent years, natural compounds have been highly investigated to elucidate their therapeutic effect on chronic human diseases including cancer, cardiovascular disease, and neurodegenerative disease. Curcumin, an active principle of the perennial herb Curcuma longa, has attracted an increasing research interest over the last half-century due to its diversity of molecular targets, including transcription factors, enzymes, protein kinases, growth factors, inflammatory cytokines, receptors, and it's interesting pharmacological activities. Despite that, the clinical effectiveness of the native curcumin is weak, owing to its low bioavailability and rapid metabolism. Preclinical data obtained from animal models and phase I clinical studies done in human volunteers confirmed a small amount of intestinal absorption, hepatic first pass effect, and some degree of intestinal metabolism, might explain its poor systemic availability when it is given via the oral route. During the last decade, researchers have attempted with new pharmaceutical methods such as nanoparticles, liposomes, micelles, solid dispersions, emulsions, and microspheres to improve the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with a varying range of enhanced bioavailability. This manuscript critically reviews the available scientific evidence on the basic and clinical effects and molecular targets of curcumin. We also discuss its pharmacokinetic and problems for marketing curcumin as a drug.

Discovering the signature of a lupus-related microRNA profile in the Gene Expression Omnibus repository.

Lupus is one of the most prevalent systemic autoimmune diseases. It is a multifactorial disease in which genetic, epigenetic and environmental factors play significant roles. The pathogenesis of lupus is not yet well understood. However, deregulation of microRNAs (miRNAs) - one of the post-transcriptional regulators of genes - can contribute to the development of autoimmune diseases. Over the last two decades, advances in the profiling of miRNA using microarray have received much attention, and it has been demonstrated that miRNAs play a regulatory role in the pathogenesis of lupus. Therefore, dysregulated miRNAs can be considered as promising diagnostic biomarkers for lupus. This article is an overview of lupus-related miRNA profiling studies and arrays in the Gene Expression Omnibus (GEO) database. The aims of our study were to widen current knowledge of known dysregulated miRNAs as potential biomarkers of SLE and to introduce a bioinformatics approach to using microarray data and finding novel miRNA and gene candidates for further study. We identified hsa-miR-4709-5p, hsa-miR-140, hsa-miR-145, hsa-miR-659, hsa-miR-134, hsa-miR-150, hsa-miR-584, hsa-miR-409 and hsa-miR-152 as potential biomarkers by integrated bioinformatics analysis.

Considerations around the SARS-CoV-2 Spike Protein with Particular Attention to COVID-19 Brain Infection and Neurological Symptoms.

Spike protein (S protein) is the virus "key" to infect cells and is able to strongly bind to the human angiotensin-converting enzyme2 (ACE2), as has been reported. In fact, Spike structure and function is known to be highly important for cell infection as well as for entering the brain. Growing evidence indicates that different types of coronaviruses not only affect the respiratory system, but they might also invade the central nervous system (CNS). However, very little evidence has been so far reported on the presence of COVID-19 in the brain, and the potential exploitation, by this virus, of the lung to brain axis to reach neurons has not been completely understood. In this Article, we assessed the SARS-CoV and SARS-CoV-2 Spike protein sequence, structure, and electrostatic potential using computational approaches. Our results showed that the S proteins of SARS-CoV-2 and SARS-CoV are highly similar, sharing a sequence identity of 77%. In addition, we found that the SARS-CoV-2 S protein is slightly more positively charged than that of SARS-CoV since it contains four more positively charged residues and five less negatively charged residues which may lead to an increased affinity to bind to negatively charged regions of other molecules through nonspecific and specific interactions. Analysis the S protein binding to the host ACE2 receptor showed a 30% higher binding energy for SARS-CoV-2 than for the SARS-CoV S protein. These results might be useful for understanding the mechanism of cell entry, blood-brain barrier crossing, and clinical features related to the CNS infection by SARS-CoV-2.