Effects of ß-sitosterol on anxiety in migraine-induced rats: The role of oxidative/nitrosative stress and mitochondrial function.

AIMS: Anxiety often coexists with migraine, and both conditions share a commonality in oxidative/nitrosative stress and mitochondrial dysfunction contributing to their pathogenesis. ß-Sitosterol, a plant sterol, has shown promise in mitigating oxidative/nitrosative stress, enhancing mitochondrial function, and exerting neuroprotective effects. In this study, we investigated the impact of ß-sitosterol on migraine-associated anxiety and whether this effect was associated with alleviation of oxidative/nitrosative stress and improvement in mitochondrial function. METHODS: Nitroglycerin was used to induce migraine in adult male Wistar rats. ß-Sitosterol treatment consisted of daily intraperitoneal injections (10 mg/kg) for 10 days following migraine induction. Anxiety levels were evaluated using open-field test (OFT) and hole-board test (HBT). Frontal cortex samples were analyzed for malondialdehyde (MDA), glutathione (GSH), reactive oxygen/nitrogen species, nitric oxide (NO) (markers of oxidative/nitrosative stress), and ATP (indicator of mitochondrial function). RESULTS: Migraine induction led to impaired performance in both the OFT and the HBT. Concurrently, it elevated MDA, reactive oxygen/nitrogen species, and NO levels while diminishing GSH levels in the frontal cortex, signifying heightened oxidative/nitrosative stress. Moreover, ATP levels decreased, indicating mitochondrial dysfunction. Treatment with ß-sitosterol significantly restored performance in both behavioral assays and normalized the levels of MDA, GSH, reactive oxygen/nitrogen species, NO, and ATP. CONCLUSION: ß-Sitosterol exerted anxiolytic effects in migraine, which can be attributed to its ability to ameliorate oxidative/nitrosative stress and enhance mitochondrial function.

The Investigation of Quercus Infectoria Gall Aqueous Extract Effect on the Cell Proliferation, Apoptosis and Expression of CCND1, TP53, BCL2 and BAX Genes in Cell Line of Lung, Gastric and Esophageal Cancers.

Background: The therapeutic potential of Quercus infectoria (QI) gall, including its anti-inflammatory, antioxidant, and anticancer properties, is well-known. However, its impact on lung, gastric, and esophageal cancer cells remain unclear. This study aims to explore the effects of QI gall aqueous extract on cell viability, apoptosis, and gene expression in A549, BGC823, and KYSE-30 cell lines. Methods: A549, BGC823, and KYSE-30 cells were seeded in complete medium and incubated with different concentrations of QI gall extract for 24 hours. Cell viability was measured by an MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. The induction of apoptosis was assessed through flow cytometric analysis after the adding FITC-conjugated Annexin V (Annexin V-FITC) and propidium iodide (PI). The mRNA expression levels of CCND1, TP53, BCL2 and BAX genes were determined using Real-time Quantitative Polymerase Chain Reaction analysis. Results: The MTT assay demonstrated that treatment with QI gall extract significantly reduced the number of viable cells in the A549, BGC823, and KYSE-30 cell lines at IC50 concentrations of 440.1, 437.1, and 465.2 mg/ml, respectively. Additionally, compared to untreated cell population, the percentages of early apoptosis, late apoptosis, and necrosis in the A549, BGC823, and KYSE-30 cells significantly increased following treatment with QI gall extract (P< 0.05). Also, the treatment with QI gall extract influenced the expression of CCND1, TP53, BCL2 and BAX genes. Conclusions: The present findings indicated that the gall extract of QI can inhibit the growth of A549, BGC823, and KYSE-30 cells by inducing apoptosis, which may be mediated via mitochondria-dependent pathway.

Evaluation of the protective effect of coenzyme Q10 on hepatotoxicity caused by acute phosphine poisoning.

Background: Aluminum phosphide (AlP) poisoning is prevalent in numerous countries, resulting in high mortality rates. Phosphine gas, the primary agent responsible for AlP poisoning, exerts detrimental effects on various organs, notably the heart, liver and kidneys. Numerous studies have documented the advantageous impact of Coenzyme Q10 (CoQ10) in mitigating hepatic injuries. The objective of this investigation is to explore the potential protective efficacy of CoQ10 against hepatic toxicity arising from AlP poisoning. Method: The study encompassed distinct groups receiving almond oil, normal saline, exclusive CoQ10 (at a dosage of 100 mg/kg), AlP at 12 mg/kg; LD50 (lethal dose for 50%), and four groups subjected to AlP along with CoQ10 administration (post-AlP gavage). CoQ10 was administered at 10, 50, and 100 mg/kg doses via Intraparietal (ip) injections. After 24 h, liver tissue specimens were scrutinized for mitochondrial complex activities, oxidative stress parameters, and apoptosis as well as biomarkers such as aspartate transaminase (AST) and alanine transaminase (ALT). Results: AlP induced a significant decrease in the activity of mitochondrial complexes I and IV, as well as a reduction in catalase activity, Ferric Reducing Antioxidant Power (FRAP), and Thiol levels. Additionally, AlP significantly elevated oxidative stress levels, indicated by elevated reactive oxygen species (ROS) production, and resulted in the increment of hepatic biomarkers such as AST and ALT. Administration of CoQ10 led to a substantial improvement in the aforementioned biochemical markers. Furthermore, phosphine exposure resulted in a significant reduction in viable hepatocytes and an increase in apoptosis. Co-treatment with CoQ10 exhibited a dose-dependent reversal of these observed alterations. Conclusion: CoQ10 preserved mitochondrial function, consequently mitigating oxidative damage. This preventive action impeded the progression of heart cells toward apoptosis.

Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans.

Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.

Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation.

Current pharmacological treatments against post-traumatic stress disorder (PTSD) lack adequate efficacy. As a result, intense research has focused on identifying other molecular pathways mediating the pathogenesis of this condition. One such pathway is neuroinflammation, which has demonstrated a role in PTSD pathogenesis by causing synaptic dysfunction, neuronal death, and functional impairment in the hippocampus. Phosphodiesterase (PDE) inhibitors (PDEIs) have emerged as promising therapeutic agents against neuroinflammation in other neurological conditions. Furthermore, PDEIs have shown some promise in animal models of PTSD. However, the current model of PTSD pathogenesis, which is based on dysregulated fear learning, implies that PDE inhibition in neurons should enhance the acquisition of fear memory from the traumatic event. As a result, we hypothesized that PDEIs may improve PTSD symptoms through inhibiting neuroinflammation rather than long-term potentiation-related mechanisms. To this end, we tested the therapeutic efficacy of cilostazol, a selective inhibitor of PDE3, on PTSD-related anxiety symptoms in the underwater trauma model of PTSD. PDE3 is expressed much more richly in microglia and astrocytes compared to neurons in the murine brain. Furthermore, we used hippocampal indolamine 2,3-dioxygenase 1 (IDO) expression and interleukin 1 beta (IL-1ß) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1ß following PTSD induction. As a result, PDE3 inhibition ameliorated the neuroinflammatory processes involved in the development of PTSD symptoms. Therefore, cilostazol and other PDEIs may be promising candidates for further investigation as pharmacological therapies against PTSD.

Some relevant mitigating agents of chronic aflatoxin exposure: a treatise.

Aflatoxins, a group of toxic secondary metabolites produced by Aspergillus species, pose significant threats to human health due to their potent carcinogenic, mutagenic, and immunosuppressive properties. Chronic exposure to these contaminants, commonly found in staple foods such as maize and groundnuts, has been linked to an increased risk of liver cancer, growth impairment, and immune dysfunction. Several agents, such as calcium montmorillonite clay and Lactobacillus rhamnosus GG, have shown promise in reducing aflatoxin bioavailability and alleviating its toxic effects. Additionally, dietary supplements such as chlorophyllin, selenium, and N-acetylcysteine have demonstrated potential as adjuvants to counteract aflatoxin-induced oxidative stress and support liver function. In this treatise, some of the most discussed approaches to mitigating aflatoxin effects are explored in terms of their efficacy, safety, and potential mechanisms of action, which include direct aflatoxin binding, detoxification, cellular antioxidative, and hepatocellular protection properties. However, the effectiveness of these strategies can be influenced by various factors, such as dose, duration of exposure, and individual susceptibility. Therefore, further research is needed to optimize these interventions and develop new, targeted therapies for the prevention and treatment of aflatoxin-related diseases. This review aims to provide a comprehensive analysis of 18 pharmaceutical, nutraceutical, supplement, and probiotic strategies currently available for mitigating the deleterious effects of chronic aflatoxin exposure in humans and animal models.

Rivastigmine ameliorates botulinum-induced hippocampal damage and spatial memory impairment in male rats.

Botulinum toxin (Botox) is widely used in beauty industry and its long-term consequences can be a matter of concern. The hippocampal cholinergic system plays a significant role in memory and learning that could be affected by Botulinum toxin. However, to date, the effect of Botox on memory system has been controversial. This survey aimed to examine the effects of Botox on spatial memory, and biochemical and histological parameters of the hippocampus in male rats by using Rivastigmine (R) as a cholinesterase inhibitor that is more selective for the central nervous system (CNS). Thirty-five male Wistar rats (200-250 g) were distributed into seven groups: Sham, Botox A (3, 6, and 15 IU intramascularly) and Botox A (3, 6, and 15 IU) plus Rivastigmine (1 mg/kg intraperitoneally). Spatial memory was assessed in the Morris Water Maze (MWM) 4 weeks later. Moreover, the hippocampal tissue was removed for histopathological and biochemical analyses. Botox significantly impaired memory performance in MWM by increasing escape latency and swim distance and decreasing the time spent in the target zone. Furthermore, in the Botox groups, the level of acetylcholine decreased, while the level of the acetylcholinesterase enzyme increased significantly in the hippocampus. Also, local lesions were observed in the form of degeneration and loss of pyramidal neurons, as well as a decrease in the volume and shrinkage of the cell body and an increase in microglia in the damaged area. Rivastigmine administration alleviated biochemical and histological parameters and partially ameliorated Botox-induced impairments. In summary, rivastigmine could be a suitable protective approach for side effects of Botox in the hippocampus.

Phosphodiesterase inhibitors in psychiatric disorders.

RATIONALE: Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. OBJECTIVES: In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. RESULTS: PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. CONCLUSIONS: Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.

Beneficial Effects of Statins on Seizures Independent of Their Lipid-Lowering Effect: A Narrative Review.

Among the many types of central nervous system (CNS) disorders, seizures and epilepsy severely affect the quality of life and routine daily activity of the sufferers. We aimed to review research studies that investigated the effect of statins on the prevention and treatment of seizures and epilepsy. Both animal models and human studies were included in this review. This article starts with a brief introduction about seizure, its prevalence, treatment, and various animal models of seizures and epilepsy. Next, we discuss statin's mechanism of action, side effects, and effects on neurological disorders with a specific focus on seizures. Finally, the effects of different types of statins on seizures are compared. The present review gives a better understanding of the therapeutic effects of statins on neurological disorders in animal models and human studies. This permits researchers to set up study designs to resolve current ambiguities and contradictions on the beneficial effects of statins on neurological disorders.

Neuronal nitric oxide synthase inhibition accelerated the removal of fluoxetine's anxiogenic activity in an animal model of PTSD.

While SSRIs are the current first-line pharmacotherapies against post-traumatic stress disorder (PTSD), they suffer from delayed onset of efficacy and low remission rates. One solution is to combine SSRIs with other treatments. Neuronal nitric oxide synthase (nNOS) has been shown to play a role in serotonergic signaling, and there is evidence of synergism between nNOS modulation and SSRIs in models of other psychiatric conditions. Therefore, in this study, we combined subchronic fluoxetine (Flx) with 7-nitroindazole (NI), a selective nNOS inhibitor, and evaluated their efficacy against anxiety-related behavior in an animal model of PTSD. We used the underwater trauma model to induce PTSD in rats. Animals underwent the open field (OFT) and elevated plus maze tests on days 14 (baseline) and 21 (post-treatment) after PTSD induction to assess anxiety-related behaviors. Between the two tests, the rats received daily intraperitoneal injections of 10 mg/kg Flx or saline, and were injected intraperitoneally before the second test with either 15 mg/kg NI or saline. The change in behaviors between the two tests was compared between treatment groups. Individual treatment with both Flx and NI had anxiogenic effects in the OFT. These effects were associated with modest increases in cFOS expression in the hippocampus. Combination therapy with Flx + NI did not show any anxiogenic effects, while causing even higher expression levels of cFOS. In conclusion, addition of NI treatment to subchronic Flx therapy accelerated the abrogation of Flx's anxiogenic properties. Furthermore, hippocampal activity, as evidenced by cFOS expression, was biphasically related to anxiety-related behavior.

Carboxymethyl chitosan-alginate hydrogel containing GSNO with the ability to nitric oxide release for diabetic wound healing.

Despite significant progress in developing diabetic wound dressing, the fabrication of an ideal one that fulfills all virtual criteria, such as promoting angiogenesis, is still lacking. Given the low vascularization in chronic diabetic wounds, they have a severe and non-healing nature. In this study, Nitric oxide (NO) was used as an angiogenic agent, which also has antibacterial properties. Briefly, S-nitrosoglutathione (GSNO) as a NO-donor was physically loaded into the carboxymethyl chitosan (CMC)/sodium alginate (ALg) composite film (CMC-ALg-GSNO). The morphological evaluation via scanning electron microscope confirms the homogeneous and porous structure of the wound dressing. The water uptake and water vapor transmission for the wound dressing were 4354.1% ± 179.3% and 2753.8 ± 54.6 g m-2per day, respectively. Anin-vitrorelease study showed a continuous delivery of NO during 168 h. Besides, the result from thein-vivotest reveals that the CMC-ALg-GSNO wound dressing developed diabetic wound healing in a rat model compared to the CMC-ALg and gauze. Thus, this study showed that CMC-ALg-GSNO wound dressing could lead to novel therapeutic invasions to treat diabetic wounds.

Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder.

RATIONALE: Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. OBJECTIVE: In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. RESULTS: Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. CONCLUSIONS: Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

Nigella sativa extract in the treatment of depression and serum Brain-Derived Neurotrophic Factor (BDNF) levels.

Background: Here, we aimed to investigate the therapeutic effects of Nigella sativa extract on serum brain-derived neurotrophic factor (BDNF) and depression score in patients with depression. Materials and Methods: This clinical trial was performed in 2021 in the hospitals of military forces in Tehran on 52 male patients with major depressive disorder treated with sertraline. We used the Depression, Anxiety, and Stress Scale-21 Items (DASS-21) questionnaire to assess the patients. Serum BDNF levels were measured by the enzyme-linked immunosorbent assay. Patients were then divided into two groups receiving 1000 mg N. sativa oil extract, daily, and placebo. Both groups received sertraline for at least 3 months. DASS-21 questionnaire and serum BDNF levels were measured after 10 weeks. Results: After treatments, we observed significantly decreased DASS-21 score (-11.24 ± 5.69) in the intervention group (P < 0.001) and placebo (-2.72 ± 6.19, P = 0.032), but patients in the intervention group had significantly lower scores (50.1 ± 6.8 vs. 58.2 ± 5.6, respectively, P < 0.001). Furthermore, patients in the intervention group had significantly decreased depression score (-5.5 ± 2.47, P < 0.001) and lower scores compared to the placebo (P < 0.001) (18.6 ± 2.7 vs. 23.4 ± 2.1 in intervention and placebo, respectively). We also observed significantly increased BDNF levels in the intervention group after the treatments (6.08 ± 3.76, P < 0.001) compared to the placebo group (29.4 ± 3.6 vs. 24.9 ± 2.1, P < 0.001). Serum BDNF levels had also significant reverse correlations with DASS-21 score (r = -0.35, P = 0.011) and depression score (r = -0.45, P = 0.001). Conclusion: The use of N. sativa resulted in decreased depression score and increase in serum BDNF levels that indicate the importance and efficacy of this drug.

Efficacy of Topical Losartan in Management of Mammoplasty and Abdominoplasty Scars: A Randomized, Double-Blind Clinical Trial.

BACKGROUND: Annually, millions of people suffer from skin scars' psychological and physical disadvantages. Pathologic scars prevention is challenging and requires developing feasible and effective therapeutic strategies. Regarding promising results of losartan (an angiotensin 1 receptor inhibitor) on skin scar in preclinical studies, we aimed to assess the losartan ointment's impact on surgical scars in a clinical setting. MATERIAL AND METHOD: Twenty-four patients with surgical wounds were enrolled from Razi hospital's plastic and reconstructive surgery department. The patients were trained to apply ointments 14-18 days post-surgery on the determined scar side, twice a day for 6 months. Two dermatologists independently evaluated scar formation at 3 and 6-month follow-ups using the Vancouver Scar Scale (VSS) score. RESULT: Twenty-four female patients with cosmetic surgeries were included. The mean VSS score of losartan-treated sides was 7.1 ± 2.06 (at month 3) and 5.21 ± 1.71 (at month 6) that significantly were different from placebo-treated sides (9.77 ± 1.55 and 8.31 ± 1.88 at 3 and 6 months, respectively) (P value < 0.001 and < 0.001, respectively, for months 3 and 6). The subset analysis demonstrated a significant improvement in height (P value < 0.001 at 3 and 6 months), pliability (P value < 0.001 at 3 and 6 months), and vascularity (P value < 0.001 at 3 and 6 months) subsets at losartan compared to placebo-treated side. Losartan ointment was well tolerated with no complication. CONCLUSION: Losartan ointment successfully improved scar formation in mammoplasty and abdominoplasty patients. The losartan preventive effect should be confirmed in future large-scale studies with long-term follow-ups. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Control algorithms and strategies of feeding for fed-batch fermentation of Escherichia coli: a review of 40 years of experience.

Fed-batch cultivation is a well-known type of submerged fermentation that is frequently used in manufacture of recombinant proteins and various kinds of enzymes, owing to its ability to produce products with high concentrations and high efficiency. In fed-batch culture, several issues must be considered; most of them are also presented in batch culture. However, feed flow rate calculation only corresponds to fed-batch fermentation and its value has a significant impact on productivity, efficiency, final concentration of product, formation of by-products, and viscosity of the culture. From this background, the present review article is an effort to gather the information on feeding strategies for fed-batch cultivation of Escherichia coli, which is a well-known microorganism in the production of recombinant proteins and industrial enzymes, especially for therapeutic applications. Moreover, this review is an aid to comprehend and compare the fundamental concept of different feeding strategies and their advantages and drawbacks.

Cardiac Complications in COVID-19: A Systematic Review and Meta-analysis.

BACKGROUND: The newly emerged coronavirus disease 2019 (COVID-19) seems to involve different organs, including the cardiovascular system. We systematically reviewed COVID-19 cardiac complications and calculated their pooled incidences. Secondarily, we compared the cardiac troponin I (cTnI) level between the surviving and expired patients. METHODS: A systematic search was conducted for manuscripts published from December 1, 2019 to April 16, 2020. Cardiovascular complications, along with the levels of cTnI, creatine kinase (CK), and creatine kinase MB (CK-MB) in hospitalized PCR-confirmed COVID-19 patients were extracted. The pooled incidences of the extracted data were calculated, and the unadjusted cTnI level was compared between the surviving and expired patients. RESULTS: Out of 1094 obtained records, 22 studies on a total of 4,157 patients were included. The pooled incidence rate of arrhythmia was 10.11%. Furthermore, myocardial injury had a pooled incidence of 17.85%, and finally, the pooled incidence for heart failure was 22.34%. The pooled incidence rates of cTnI, CK-MB, and CK elevations were also reported at 15.16%, 10.92%, and 12.99%, respectively. Moreover, the pooled level of unadjusted cTnI was significantly higher in expired cases compared with the surviving (mean difference = 31.818, 95% CI = 17.923-45.713, P value <0.001). CONCLUSION: COVID-19 can affect different parts of the heart; however, the myocardium is more involved.

Melatonin attenuated the behavioral despair induced by acute neurogenic stress through blockade of N-methyl D-aspartate receptors in mice.

It has been well documented that administration of melatonin could reveal antidepressant-like effect in rodents. However, the protective effect of melatonin on stress-induced depression/anxiety and its underlying mechanism is yet to be understood. In this regard, in the current study, acute foot-shock stress (FSS) was used to evaluate the antidepressant-like effect of melatonin on neurogenic stress-induced depression in mice. Behavioral evaluation was done by using the forced swimming test (FST) and Open-field test (OFT). Melatonin, MK-801, and ketamine (NMDA receptor antagonists), and NMDA (NMDA receptor agonist) were used to elucidate any association between melatonin and NMDA pathway in behavioral despair induced by acute-FSS. Applying acute-FSS to mice significantly induced depressant-like behavior in FST without any significant impact on locomotor activity in the OFT. We observed that melatonin (dose-dependently) significantly improved the depressant-like effect of FSS, but it did not impact the locomotion in animals. Acute injection of MK-801 at sub-effective doses (0.01 mg/kg) or ketamine (0.1 mg/kg) potentiated the antidepressant-like effect of a sub-effective dose of melatonin. However, the sub-effective dose of NMDA (30 mg/kg) abolished the protective effect of melatonin on the behavioral profile of stressed animals. Our results could reflect the antidepressant-like effect of melatonin on neurogenic stress-induced depressive behaviors in mice. Also, our results showed that NMDA receptors could be involved in the antidepressant-like effect of melatonin.

Bone Regeneration Using Bio-Nanocomposite Tissue Reinforced with Bioactive Nanoparticles for Femoral Defect Applications in Medicine.

BACKGROUND: In recent years, the method of constructing and evaluating the properties of polymer nanocomposite and bioactive ceramics in tissue engineering such as biocompatible scaffolds was studied by some researchers. METHODS: In this study, the bio-nanocomposite scaffolds of Chitosan (CS)-Hydroxyapatite (HA)-Wllastonite (WS), incorporated with 0, 10, 20 and 30 wt% of zirconium were produced using a freeze-drying method. Also, the phase structure and morphology of scaffolds were investigated using X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS). By analyzing the SEM images, the porosity of the scaffolds was observed in the normal bone area of the body. In the next step, bioactivity and biodegradability tests of the scaffolds were carried out. Due to the presence of hydrophilic components and the high-water absorption capacity of these materials, the bio-nanocomposite scaffolds were able to absorb water properly. After that, the mechanical properties of the scaffolds were studied. RESULTS: The mechanical test results showed that the preparation of reinforced bionanocomposites containing 10 wt% of zirconium presented better properties compared to incorporated bio-nanocomposites with different loadings of zirconium. CONCLUSION: According to MTT assay results, the prepared scaffolds did not have cytotoxicity at different concentrations of scaffold extracts. Consequently, the investigated scaffold can be beneficial in bone tissue engineering applications because of its similarity to natural bone structure and its proper porosity.

Therapeutic Effects of Minocycline Pretreatment in the Locomotor and Sensory Complications of Spinal Cord Injury in an Animal Model.

Spinal cord injury (SCI) is known as a debilitating condition which usually occurs due to traumas to the spine. However, the injury could also occur during clinical interventions such as spinal deformity and thoracoabdominal aortic surgeries. Intraoperative cord compression and ischemia are considered the mechanisms of primary injury in this regard. In the current study, we aimed to evaluate the therapeutic effects of minocycline, a promising agent for post-injury treatment, prophylactic administration. In a rat model of SCI through contusion injury, T9 vertebra laminectomy was performed on 40 Sprague-Dawley male rats provided from Pasteur Institute (Tehran, Iran). The reason behind selecting only male rats in our study was the fact that menstrual cycle of female rats affects healing process. Rodents were divided into a sham-operated group, a control group receiving only saline, a minocycline-treated group, and a minocycline pretreated group. Locomotor scaling, behavioral tests for neuropathic pain, and weight changes were evaluated and compared through a 28-days period. At the end of the study, tissue samples were taken to assess neuroinflammatory cytokine and histopathological changes. Minocycline pretreatment was as effective as its post-SCI administration regarding locomotor activity recovery, mechanical pain, and thermal allodynia. Furthermore, spinal cord inflammation and histopathological alterations were both similar in pretreatment and treatment groups indicating substantially better status. None of the treatments could have completely restore or prevent the spinal cord damage. Minocycline pretreatment can show promising therapeutic effects similar to its post-injury administration, inhibiting inflammatory microglial activity.

Neuroprotective effects of lipopolysaccharide and naltrexone co­preconditioning in the photothrombotic model of unilateral selective hippocampal ischemia in rat.

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co­preconditioning effect of toll­like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co­preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty­eight hours after LPS and twenty­four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5­triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co­preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co­preconditioning with LPS and NTX resulted in a synergistic protective effect.