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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.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.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.Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

/objectives. Single nucleotide polymorphisms (SNPs) located at the 3'-UTR region of the target genes of microRNAs (miRNAs) can dysregulate their expression via disrupting the binding site of miRNAs. Interleukin-16 (IL-16) is involved in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, we assessed the possible association between rs1131445 polymorphism in IL-16 gene with risk and clinical characteristics of RA and SLE in the Iranian population.In this case-control study, 120 patients with RA, 120 patients with SLE, and 120 unrelated healthy subjects were collected to estimate rs1131445 (T C) polymorphism in IL-16 gene using real-time PCR high-resolution melting (HRM) method.Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (ORThese results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE.

Introduction In this study, we aim to assess the intra-operative effect of dexmedetomidine administration on the hemodynamic parameters and bleeding volume during hip fracture surgery. Patients and methods we designed and implemented a triple-blinded randomized clinical trial to objectively compare the effects of 0.5 µg/kg/h infusion of dexmedetomidine with placebo (equal amount of normal saline) during hip fracture surgery. All included cases were between 30 and 70 years old and underwent surgery for fixation of a proximal femur fracture from September 26, 2020 until February 15, 2021. They were all ASA class I or II with preoperative hemoglobin levels of 10 mg/dL or higher. Surgical blood loss and hemodynamic parameters were documented. Results 76 patients were enrolled. There were no significant differences in baseline patient characteristics. The bleeding rate was 620 ± 190.0 mL for the normal saline group and 476 ± 177.98 mL in the dexmedetomidine group (P = 0.04). No significant effect on hemodynamic parameters was observed. Conclusion Based on the current study, intravenous infusion of dexmedetomidine during hip fracture surgery under general anesthesia reduced the amount of intraoperative bleeding without causing any significant hemodynamic disturbances. Registration number IRCT20191222045857N1 (Iranian Registry of Clinical Trials)

Introduction: Recent investigations have indicated the potential therapeutic role of cannabinoid type 2 (CB2) receptors in various inflammatory-related disorders. However, the role of these receptors has not been studied in skin flap models to date. In this study, we aimed to evaluate the possible involvement of CB2 receptors in the anti-inflammatory effects of sumatriptan, improving the random-pattern skin flap survival in rats. Methods: In a controlled experimental study, 36 male Wistar rats were randomly divided into 6 study groups (n = 6 per group). Two doses of sumatriptan (0.1 and 0.3 mg/kg) were administered intraperitoneally 30 min before harvesting the flap tissue. In a separate group, SR144528 (a selective CB2 receptor inverse agonist) was injected before the most effective dose of sumatriptan to determine the possible involvement of CB2 receptors in its action. Histopathological examinations, the expression level of CB2 receptors (Western blot analysis), and IL-1β and TNF-α concentrations (ELISA) were explored in the skin flap sampled tissues. Results: Sumatriptan 0.3 mg/kg remarkably enhanced the skin flap survival in all macroscopic and microscopic investigations compared to the control group (p < 0.001). IL-1β and TNF-α levels were significantly attenuated (p < 0.001), and the expression of CB2 receptors in skin cells was amplified in rats treated with sumatriptan 0.3 mg/kg (p < 0.05) compared to the control group. However, the administration of SR144528 (2 mg/kg) nullified all the protective effects of sumatriptan 0.3 mg/kg. Conclusion: We discovered that CB2 receptors play a crucial role in the favorable effects of sumatriptan on skin flap survival as a novel mechanism of action. So, targeting these receptors seems to be a dependable method in skin flap surgeries to ensure its survival and prevent tissue necrosis. Further experimental and clinical investigations are needed to ensure the safe clinical application of this method.

Biofilms represent longstanding challenges to oral health care. Candida albicans and Streptococcus mutans are the common pathogens forming biofilms. The growing resistance to and the adverse effects of antibiotics limit their usage and raise the need for novel approaches. Herbal extracts have emerged as efficient choices with lower costs and fewer adverse effects. Metal frameworks have captivated interest due to their high surface area, special biocompatibility, and non-toxicity. The effects of zeolitic imidazolate frameworks/layered double hydroxide (ZIF/LDH) on fungal infections and the potential effects of Eremostachys binalodensis on bacteria encouraged the researchers to evaluate the effect of ZIF/LDH, E. binalodensis, and their combination on C. albicans and S. mutans biofilms. ZIF/LDH nanocomposite was synthesized and characterized using scanning electron microscopy, Fourier transform infrared spectra, and X-ray diffraction to assess morphology and chemical structure. Methanol extracts of the areal parts of E. binalodensis were obtained by Soxhlet extraction. The microdilution tests and biofilm crystal violet staining were applied. Concentrations of 2.048 and 4.096 mg/ml E. binalodensis prevented C. albicans and S. mutans biofilm formation. The combination of ZIF/LDH + E. binalodensis prevented C. albicans and S. mutans biofilm formation. This research suggests the use of E. binalodensis-loaded ZIF/LDH nanocomposites for removing biofilms.

In this work, a new series of 2-((1,5-diphenyl-1H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide derivatives (9a–k) were synthesized and then evaluated for their antiepileptic activity against pentylen...

Curcumin has been previously shown to possess anti-myeloma effects. However, almost all of the previous reports are only based on observations from single viability methods in commonly used cell li...

Considering the outbreak pandemic of Coronavirus Disease 2019 (COVID-19), the lack of effective therapeutic strategies for the management of this viral disease, and the increasing evidence on the antiviral potential of silymarin, this study aimed to investigate the effectiveness of silymarin nanomicelles on the symptom's resolution time, laboratory parameters, and liver enzymes in patients with COVID-19. The participants were assigned to the nano-silymarin (n = 25) (receiving SinaLive soft gel, containing 70 mg silymarin as nanomicelles) or placebo groups (n = 25) three times daily for two weeks. Patients' symptoms and laboratory findings were assessed at baseline and during the follow-up period (one week and one month after the beginning of the treatment). No significant differences were observed between the two groups in terms of symptoms resolution time, laboratory parameters, and hospitalization duration (p 0.05). However, the alanine aminotransferase level decreased significantly in the treatment group, compared to the placebo group (p 0.001). Concomitant use of dexamethasone and remdesivir with silymarin might make the effects of silymarin on the improvement of patients' condition unclear. Further clinical trials are recommended with diverse dosages and larger sample sizes.

Aims: Diabetic neuropathy has been identified as a common complication caused by diabetes. However, its pathophysiological mechanisms are not fully understood yet. Statins, also known as HMG-CoA reductase inhibitors, alleviate the production of cholesterol. Despite this cholesterol-reducing effect of statins, several reports have demonstrated their beneficial properties in neuropathic pain. In this study, we used streptozotocin (STZ)-induced diabetic model to investigate the possible role of nitric oxide (NO) in the antineuropathic-like effect of atorvastatin. Methods: Diabetes was induced by a single injection of STZ. Male rats orally received different doses of atorvastatin for 21 days. To access the neuropathy process, the thermal threshold of rats was assessed using hot plate and tail-flick tests. Moreover, sciatic motor nerve conduction velocity (MNCV) studies were performed. To assess the role of nitric oxide, N(G)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG), and 7-nitroindazole (7NI) were intraperitoneally administered along with some specific doses of atorvastatin. Key findings: Atorvastatin significantly reduced the hyperalgesia in diabetic rats. L-NAME pretreatment with atorvastatin showed the antihyperalgesic effect, suggesting the possible involvement of the NO pathway in atorvastatin protective action. Furthermore, co-administration of atorvastatin with AG and 7NI resulted in a significant increase in pain threshold in diabetic rats. Significance: Our results reveal that the atorvastatin protective effect on diabetic neuropathy is mediated at least in a part via the nitric oxide system.

Despite major progress in the field of skin tissue engineering and wound care products, reconstruction of skin defects still represents a significant challenge associated with impaired healing and ...

The purpose of the present study is to explore the anti-inflammatory potential of risperidone in acetic acid-induced rat colitis through inhibition of TLR4/NF-kB pathway.Acute colitis induction was done by intra-rectal administration of 2 mL of 4% diluted acetic acid solution. Two h after colitis induction, dexamethasone (2 mg/kg) as standard drugorrisperidone (2, 4 and 6 mg/kg) were administered orally to wistar rats for five consecutive days. 24 h after the last treatment, animals were sacrificed by cervical dislocation. Macroscopic and microscopic damage evaluation was done. Biochemical and ELISA methods were used to assess myeloid peroxidase (MPO) enzyme activity and tumor necrosis factor-α (TNF-α) level respectively. Moreover, immunohistochemistry (IHC) was performed to detect the expression of TLR4 and pNF-kBproteins.Dexamethasone (2 mg/kg) or risperidone (2, 4 and 6 mg/kg) improved acetic acid-induced macroscopic (The anti-inflammatory effect of risperidone on acetic acid-induced colitis in rats may involve inhibition of TLR4 and NF-kB signaling pathway.

Inflammatory bowel disease composed of ulcerative colitis and Crohn's disease is a disorder that may involve entire gastrointestinal tract. Its pathogenesis is mainly an immune-mediated inflammation. Recently, it has been indicated that bupropion possesses anti-inflammatory properties; hence, the objective of this experiment is the investigation of the anti-inflammatory influence of bupropion on colonic lesions that emerged following the intrarectal administration of acetic acid. Thirty-six male Wistar rats were allocated randomly into six groups, including control, acetic acid, dexamethasone (2 mg/kg), and bupropion (40, 80, and 160 mg/kg). Colitis was induced by intrarectal administration of acetic acid in all study groups except control group, and animals were treated by oral administration of dexamethasone and bupropion. While macroscopic and microscopic lesions were observed after colitis induction, administration of dexamethasone and bupropion 160 mg/kg led to the remarkable improvement in lesions. In addition, the expression of TLR4 and NF-ĸB was decreased after colitis induction; however, treatment with dexamethasone (2 mg/kg) and bupropion (160 mg/kg) resulted in a significant decrease in their expression. Regarding biochemical factors, following colitis induction, TNF-α level and MPO activity were increased; nevertheless, dexamethasone (2 mg/kg) and bupropion (160 mg/kg) decreased the TNF-α and MPO activity. In conclusion, bupropion exerts anti-inflammatory influence through suppressing the TLR4 and NF-ĸB expression in the rat model of acute colitis.

Nassireslami, Ehsan/0000-0003-0330-5785 WOS:000518340300002 PubMed: 32144723 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.

Recent investigations have indicated the potential therapeutic role of cannabinoid type 2 (CB2) receptors in various inflammatory-related disorders. However, the role of these receptors has not been studied in skin flap models previously. In this study, we aimed to evaluate the possible involvement of CB2 receptors in the anti-inflammatory effects of sumatriptan and improvement of the random-pattern skin flap survival in rats.In a controlled experimental study, 36 male Wistar rats were randomly divided into six study groups (n = 6 per group). Two doses of sumatriptan (0.1 and 0.3 mg/kg) were administered intraperitoneally (i.p) 30 minutes before harvesting the flap tissue. In a separate group, SR144528 (a selective CB2 receptor inverse agonist) was injected before the most effective dose of sumatriptan to determine the possible involvement of CB2 receptors in its action. Histopathological examinations, the expression level of CB2 receptors (by western blot analysis), and IL-1 and TNF-α concentrations (ELISA) were explored in the skin flap samples.Sumatriptan 0.3 mg/kg remarkably enhanced the skin flap survival in all macroscopic and microscopic investigations compared to the control group (P0.001). IL-1 and TNF-α levels were significantly attenuated (P0.001), and the expression of CB2 receptors in skin cells was amplified in rats treated with sumatriptan 0.3 mg/kg (p0.05) compared to the control group. However, the administration of SR144528 (2 mg/kg) nullified all the protective effects of sumatriptan (0.3 mg/kg).We discovered that CB2 receptors play a crucial role in the favorable effects of sumatriptan on skin flap survival as a novel mechanism of action. So, targeting these receptors seems to be a dependable method in skin flap surgeries to ensure its survival and prevent tissue necrosis. Further experimental and clinical investigations are needed to ensure the safe clinical application of this method.

Objectives: In this study we aimed to evaluate the effect of E. binalodensis on gingival inflammatory wounds. Methods: In-vitro wound was induced by scratching the surface layer of human gingival fibroblasts (hGFs). Cells were pretreated with 1,10,100,1000 µg/ml of E. binalodensis methanol extract prior to 1µg/ml LPS stimulation. hGFs proliferation was assessed by MTT test. Also levels of critical inflammatory cytokines such as IL-1𝛽, IL-6 and TNF-𝛼 were determined by enzyme-linked immunosorbent assay (ELISA). Results: Wound induction was associated with secretion of IL-1β, IL-6 and TNF-α from hGFs. E. binalodensis enhanced the hGFs proliferation besides reducing the level of IL-1β, IL-6 and TNF-α in LPS-scratch-stimulated hGFs. Conclusions: Regarding anti-inflammatory and proliferative effects of E. binalodensis on hGFs, availability and safety of it, it is suggested for enhancing the wound healing process in gingival inflammatory wounds.

Since the inflammation and oxidative stress is the main pathophysiological pathway of neural damage in spinal cord injury (SCI), we tried to evaluate the role of ivermectin (IVM) combined with multi-walled carbon nanotube (MWCNT) in the treatment settings of SCI and its underlying mechanism. Wistar rats with T9 vertebra laminectomy in five groups of: sham-operated, vehicle, IVM (0.1 mg/kg), IVM-MWCNT (0.1 mg/kg), and minocycline (90 mg/kg) were used. We evaluated the locomotor scaling and other behavioral tests for neuropathic pain. Also, tissue samples were obtained to evaluate the expression of M1 and M2 macrophage marker, concentration of TNF-α, IL-1β, and IL-1, and oxidative stress level to assess neuroinflammatory changes. Both IVM and IVM-MWCNT after induction of SCI significantly enhanced the experimental tasks’ outcomes, including locomotion and neuropathic tests. Also, decreasing in pro-inflammatory cytokines including TNF-α, IL-1β, and IL-1 in the spinal cord and dorsal root ganglion tissues was also notable in both IVM and IVM-MWCNT-treated groups 28 days after induction of SCI in compared to the vehicle-treated SCI group. Both IVM and IVM-MWCNT significantly decreased oxidative stress, induced by SCI, based on the results of ROS and NADPH activity. IVM-MWCNT-treated animals indicated better outcome in every previous experiment in comparison to IVM-treated animals. The effectiveness of IVM-MWCNT was similar to minocycline treatment in all experimental task (as positive control group). IVM-MWCNT might be a novel treatment in spinal cord injury, which could act through decreasing the oxidative stress and increase the polarization of M1 in comparison to M2 macrophages., Spinal cord injury, Ivermectin, Care setting, Oxidative stress, M1 macrophage, M2 macrophage.

Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. All drugs were given intraperitoneally (ip). Selegiline (10 mg/kg) decreased the immobility time in the FST similar to fluoxetine (20 mg/kg). Pretreatment with l-arginine (NO precursor, 750 mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5 mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1 mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10 mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30 mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50 mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10 mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.

Inflammatory bowel disease (IBD) consists of ulcerative colitis and Crohn's disease, which affects gastrointestinal tract. The immune-mediated inflammation is mostly considered as the pathogenesis of IBD. It has been demonstrated that amitriptyline exerts anti-inflammatory influence; therefore, the aim of the current experiment is to evaluate the anti-inflammatory impact of amitriptyline on intestinal disorders following acetic acid-induced colitis in rats. Thirty male Wistar rats were randomly divided into five groups, including sham, control, dexamethasone (2 mg/kg), and amitriptyline (10 and 20 mg/kg). Intrarectal administration of acetic acid was applied to colitis induction in all study groups except for sham group. Animals were treated by oral administration of dexamethasone or amitriptyline. While macroscopic and microscopic lesions appeared after colitis induction treatment with dexamethasone and amitriptyline 10 and 20 mg/kg significantly improved lesions. Moreover, Toll-like receptor 4 (TLR4) and nuclear factor binding kappa light-chain (NF-ĸB expression), tumor necrosis factor-alpha (TNF-α) level, and myeloperoxidase (MPO) activity were increased after colitis induction, whereas treatment with dexamethasone (2 mg/kg) or amitriptyline (10 and 20 mg/kg) caused a noticeable decrease in the TLR4 and pNF-ĸB expression, TNF-α level, and MPO activity. In conclusion, amitriptyline plays an anti-inflammatory role through the suppression of TLR4/pNF-ĸB signaling pathway in the rat model of acute colitis.

Background: Covid-19 is now global concern and widely spread to the world due to high mortality among the nations we tried to evaluate the efficacy of methylprednisolone pulse in COVID-19 patients with severe respiratory failure.Methods: This study was phase2, double-blind, randomized, clinical trial in adults with COVID-19 (aged ≥18 years old) admitted to the intensive care unit (ICU) of *. Patients with intermediate or severe COVID-19 with PaO2/FiO2 less than 300 and progressive disease unresponsive to standard treatments admitted to ICU. Patients were randomly allocated in either control or investigation group. The control group received recommended regimen for COVID-19. The investigation group received the recommended regimen plus Methylprednisolone (1000mg/day for three days) and oral prednisolone 1mg/kg with tapering of dose within ten days. Results: A total of 29 ICU patients with intermediate or severe COVID-19 pneumonia recruited in this study. Fourteen patients (4 female, ten male) allocated in the investigation group, and 15 patients (6 female, nine male) assigned to the control group. The participant’s average age was 64.03±13.545 (case: 61.07±12.83, control: 66.80±14.03). The patients with methylprednisolone pulse had significantly higher systolic (P=0.018) and diastolic (P=0.001) blood pressure, meanwhile, the Glasgow coma scale (GCS) of methylprednisolone group was considerably (PConclusion: This study demonstrated methylprednisolone pulse in COVID-19 severe respiratory failure dramatically improves the clinical condition of patients including, GCS, and SpO2 of patients.Clinical Trial Registration Number: IRCT20200406046963N1

In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests. Furthermore, the possible side effects of the most potent compounds on the memory, motor coordination, and muscle strength were evaluated in passive avoidance, rotarod, and grip strength tests, respectively. The designed compounds with the main benzodiazepine pharmacophores including aromatic ring and proton accepting group completely mimiced the structure of zolpidem as an α1-selective agonist of GABA

Inflammatory bowel disease (IBD) is a lifelong and recurrent disease of the gastrointestinal tract that afflicts many people in the world. Growing evidence has currently indicated that dysfunction of immune system, particularly toll-like receptors 4 (TLR4) signaling pathway dysfunction plays a pivotal part in the pathogenesis of IBD. TLR4 signaling is involved both in the pathogenesis and in the efficacy of treatment of IBD. There are some medicinal products and herbal medicines, which their role in the treatment of IBD through modulation of TLR4 signaling has been implicated. The purpose of this review article is to summarize those medicinal products and herbal medicines.

The aim of the present study is to investigate the anti-inflammatory effect of melatonin in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis through the inhibition of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway and activation of melatonin receptor. Colitis was induced in Wistar rats by administration of 100 mg/kg TNBS dissolved in 0.25 ml of 50% ethanol solution using a flexible plastic rubber catheter into the colon via the anus. This resulted in incidence of colitis on the first day, and all treatments were conducted for 10 days after induction of colitis. Melatonin was administered intraperitoneally (i.p.) at doses of 1, 5, and 10 mg/kg/day. Luzindole (non-selective MT1/MT2 receptor antagonist) was administered i.p. at dose of 5 mg/kg/day 15 min prior to melatonin injection. During the experiment, animals were monitored for the appearance of diarrhoea, body weight loss, and rectal bleeding. Myeloid peroxidase enzyme and tumour necrosis factor-α (TNF-α) activities were detected by immunohistochemistry. The protein expression level of TLR4, myeloid differentiation factor 88 (MyD88), NF-κB p65, and inhibitor of kappa B (I-κB) were detected by western blotting analysis. Treatment with melatonin improved weight loss, mucosal, and histological damage compared with TNBS group. In addition, melatonin decreased TNBS-induced up-regulation of TLR4, MyD88, and NF-κB p65, and increased down-regulation of I-κB proteins. On the other hand, the administration of luzindole resulted in the inhibition of melatonin effects. It seems that the inhibition of TLR4/NF-κB signalling pathway may mediate the anti-inflammatory effects of melatonin in TNBS-induced rat colitis.

Aim: The purpose of this study is to examine the protective effects of Dapsone on inflammation of intestinal tissue through inhibition of NF-kB pathway in acetic acid-induced colitis in rats.Method...

Silymarin contains a group of closely-related flavonolignan compounds including silibinin, and is extracted from Silybum marianum species, also called milk thistle. Silymarin has been shown to protect the liver in both experimental models and clinical studies. The chemopreventive activity of silymarin has shown some efficacy against cancer both in vitro and in vivo. Silymarin can modulate apoptosis in vitro and survival in vivo, by interfering with the expression of cell cycle regulators and apoptosis-associated proteins. In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity. The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in gastrointestinal cancers. This review examines the recent studies and summarizes the mechanistic pathways and down-stream targets of silymarin in the therapy of gastrointestinal cancer.

Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.

Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10-100mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3mg/kg), while the inducible NOS inhibitor, aminoguanidine (100mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60mg/kg) blunted the anticonvulsant effect of DM (100mg/kg). Also, NMDA antagonists, ketamine (0.5mg/kg) and MK-801 (0.05mg/kg), augmented the anticonvulsant effect of DM (3mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.

Aims Poisoning with aluminium phosphide (AlP) commonly has a high rate of mortality and morbidities. Phosphine gas is the main cause of AlP poisoning that has deleterious effect on multi-organs especially heart, kidney, and liver. Furthermore, several studies reported that resveratrol has cytoprotective effects through its pleiotropic property. The purpose of this study was to estimate the dose-dependent role of resveratrol on phosphine induced acute hepatic toxicity in rat model. Main methods The rats have been exposed to LD 50 of AlP (12 mg/kg) by gavage, and resveratrol doses (20, 40, and 80 mg/kg) were injected 30 min after intoxication. After 24 h, the serum and liver tissue were collected for present study. Key findings The results indicated that phosphine causes an alteration in oxidative stress markers including elevation of ROS, and GSH level, MPO activity, reduction in SOD, catalase and G6PD activity as well as reduction in SOD1 and catalase expression. Furthermore, phosphine significantly induced phosphorylation of IkappaB, NF-kappaB and up-regulation of TNF-α, IL-1β, IL-6, and ICAM-1 expression. Also, phosphine induces markedly reduced hepatocytes lives cell and elevated apoptosis and necrosis. Co-treatment of resveratrol in a dose-dependent manner reversed aforementioned alterations. All in all, histological analysis indicated a deleterious effect of phosphine on the liver, which is mitigated by resveratrol administration. Significance The results of the present study suggest targeting ROS/NF-kappaB signalling pathway by resveratrol may have a significant effect on the improvement of hepatic injury induced by phosphine. It also may be a possible candidate for the treatment of phosphine-poisoning.

Aim: The aim of the present study is to investigate the anti-inflammatory effect of agmatine through the inhibition of iNOS enzyme in acetic acid-induced rat colitis. Methods: Acute colitis was induced by administration of 2 mL of diluted acetic acid (4%) solution rectally. Two hours after colitis induction, animals were treated with normal saline, dexamethasone (2 mg/kg), agmatine (2, 5, 10 mg/kg), L-NAME (30 mg/kg), Aminoguanidine (20 mg/kg), agmatine (2 mg/kg) with L-NAME (30 mg/kg) and agmatine (2 mg/kg) with aminoguanidine (20 mg/kg) intraperitoneally and continued for 3 consecutive days. Assessment of macroscopic and microscopic damage was performed. MPO activity was evaluated by biochemical method. Furthermore, the tissue level of TNF-α was determined by ELISA and the expression level of iNOS protein was detected by immunohistochemistry (IHC). Results: Dexamethasone (2 mg/kg) and agmatine (5, 10 mg/kg) and subeffective doses of agmatine (2 mg/kg) with aminoguanidine (20 mg/kg) improved macroscopic and microscopic damage compared to acetic acid group (p < .001). In addition, these drugs reduced the activity of MPO (p < .001) and the level of TNF-α (p < .001) in colon tissue compared to acetic acid group. Furthermore, they decreased acetic acid-induced expression of iNOS protein in colon tissue (p < .01, p < .001). Conclusion: It is suggested that the anti-inflammatory activity of agmatine on acetic acid-induced rat colitis may involve the inhibition of iNOS enzyme.

A simple free labeled electrochemical immunosensor based on chitosan (CHI) and quantum dots (QDs) was developed for the determination of procalcitonin (ProCT) antigen (Ag) which can act as a target biomarker of infectious diseases. The antibodies of the ProCT biomarker were successfully incubated on the CHI-QDs platform. Electrochemical impedance spectroscopy and cyclic voltammetry were used for the evaluation and characterization of various layers coated onto the electrode. Under the optimum conditions, the electron transfer resistance (Rct) of the immunosensor was altered linearly by the ProCT concentration. The proposed immunosensor was proportional to the ProCT biomarker concentration from 0.005 to 0.35ng/mL with a calculated detection limit of 0.015 pg/mL. The proposed biosensing device also exhibited high stability and reproducibility, which can be used for the quantitative assay of the ProCT biomarker in clinic analyses.

In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests. Furthermore, the possible side effects of the most potent compounds on the memory, motor coordination, and muscle strength were evaluated in passive avoidance, rotarod, and grip strength tests, respectively. The designed compounds with the main benzodiazepine pharmacophores including aromatic ring and proton accepting group completely mimiced the structure of zolpidem as an α1-selective agonist of GABAA receptor. Compounds 5c (ED50 ≈ 52.5 mg/kg) and 5 g (ED50 ≈ 16.5 mg/kg) in the PTZ test were the most potent compounds among the designed compounds. In the MES test, the observed ED50s for compounds 5c and 5 g were reduced to around 11.8 mg/kg and 10.5 mg/kg, respectively. The considerable hypnotic effect in a dose-dependent manner was observed following the administration of newly synthesized compounds. In all experiments administration of flumazenil as an antagonist of benzodiazepines receptor fully antagonized observed effects which indicated the involvement of GABAA receptors. Since there was no negative effect on memory, motor coordination, and muscle strength following the administration of compounds 5c and 5g as the most potent compounds, it could be concluded that the novel compounds most likely act through α1-containing GABAA receptors and possess no affinity for α5-containing receptors. The newly designed compounds could be considered as leading compounds in synthesizing novel GABAA receptor agonists with minimum side effects.