Neurobehavioral protective effects of Japanese sake yeast supplement against chronic stress-induced anxiety and depression-like symptoms in mice: Possible role of central adenosine receptors.

RATIONALE: Using routine synthetic drugs in the treatment of psychiatric disorders may have some restrictions due to serious side effects and pharmacoresistance. Some natural agents may be promising alternatives in this case. The neuroprotective activity of the neuromodulator adenosine and its receptor, A1 receptor (A1R) in the central nervous system has been mentioned in different studies. OBJECTIVE: We aimed to determine the anxiolytic, antidepressant and sedative effects of Japanese sake yeast as the first report. METHOD: Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose levels of 100, 200 and 300 mg kg-1 once daily for a week. The anxiolytic, antidepressant, and sedative actions of sake yeast were evaluated with the related tests. RESULTS: In all dose regiments, sake yeast significantly improved functions in the EPM and FST. 200 and 300 mg/kg of sake yeast significantly increased sleep duration and reduced sleep latency. Anxiolytic and antidepressant-like activities of sake yeast were maintained by the injection of ZM241385 (15 mg kg-1), a selective adenosine A2AR antagonist but completely counteracted by the injection of 8-cyclopentyltheophylline (10 mg kg-1), a selective adenosine A1R antagonist. 300 mg/kg of the yeast significantly increased the BDNF levels. Amygdala corticosterone levels did not show any significant changes at any dosage. Amygdala TNF-α, IL-6 and IL-1ß levels also decreased significantly with all the sake regiments compared to the control group. CONCLUSIONS: We conclude that oral sake yeast supplement exerts a neurobehavioral protective effect predominantly by activating central A1Rs.

Reversal of chronic restraint stress-induced memory impairment by Japanese sake yeast supplement in mice: Role of adenosine A1 and A2A receptors.

Controversial studies indicate the adenosine compound (a neuromodulator with neuroprotective activity) intervention on cognitive performance. On the other hand, Japanese sake yeast has been enriched with oral adenosine analogs as a novel natural agent. As the first report, we aimed to evaluate the effects of Japanese sake yeast supplement in a mouse model of chronic restraint stress-induced cognitive dysfunction. Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose level of 100, 200 and 300 mg/kg once daily for a week. The spatial and conditioned fear memory functions were evaluated with the Morris Water Maze (MWM) and the Passive Avoidance Learning (PAL) test, respectively. In all dosing regimens, improvements in spatial cognition were observed significantly in the MWM. 200 and 300 mg/kg of sake yeast significantly improved short- and long-term fear memory functions in the PAL test. Memory-enhancing effect of sake yeast was potentiated by the injection of ZM241385 (15 mg/kg), a selective adenosine A2A receptor (A2AR) antagonist, but completely disappeared by the injection of 8-cyclopentyltheophylline (CPT-8, 10 mg/kg), a selective adenosine A1 receptor (A1R) antagonist. The findings of the present study demonstrate the efficacy of sake yeast in acting as a cognitive performance-enhancing agent. Eventually, sake yeast and its ingredient S-adenosyl methionine (SAM) may be useful in improving memory in patients suffering from many dementia forms including Alzheimer's disease (AD).

The effect of tetrahydrocannabinol:cannabidiol oromucosal spray on cognition: a systematic review.

PURPOSE: Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC:CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies. METHODS: A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC:CBD oromucosal spray compared with a control condition. RESULTS: Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD. CONCLUSIONS: Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC:CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.

Psoralidin exerts anti-tumor, anti-angiogenic, and immunostimulatory activities in 4T1 tumor-bearing balb/c mice.

BACKGROUND: Psoralidin as a compound of the Psoralea corylifolia seeds exhibited several anti-cancer potentials in various cancers. MATERIALS AND METHODS: In this study, 4T1 tumor-bearing Balb/c mice were treated by intraperitoneal administration of Psoralidin, and Paraffin, as a control group to investigate anti-tumor, anti-angiogenic, and immunostimulatory activities in breast cancer. Body weight and tumor volume measurement were performed. Hematoxylin and Eosin (H&E) staining as well as immunohistochemistry for Ki-67, CD31 and VEGF markers were conducted. In addition, ELISA assay was performed for evaluating the serum level of IFN-γ and IL-4. Moreover, real time assay was performed to evaluate the expression of angiogenesis and immunostimulatory related genes. RESULTS: There were no significant changes in the body weight of all animal groups. The anti-cancer effects of Psoralidin were significantly observed after 24 days of the last treatment, confirmed by smaller tumor volume and also H&E staining. The expression level of Ki-67, CD31 and VEGF were significantly decreased in tumor tissues of the Psoralidin-treated group in comparison with Paraffin-treated group. Moreover, there was a significant reduction in the serum level of IL-4 in tumor-bearing mice after Psoralidin treatment while the serum level of IFN-γ was significantly augmented in all groups. Moreover, the reduction in expression of VEGF-a and IL-1ß was observed. Interestingly Psoralidin treatment led to expression increase of FOXp3. CONCLUSIONS: Psoralidin shows the anti-cancer potential in an animal model of breast cancer; however, further studies are recommended to elucidate its mechanisms of action.

Effectiveness of crocin of saffron (Crocus sativus L.) against chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the complications vexes patients treated with anti-cancer agents. Saffron has been demonstrated to attenuate symptoms of peripheral neuropathy in animal models. Also, there is a published clinical trial that investigated the pain relieving effect of saffron following nationally accepted rules and concluded that saffron was successful in alleviating pain symptoms in patients suffering from fibromyalgia. AIM OF THE STUDY: We aimed to determine the efficacy of crocin as a constituent of saffron in CIPN as the first report. MATERIALS AND METHODS: One hundred and seventy-seven enrolled eligible patients (between December 2018 and March 2020) for study entry were cases demonstrating mild to severe symptomatic CIPN for at least a month. These cases were randomly assigned to two main groups including 15 mg crocin tablet, bid (30 mg total daily target dose) and placebo tablet for 8 weeks. A crossover study was performed with a 2-week washout period. Patient outcomes were measured once a week for 8 consecutive weeks. RESULTS: Grade of sensory, motor and neuropathic pain decreased considerably and significantly in the crocin group compared with placebo (P < 0.05). Observed toxicities were mild and adverse effects had no significant differences between the two groups (P > 0.05). CONCLUSIONS: Crocin considerably seems to be effective for relieving symptoms of CIPN in cancer patients receiving chemotherapy agents. However, further studies are needed about crocin with its beneficial neuropharmacological effects and lower adverse effects than the chemical agents such as antidepressants, lamotrigine, and gabapentin.

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects.

Dexmedetomidine (Dexdor or Precedex®) is considered as a sedative agent which is widely used as an adjuvant in general anesthesia and critical care practice. There is extensive evidence indicating its neuroprotective properties especially in various ischemic and hemorrhagic brain injury models of animals. Clinical trials have shown that dexmedetomidine (DEX) can improve the outcome of intensive care unit (ICU) patients. Also, DEX is appropriate as a non-opioid analgesic therapy whenever minimizing opioid-related side effects is necessary. The present article reviews the recent advances in the use of DEX as a neuroprotective agent in both animal and human studies including newest findings about the mechanism of the drug as well as analgesic efficacy of this drug at all perioperative stages. In spite of the beneficial effects of the drug on the nervous system, there are potential adverse effects, such as hypotension and bradycardia, which can be treated pharmacologically and must be taken into consideration by clinicians.

Safety and Efficacy of Dexmedetomidine in Breast Surgeries: A Systematic Review and Meta-Analysis.

PURPOSE: Pain control during and after breast surgery is still a challenging task. Dexmedetomidine (DEX) is considered as a sedative agent that is widely used perineurally or intravenously as an adjuvant in general anesthesia and critical care medicine practice. The aim of this study is to evaluate the efficacy of perineural DEX and intravenous (IV) DEX and their effects on postoperative complications in breast surgeries. DESIGN: Systematic review and meta-analysis. METHODS: The present study systematically reviewed all identified randomized controlled trials for efficacy and safety of IV and perineural use of DEX in breast surgeries. Databases were searched for articles published before October 2019. FINDINGS: Twelve trials were identified including 803 patients undergoing breast surgery. Although administration of IV DEX and its use with pectoral nerve (Pecs) block significantly postponed time for first analgesic request and decreased pain score at 1 and 12 hours after surgery, paravertebral use of DEX had no statistically significant effect. Pooled data about perineural DEX showed no significant effect on postoperative nausea and vomiting (PONV), whereas IV DEX significantly reduced PONV. Pooled analysis also showed that DEX administration did not significantly affect postoperative complications, such as postoperative itching, bradycardia, and pneumothorax in patients undergoing breast surgery. CONCLUSIONS: The results showed that unlike paravertebral DEX, both DEX use with Pecs blocks and IV DEX were effective in control of postoperative pain in patients undergoing breast surgeries. Unlike perineural DEX, IV DEX significantly reduced PONV.

Protective Effect of Dizocilpine (MK-801) On TNBS-Induced Experimental Colitis in Mice.

Ulcerative colitis is chronic and recurrent disease of the gastrointestinal tract with uncertain etiology and incomplete treatment options. N-methyl-d-aspartate (NMDA) receptor suppression has shown anti-inflammatory effects in-vitro and in-vivo. The aim of present study was to evaluate the role of dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist, on TNBS (trinitrobenzene sulfonic acid)-induced murine model of colitis. Dizocilpine (0.1, 1 and 5 mg/kg) was given to mice intraperitoneally from 24 h before induction of colitis and daily thereafter for 4 days. Dexamethasone (1 mg/kg) was used as the reference drug. Colitis was induced by intracolonic administration of TNBS/Ethanol (50/50 v/v, 40mg/kg). Animals were sacrificed 5 days after colitis induction and distal colons were examined macroscopically and microscopically. The colonic tissue level of pro-inflammatory cytokines including interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed by ELISA. Myeloperoxidase (MPO) level was also measured in colon. Dizocilpine, particularly with intermediate dose of 1mg/kg significantly improved animal's weight loss as well as macroscopic and microscopic signs of colitis, reduced colonic levels of IL-1ß, IL-6, TNF-α and MPO activity. Hence, dizocilpine has significant protective effects in TNBS-induced colitis and NMDA suppression may be a new and effective therapeutic strategy in ulcerative colitis via decreasing in pro-inflammatory cytokine production.

Etrolizumab versus infliximab in the treatment of induction phase of ulcerative colitis: A systematic review and indirect comparison.

OBJECTIVES: There is still a need to develop new effective medications for the treatment of ulcerative colitis, particularly for patients who are intolerant or resistant to first line therapies. This article compared the efficacy and safety of etrolizumab and infliximab in moderate to severe ulcerative colitis. METHODS: This meta-analysis was performed according to the PRISMA statement protocol. A systematic literature search of three major bibliographic databases (Scopus, PubMed, and Cochran) was performed until June 30, 2018. This review included studies that evaluated the efficacy of etrolizumab or infliximab in ulcerative colitis and were placebo controlled randomized trials. Pooled data from each treatment were indirectly compared using Bucher's method. RESULTS: Seven trials were sufficiently homogeneous to be used for indirect comparison of the induction phase of the treatment. There were no significant differences in clinical remission and serious adverse events between etrolizumab and infliximab. Moreover, adverse events of etrolizumab were significantly less than those of infliximab. However, further trials are required to compare other parameters of efficacy such as the clinical response and mucosal healing of etrolizumab with infliximab in anti-TNF alpha naïve patients.

First evidence of the presence of adenovirus type 8 in myocardium of patients with severe idiopathic dilated cardiomyopathy.

Previous studies have detected adenovirus and cytomegalovirus (CMV) in cardiac tissue of patients with myocarditis. Therefore, in this study, we investigated the frequency of these viruses, which may be involved in the development of severe dilated cardiomyopathy (DCM). Myocardial tissue from of 23 cardiac transplant candidates with acute idiopathic DCM below the age of 40 years were analyzed by amplification of adenovirus and CMV DNA and subsequent sequencing. Adenovirus was detected in four (17.4%) and CMV in one (4.3%) of the patients. All controls were negative for the presence of both viruses. Our study shows that myocardial infection with adenovirus may play an important role in the pathogenesis of severe DCM and suggests that vaccination against adenovirus might be helpful in decreasing the prevalence of severe idiopathic DCM. This is the first study in which adenovirus type 8 has been detected in the hearts of patients with DCM.

The effect of theophylline on acetic acid induced ulcerative colitis in rats.

BACKGROUND: Ulcerative colitis is a relapsing inflammatory disorder of the colon. There is a need to explore the new treatments for this disorder. Theophylline, a competitive inhibitor of phosphodiesterase, is shown to have anti-inflammatory properties. However, the effect of theophylline on ulcerative colitis has not yet been investigated. The present study evaluated the effect of theophylline on acetic acid induced ulcerative colitis in rats. MATERIALS AND METHODS: Colitis was induced by instillation of 2ml of acetic acid solution (3%). Colon samples were evaluated grossly and microscopically and assayed for myeloperoxidase (MPO) activity and proinflammatory cytokine concentrations. RESULTS: Treatment with theophylline at the doses of 20 and 50mg/kg attenuated acetic acid induced ulcerative colitis as shown by improvement in body weight loss, macroscopic score, ulcer area, hematocrit and histopathological score. Theophylline treatment also reduced MPO activity and tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1 ß) and interleukin 6 (IL-6) concentrations in inflamed colon. CONCLUSION: Theophylline has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities. Therefore, theophylline has the potential to be used for successful treatment of ulcerative colitis.

The effect of menthol on acute experimental colitis in rats.

Menthol is an aromatic compound with high antiinflammatory activity. The purpose of the current research is to investigate the effectiveness of menthol on acetic acid induced acute colitis in rats. Animals were injected with menthol (20 and 50 and 80mg/kg, i.p.) 24h prior to induction of colitis for 3 consecutive days. Menthol at medium and higher doses similar to dexamethasone as a reference drug significantly reduced body weight loss, macroscopic damage score, ulcer area, colon weight, colon length and improved hematocrit in rats with colitis. The histopathological examination also confirmed anti-colitic effects of menthol. Menthol also reduced significantly the colonic levels of tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and myeloperoxidase (MPO) activity in inflamed colons. Thus, the findings of the current study provide evidence that menthol may be beneficial in patients suffering from acute ulcerative colitis.

The effect of sodium valproate on acetic acid-induced colitis in rats.

Ulcerative colitis is a chronic recurrent disease with incomplete treatment options. The current article evaluated the effect of sodium valproate on acetic acid-induced ulcerative colitis in rats. Rats were randomly distributed into six groups including Sham group, colitis control group, sodium valproate treatment groups (50, 100 and 300 mg/kg, i.p.) and dexamethasone-treatment group. Dexamethasone was used as a reference drug. Colitis was induced by intracolonic instillation of 2 mL of 3% acetic acid solution. The efficacy of sodium valproate was evaluated by macroscopical and histopathological scoring systems, hematocrit measurement as well as biochemical analysis including myeloperoxidase (MPO) and pro-inflammatory cytokines assessment. Sodium valproate, particularly with doses of 100 and 300 mg/kg significantly improved weight loss, and macroscopic damage, reduced ulcer area, colon weight, microscopic colitis index and elevated hematocrit level. Biochemical experiments showed elevated levels of colonic MPO activity, interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in colitis control group. Treatment with sodium valproate at the doses of 100 and 300 mg/Kg) decreased the MPO activity and colonic concentrations of IL-1ß, IL-6 and TNF-α. The results provide evidence that sodium valproate has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities, and it may be useful in patients with ulcerative colitis.

The effect of memantine on trinitrobenzene sulfonic acid-induced ulcerative colitis in mice.

Previous reports suggest a significant role for N-Methyl-D-aspartate (NMDA) activation in inflammatory processes. So, this study was conducted to investigate the effect of memantine, a commonly used NMDA receptor antagonist, on inflammatory changes in mice model of colitis. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS) (40mg/kg). Animals received memantine (12.5, 25 and 50mg/kg, i.p.), glutamate (2g/kg, p.o.) or dexamethasone (1mg/kg, i.p.) 24h before TNBS instillation and daily thereafter for 4 days. The colonic injury was measured by clinical, macroscopic, microscopic and biochemical analysis. Memantine significantly attenuated the body weight loss, colon weight, the plasma levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and colon level of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO); as well as macroscopic and microscopic signs of colitis. Oral administration of glutamate had no significant effect on investigated parameters. Memantine as a NMDA antagonist may provide a novel venue for the development of strategies for the treatment of ulcerative colitis.

The In vitro Fertilization of Ovine Oocytes in the Presence of Oviductal Cells and its Effect on the Expression of Zygote Arrest 1 (Zar1) and Subsequent Embryonic Development.

BACKGROUND: The cells of mammalian female reproductive tract have been widely used for in vitro fertilization (IVF). This study was designed to study the effects of oviductal epithelial cells (OECs) and their conditioned medium during IVF on subsequent embryonic development and the relative abundance of zygote arrest 1 (Zar1) transcript in ovine zygotes. METHODS: The in vitro matured ovine oocytes were randomly fertilized in the following culture conditions: I) SOFaaBSA+20% sheep serum (control), II) SOFaa BSA+20% sheep serum (50 µl) in the presence of OECs, III) SOFaaBSA+20% sheep serum (100 µl) in the presence of OECs, and IV) OECs conditioned medium (CM). Sigma Stat (Version 2.0) software and one-way ANOVA were considered for statistical analysis. A p<0.05 was considered statistically significant. RESULTS: The cleavage, blastocyst, and hatched blastocyst rates in OECs and CM groups were significantly lower than the control group (p<0.01). In co-cultured groups, the application of two different volumes of IVF medium showed no difference in embryonic developmental indices. The Zar1 gene expression in zygotes produced in the presence of OECs was significantly higher than those produced in the control and CM groups (p<0.05). CONCLUSION: Neither the presence of oviductal epithelial cells nor their conditioned medium could improve the developmental potential of ovine embryos during IVF. Moreover, no relationship was observed between the relative abundance of Zar1 transcript in zygotes produced in different conditions and the corresponding subsequent embryonic development.