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In the modern time, cancer immunotherapies have increasingly become vital treatment options, joining long-established methods like surgery, chemotherapy, and radiotherapy treatment. Central to this emerging approach are dendritic cells (DCs), which boast a remarkable ability for antigen presentation. This ability is being leveraged to modulate T and B cell immunity, offering a groundbreaking strategy for tackling cancer. However, the percentage of patients experiencing meaningful benefits from this treatment remains relatively low, underscoring the ongoing necessity for further research and development in this field. This review offers a comprehensive analysis of the present-day progress in dendritic cell (DC)-based vaccines and recent efforts to enhance their efficacy. We explore the intricacies of DC function, from antigen capture to T cell stimulation, and discuss the outcomes of both preclinical and clinical trials across various cancer types. While the results are promising, the real-world application of DC-based vaccines is still nascent, posing multiple challenges that need to be overcome. These obstacles include optimizing the methods for DC generation and antigen loading, overcoming the immunosuppressive nature of the tumor microenvironment, and enhancing specificities of the immunologic response through personalized vaccines. The review concludes by emphasizing prospective opportunities for future research and emphasizing the critical need for extensive clinical trials. These trials are essential to validate the effectivity of DC-based vaccines and solidify their role in the broader spectrum of cancer immunotherapy options., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare that there are no conflicts of interest, financial or otherwise, that could potentially influence or bias the work presented in this study. No funding sources or external support have been received for this research, and all authors have fully disclosed any relevant personal, professional, or financial relationships or interests that may potentially impact the integrity of the research. The authors affirm that the work was conducted in accordance with ethical and research standards, adhering to the highest level of scientific integrity and objectivity., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Migraine, a common disorder marked by severe and repetitive headaches, has been linked to the involvement of the NMDA receptor (NMDAR), a receptor responsible for glutamate signaling. Moringa oleifera (M. oleifera), recognized for its anti-inflammatory properties and therapeutic potential in various conditions, has been investigated. This study aims to assess the efficacy and precise mechanisms of M. oleifera for the treatment of migraine, for which evidence is limited., Methods: Rats were stratified into four distinct groups. The control group did not undergo the migraine-induction protocol. Post-induction, the "sumatriptan" group was administered sumatriptan injections, the "treatment" group received oral M. oleifera extract, and the "vehicle" group was provided with oral solvent treatment. Behavioral evaluations encompassing Von Frey's and hot plate assessments, in addition to qPCR analysis targeting Nr2a, Nr2b, Bax, Bcl-2, and Caspase-3, were conducted., Results: Von Fery's and hot plate tests revealed a notable decrease in triggering pressure and temperature within the vehicle group when compared to the other groups (both ps < 0.001). The Nr2a expression levels in both the vehicle and treatment cohorts exhibited significantly higher values than those observed in the control group (p < 0.001, p = 0.001) and the sumatriptan group (p < 0.001, p = 0.002). Conversely, no substantial alterations in Nr2b or Bcl-2 expression levels were observed across the study groups (p = 0.404, p = 0.976). Notably, heightened expressions of Caspase-3 and Bax were evident in the vehicle group relative to the other groups (p = 0.013, p = 0.010)., Conclusions: Moringa oleifera extract appears to mitigate symptoms of migraine by inhibiting apoptosis, suggesting potential efficacy in migraine treatment; however, additional research investigating a wider range of pathways is necessary., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: The entire experimental protocol adhered to the guidelines set forth by the National Institutes of Health (NIH) [22] and was approved by the Ethics Committee of AJA University of Medical Sciences (Ethics code: IR.AJAUMS.REC.1401.040). We confirm that the animals used in this study were not privately owned by another institution, individual, or farm. They were obtained from an established laboratory animal facility for research purposes Consent for publication: All authors declare their consent for the publication of the current manuscript in the journal BMC Neuroscience Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Aflatoxin B1 is the most toxic form of aflatoxins found in food. Nitric oxide in the hippocampus is essential for learning and memory. Necroptosis plays a role in cell death and pathology of many diseases, including neurodegenerative diseases. This study aimed to explore the role of the nitric oxide pathway and necroptosis signaling in Aflatoxin B1 neurotoxicity. A total of 35 male NMRI mice were divided into 5 groups as follows: Control group, Aflatoxin B1, Aflatoxin B1+L-Arginine, Aflatoxin B1+Aminoguanidine, and Aflatoxin B1+L-NAME. The spatial memory of the mice was assessed using the Barnes Maze test, and Western blot was conducted to evaluate the expression of RIP1, RIP3 and MLKL biomarkers in the hippocampus of mice brain. The behavioral tests indicated a significant memory impairment caused by Aflatoxin B1, which was significantly altered by L-Name and Aminoguanidine. The molecular tests showed an elevation of RIP1, RIP3 and MLKL biomarkers triggered by Aflatoxin B1 and a significant neutralization was then observed by L-Name. This study demonstrated that necroptosis pathway could be a possible mechanism of AFB1-induced memory damages and the nitric oxide pathway could play a role in altering these changes., Competing Interests: Declaration of competing interest The authors declare that there was no conflict of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Cancer, a leading cause of global mortality, remains a significant challenge to increasing life expectancy worldwide. Forkhead Box R2 (FOXR2), identified as an oncogene within the FOX gene family, plays a crucial role in developing various endoderm-derived organs. Recent studies have elucidated FOXR2-related pathways and their involvement in both tumor and non-tumor diseases. Dysregulation of FOXR2 has been linked to numerous malignant tumors, spanning the brain, nervous system, thyroid, osteosarcoma, Hodgkin lymphoma, colorectal, liver, pancreatic, lung, breast, ovarian, prostate, female genital tract, endometrial, and uterine cancers. Despite extensive research on FOXR2 dysregulation, its practical applications remain underexplored. This review delves into the mechanisms underlying FOXR2 dysregulation during oncogenesis and its implications for cancer diagnosis, prognosis, and treatment., Competing Interests: The authors declare no conflicts of interest to report regarding the present study., (© 2025 The Authors.)

Neuropathic pain is a debilitating complication following spinal cord injury (SCI). Currently, effective treatments for SCI-induced neuropathic pain are highly lacking. This clinical trial aimed to investigate the efficacy of combined intrathecal injection of Schwann cells (SCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in improving SCI-induced neuropathic pain. This study was a parallel-group, randomized, open-label, active-controlled phase II trial with two arms, including treatment and control groups. Patients with complete SCI-induced neuropathic pain in the treatment group received a single combined intrathecal injection of BMSCs and SCs. Study outcome measures were International SCI Pain Basic Data Set (ISCIPBDS) and World Health Organization (WHO) Quality of Life Assessment Instrument (WHOQOL-BREF). A total of 37 (55.2%) and 30 (44.8%) patients in the treatment and control groups were followed up for 6 months, respectively. Significant reductions in mean scores of interference items in the treatment group, including daily activities ( P < 0.001), mood ( P < 0.001), and sleep ( P < 0.001), were found at 6 months after the injection compared with the control one. Similarly, pain frequency ( P = 0.002), mean ( P = 0.001), and worst ( P = 0.001) numeric rating scale (NRS) pain intensity scores showed significant reductions in the treatment group after 6 months compared with the control one. Based on multiple regression analysis controlled for potential confounders, significant associations between changes in all outcome measures over the study period and the treatment group were found. This clinical trial indicated the efficacy of combined cell therapy in improving the neuropathic pain and quality of life in complete SCI patients. Future investigations should evaluate the effects of combination of this strategy with other existing therapies for SCI-induced neuropathic pain. This clinical trial was also registered prospectively at the Iranian Registry of Clinical Trials (IRCT20200502047277N8)., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In recent years, the use of gold nanorods (AuNRs) has garnered considerable attention in biomedical applications due to their unique optical and physicochemical properties. They have been considered as potential tools for the advanced treatment of diseases by various stimuli such as magnetic fields, pH, temperature and light in the fields of targeted therapy, imaging and drug delivery. Their biocompatibility and tunable plasmonic properties make them a versatile platform for a range of biomedical applications. While endogenous stimuli have limited cargo delivery control at specific sites, exogenous stimuli are a more favored approach despite their circumscribed penetration depth for releasing the cargo at the specific target. Dual/multi-stimuli responsive AuNTs can be triggered by multiple stimuli for enhanced control and specificity in biomedical applications. This review provides to provide a summary of the biomedical applications of stimuli-responsive AuNRs, including their endogenous and exogenous properties, as well as their dual/multi-functionality and potential for clinical delivery. This review provides a comprehensive review on the improvement of therapeutic efficacy and the effective control of drug release with AuNRs, highlights AuNRs design strategies in recent years, discusses the advantages or challenges so far in the field of AuNRs. Finally, we have addressed the clinical translation bio-integrated nanoassemblies (CTBNs) in this field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: One of the main risks of infection after hematopoietic stem cell transplantation (HSCT) is infection by gram-positive bacteria, including vancomycin-resistant enterococci (VRE). Based on the format of a global review and meta-analysis study, this study aims to investigate the incidence of VRE bloodstream infection (BSI) after HSCT in colonized individuals., Methods: The keywords of the systematic search included vancomycin-resistant enterococci and HSCT. These words were searched in Google Scholar, PubMed/Medline, Scopus, and Web of Science databases from January 1, 2000, to March 1, 2024. Studies that reported the prevalence of vancomycin-resistant enterococci in patients undergoing HSCT were included. The random effects model was used for the meta-analyses. Investigations were conducted according to PRISMA guidelines, and the protocol was registered in PROSPERO: CRD42024543491., Results: Out of 1100 screened papers, 28 were eligible. The random effects model was established to analyze the incidence of VRE BSI after HSCT. The pooled prevalence of co-infection for Allo-HSCT recipients was 3.023 (95% CI, Z-value = -3.5, p-value < 0.0001), and this value for Auto-HSCT recipients was 11.89 (95% CI, Z-value = -2.923, p-value < 0.001). These results showed that the rate of BSI due to vancomycin-resistant enterococcus in Auto-HSCT recipients is higher than Allo-HSCT., Conclusions: The prevalence of vancomycin-resistant enterococci in Auto-HSCT recipients is higher than that of Allo-HSCT, possibly due to colonization of the intestines of these people with vancomycin-resistant enterococci before transplantation. VRE Colonization before transplantation increases the likelihood of post-transplant VRE BSI and other bacterial infections, including Gram-negative. The strains should be analyzed by sequencing before and after HSCT for a more detailed investigation., (© 2024. The Author(s).)

Background: Glioblastoma multiforme (GBM) is one of the most invasive types of brain cancer. LncRNAs can be considered a new prognostic and diagnostic biomarker in GBM. This study comprehensively explored the interaction of lncRNAs with mRNAs in the TCGA database and proposed a novel promising biomarker with favorable diagnostic and prognostic values., Methods: The public data of RNA-seq and related clinical data were downloaded from the TCGA database. Differential expression analysis was conducted in R. GO and KEGG signaling pathways were used for enrichment. The STRING database was used for PPI analysis. CE-network was constructed by STAR database. Kaplan-Meier survival analysis and ROC curve analysis to indicate the biomarkers' diagnostic and prognostic values., Results: Differentially expressed data illustrated that 4428 mRNAs were differentially expressed in GBM. The GO and KEGG pathway analysis showed that the differentially expressed mRNAs were enriched in critical biological processes. The PPI showed that WEE1, BARD1, and CDK6 were the important PPI hubs. The ceRNA network data demonstrated critical lncRNAs. The data revealed that the lncRNA CRNDE , LINC00957 , AC072061.1 , AC068888.1, and DBH-AS1 are potential diagnostic prognostic biomarkers in the GBM patients., Conclusion: Altogether, we demonstrated lncRNA, and mRNA interaction and mentioned regulatory networks, considered a therapeutic option in GBM. In addition, we proposed potential diagnostic and prognostic biomarkers for the patients., (Copyright© 2024 Poursheikhani et al. Published by Tehran University of Medical Sciences.)

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.

Objective: Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI., Methods: This study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire., Results: Nine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline., Conclusions: This study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required., Trial Registration: Iranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 ., (© 2024. The Author(s).)

Cinacalcet is a calcimimetic medicine that has been used to treat secondary hyperparathyroidism and parathyroid cancer. Various studies have proposed the positive role of calcium and its receptor in skin wound healing. Furthermore, Cinacalcet interacts with other skin repair-related mechanisms, including inflammation and nitric oxide pathways. The present study evaluated the effect of Cinacalcet on the random-pattern skin flap survival. Eighty-four Wistar male rats were used. Multiple doses of Cinacalcet (30, 3, 1, 0.3, and 0.05 mg/kg) were used in 3 different routes of administration before the surgery. Histopathological evaluations, quantitative assessment of IL-6, TNF-α, and nitric oxide (NO), and the expression of calcium-sensing receptor (CaSR) and E-cadherin were evaluated in the skin tissue. To assess the role of NO, a NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME), was used, and histopathological effects were investigated. Cinacalcet pretreatment at the IP chronic 1 mg/kg dose significantly increased the skin flap survival rate and enhanced the NO tissue level compared to the control. However, the administration of L-NAME abolished its protective effects. IP Chronic 1 mg/kg of Cinacalcet could also decline the levels of IL-6 and TNF-α and also increase the expression of CaSR and E-cadherin in the flap tissue compared with the control group. Chronic Cinacalcet at 1 mg/kg could improve skin flap survival, probably mediated by the CaSR, NO, and inflammation-related pathways., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Infectious diarrhea, a significant global health challenge, is exacerbated by flooding, a consequence of climate change and environmental disruption. This comprehensive study aims to quantify the association between flooding events and the incidence of infectious diarrhea, considering diverse demographic, environmental, and pathogen-specific factors., Methods: In this systematic review and meta-analysis, adhering to PROSPERO protocol (CRD42024498899), we evaluated observational studies from January 2000 to December 2023. The analysis incorporated global data from PubMed, Scopus, Embase, Web of Science, and ProQuest, focusing on the relative risk (RR) of diarrhea post-flooding. The study encompassed diverse variables like age, sex, pathogen type, environmental context, and statistical modeling approaches., Results: The meta-analysis, involving 42 high-quality studies, revealed a substantial increase (RR = 1.40, 95% CI [1.29-1.52]) in the incidence of diarrhea following floods. Notably, bacterial and parasitic diarrheas demonstrated higher RRs (1.82 and 1.35, respectively) compared to viral etiologies (RR = 1.15). A significant sex disparity was observed, with women exhibiting a higher susceptibility (RR = 1.55) than men (RR = 1.35). Adults (over 15 years) faced a greater risk than younger individuals, highlighting age-dependent vulnerability., Conclusion: This extensive analysis confirms a significant correlation between flood events and increased infectious diarrhea risk, varying across pathogens and demographic groups. The findings highlight an urgent need for tailored public health interventions in flood-prone areas, focusing on enhanced sanitation, disease surveillance, and targeted education to mitigate this elevated risk. Our study underscores the critical importance of integrating flood-related health risks into global public health planning and climate change adaptation strategies., Competing Interests: The authors declare that they have no competing interests

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., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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-1β) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1β 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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 Q 10 (CoQ 10 ) in mitigating hepatic injuries. The objective of this investigation is to explore the potential protective efficacy of CoQ 10 against hepatic toxicity arising from AlP poisoning. Method : The study encompassed distinct groups receiving almond oil, normal saline, exclusive CoQ 10 (at a dosage of 100 mg/kg), AlP at 12 mg/kg; LD 50 (lethal dose for 50%), and four groups subjected to AlP along with CoQ 10 administration (post-AlP gavage). CoQ 10 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 CoQ 10 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 CoQ 10 exhibited a dose-dependent reversal of these observed alterations. Conclusion : CoQ 10 preserved mitochondrial function, consequently mitigating oxidative damage. This preventive action impeded the progression of heart cells toward apoptosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: A new analytical method based on the coupling of microextraction and microfluidics was developed and investigated for the pre-concentration, separation, and electrochemical detection of fenitrothion (FT) and parathion (PA) at the sub-ppm concentrations., Methods: In the first step, the microchip capillary electrophoresis technique was used to serve as a separation and detection system. Analytes were injected in the 40 mm long microchannel with 10 mm sidearms. Then, they were separated by applying a direct electrical field (+1800 V) between the buffer and detection reservoirs. 2-(n-morpholino)ethanesulfonic acid (MES) buffer (20 mM, pH 5) was used as a running buffer. The electrochemical detection was performed using three Pt microelectrodes with the width of working, counter, and reference electrodes (50, 250, and 250 µm, respectively) in the out-channel approach., Results: The system was devised to have the optimum detection potential equal to -1.2 V vs. pseudo-reference electrode. The dimensions of the SU-8 channel have 20 µm depth and 50 µm width. In the second step, an air-assisted liquid-liquid microextraction technique was used to extract and preconcentration of analytes from human blood plasma. Then, 1, 2 di-bromoethan was used as extractant solvent, the analytes were preconcentrated, and the sedimented solvent (50 µL) was evaporated in a 60 ˚C water bath followed by substitution of running buffer containing 10% ethanol. The optimal extraction cycles were found to be 8 with adding 1% NaCl to the aqueous phase. Analyzing time of the mentioned analytes was less than 100s, the precision range was 3.3 - 8.2 with a linear range of 0.8-100 ppm and 1.2-100 ppm for FT and PA, respectively. The extraction recoveries were about 91% and 87% for FT and PA, respectively. The detection limits for FT and PA were 240 and 360 ppb, respectively. Finally, the reliability of the method was investigated by GC-FID., Conclusion: The proposed method and device were validated and can be used as in situ and portable detection systems for detecting fenitrothion and parathion insecticides., Competing Interests: There is none to be clarified., (© 2024 The Author(s).)

Background: Brachial plexus block (BPB) has been accepted as a reliable alternative for general anesthesia in upper limb surgeries. Adding adjuvant drugs like dexmedetomidine and sufentanil has been shown to have clinical and pharmacologic advantages. In this randomized parallel clinical trial, we aim to compare the effects of these two adjuvants for bupivacaine in BPB., Methods: In this double-blinded study, by using computer-assisted block randomization, 40 patients ranged from 20 to 65 years old and scheduled for elective upper limb surgeries were assigned to two equal study groups (n = 20), receiving 1 mL of 5 ..g.mL -1 sufentanil (group S) or 1 mL of 100 ..g.mL -1 dexmedetomidine (group D) in adjunction to 30 mL of 0.5% bupivacaine for supraclavicular BPB under the guidance of ultrasonography. Characteristics of local anesthesia and postoperative analgesia were evaluated (n = 40)., Results: The duration of blocks significantly improved in group S (sensory: estimated median difference (EMD) [95%CI] = 100.0 [70.0...130.0], p < 0.001; motor: EMD [95%CI] = 120.0 [100.0...130.0], p < 0.001). Group S also had significantly longer postoperative analgesia and lower opioid consumption within 24 hours after the surgery (EMD [95%CI] = 4.0 [3.0...7.0], p < 0.001; EMD [95%CI] = -5.0 [-5.0...-5.0], p < 0.001; respectively). None of the patients showed adverse effects concerning vital signs, nausea, or vomiting., Conclusion: Our study showed that during ultrasound-guided supraclavicular BPB, sufentanil is a fairly better choice than dexmedetomidine as an adjuvant for bupivacaine and can provide preferable sensory and motor blocks. No significant side effects were seen in either of the study groups., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Combination therapy is a novel cancer therapy approach that combines two or more chemotherapy drugs. This treatment modality enhances the efficacy of chemotherapy by targeting key pathways in an additive or synergistic manner. Therefore, we investigated the efficacy of combination therapy by widely used chemotherapy drug doxorubicin (DOX) and oleanolic acid (OA) to induction of apoptosis for pancreatic cancer (PC) therapy. The effects of DOX, OA, and their combination (DOX-OA) were investigated on proliferation and viability of PC cell line (PANC-1) by MTT assay. Moreover, migration and invasion of the cancer cells were evaluated by trans-well migration assay and wound healing assay. Flow cytometry and DAPI (4',6-diamidino-2-phenylindole) staining were employed to investigate apoptosis quantification and qualification of the treated cancer cells. Finally, mRNA expression of apoptosis-related genes was assessed by quantitative real-time polymerase chain reaction. Our results demonstrated that the proliferation and metastasis potential of PC cells significantly decreased after treatment by DOX, OA, and DOX-OA. Moreover, we observed an increase in apoptosis percentage in the treated cancer cells. The apoptosis-related gene expression was modified to increase the apoptosis rate in all of the treatment groups. However, the anticancer potency of DOX-OA combination was significantly more than that of DOX and OA treatments alone. Our study suggested that DOX-OA combination exerts more profound anticancer effects against PC cell lines than DOX or OA monotherapy. This approach may increase the efficiency of chemotherapy and reduce unintended side effects by lowering the prescribed dose of DOX., (© 2023 Wiley Periodicals LLC.)

Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through "Darwinian" treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Biosurfactants are amphiphilic surface-active agents that mainly produced by various microorganisms. In this study, the anti-biofilm and inhibition of bacterial adhesion activities of two bacterial biosurfactants were investigated., Materials and Methods: After extraction and evaluation of Bacillus cereus and Serratia nematodiphila biosurfctants, inhibition of bacterial adhesion and anti-biofilm effects of them on Staphylococcus aureus and Pseudomonas aeruginosa were determined., Results: On average, the synergistic effect of two bacterial biosurfactants, caused about 60% decrease in adhesion and about 80% decrease in biofilm formation of S. aureus and P. aeruginosa ., Conclusion: The results of this study showed that combination of B. cereus and S. nematodiphila biosurfactants would increase the potential of attachment inhibition and biofilm eradication with very low toxicity., (Copyright © 2023 The Authors. Published by Tehran University of Medical Sciences.)

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., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: None declared., (Copyright: © Iranian Journal of Medical Sciences.)

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., (© 2022 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

Background: Previous studies have shown controversial results regarding the pro- or anticonvulsant effects of tramadol. Additionally, the underlying mechanism of seizure induction or alleviation by tramadol has not been fully understood. In the current study, the effects of tramadol on pentylenetetrazole (PTZ)-induced seizure and the possible involvement of the N-methyl-D-aspartate (NMDA) pathway were assessed in mice., Methods: Male Naval Medical Research Institute (NMRI) mice were treated with intravenous infusion of PTZ in order to induce clonic seizures and determine seizure threshold. Tramadol was injected intraperitoneally (0.1-150 mg/kg) 30 minutes prior to elicitation of seizures. The possible effects of intraperitoneal injections of NMDA receptor antagonists, ketamine (0.5 mg/kg) and MK-801 (0.5 mg/kg) on the anticonvulsant property of tramadol were investigated subsequently., Results: Tramadol (1-100 mg/kg) increased PTZ-induced seizure threshold in a dose-dependent, time-independent manner, with optimal anticonvulsant effect at a dose of 100 mg/kg. Acute administration of either ketamine (0.5 mg/kg) or MK-801 (0.5 mg/kg) potentiated the anticonvulsant effect of a subeffective dose of tramadol (0.3 mg/kg)., Conclusion: These results suggest a possible role of the NMDA pathway in the anticonvulsant effect of tramadol., Competing Interests: Conflict of interest: Authors declare no Conflict of Interests for this article., (© 2022 the Author(s), licensee AIMS Press.)

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., (© 2022 John Wiley & Sons, Ltd.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups ( n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of V Max , 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

Introduction: /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., Methods: 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., Results: Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (OR for TC genotype  = 3.01; 95%CI [1.667-5.526], P < 0.001; OR for C allele  = 1.96; 95%CI [1.314-2.941], P < 0.001). Besides, there was a marginal association between CC genotype and increased risk of RA (P: 0.031). However, there was an insignificant correlation between genotypes and allele frequencies of rs1131445 with incidence risk of SLE (P > 0.05). Moreover, stratification analysis indicated that the C allele in rs1131445 was linked with disease activity-associated laboratory parameters such as CRP and ESR in both RA and SLE patients, as well as the higher incidence of neurological symptoms in SLE subjects (P < 0.05)., Conclusion: These results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Nano-selenium oxide (NSeO) particles are highly noticeable due to their tissue-protective and antioxidant properties. For this purpose, the effect of NSeO was evaluated on skin flap survival and flap oxidative stress markers in rats. Also, another effect of NSeO was investigated on the expression of mTOR and p-mTOR., Materials and Methods: Fifty rats were divided into five groups of ten. Skin flap size was 3×8 cm in all groups. Groups were: (1) Sham, (2) Flap Surgery group, (3) Flap Surgery + NSeO, (4) Flap Surgery + Rapamycin (mTOR inhibitor), (5) Flap Surgery + Rapamycin + NSeO. The flap necrosis rate was computed using the paper pattern method on day seven after surgery. After day seven, flap tissues were collected for histological evaluations. Then, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured. Furthermore, the expression levels of mTOR and p-mTOR were measured using the Western blot method., Results: Treatment with NSeO significantly reduced necrosis (P&lt;0.05). It also resulted in a decrease in MDA level (P&lt;0.05). Histologically, NSeO reduced inflammation and increased positive signs of tissue healing (epithelialization, neovascularization, fibroblast migration, and granulation tissue). NSeO increased SOD activity significantly (P&lt;0.05), whereas, using rapamycin reversed these effects. Also, in all groups, mTOR changes were not significant. Additionally, p-mTOR expression was significantly reduced in groups that rapamycin was injected., Conclusion: NSeO can reduce flap necrosis and enhance tissue healing in rats. So, it can potentially be used clinically to promote tissue repair significantly, and its effects are independent of the mTOR pathway., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. 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 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

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)., Competing Interests: Declaration of Competing Interest The authors hereby declare no conflict of interest regarding the present study., (Copyright © 2021. Published by Elsevier Ltd.)

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., (© 2021 S. Karger AG, Basel.)

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancers of the gastrointestinal (GI) tract are often life-threatening malignancies, which can be a severe burden to the health care system. Globally, the mortality rate from gastrointestinal tumors has been increasing due to the lack of adequate diagnostic, prognostic, and therapeutic measures to combat these tumors. Coumarin is a natural product with remarkable antitumor activity, and it is widely found in various natural plant sources. Researchers have explored coumarin and its related derivatives to investigate their antitumor activity, and the potential molecular mechanisms involved. These mechanisms include hormone antagonists, alkylating agents, inhibitors of angiogenesis, inhibitors of topoisomerase, inducers of apoptosis, agents with antimitotic activity, telomerase inhibitors, inhibitors of human carbonic anhydrase, as well as other potential mechanisms. Consequently, drug design and discovery scientists and medicinal chemists have collaborated to identify new coumarin-related agents in order to produce more effective antitumor drugs against GI cancers. Herein, we summarize the therapeutic effects of coumarin and its derivatives against GI cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Banikazemi, Mirazimi, Dashti, Mazandaranian, Akbari, Morshedi, Aslanbeigi, Rashidian, Chamanara, Hamblin, Taghizadeh and Mirzaei.)

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., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

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., Competing Interests: The authors declare no conflict of interest., (© 2021 Published by Elsevier Ltd.)

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., Competing Interests: The authors report no conflicts of interest in this work.

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., (© 2020 John Wiley & Sons Ltd.)

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., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

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 A receptor. Compounds 5c (ED 50 ≈ 52.5 mg/kg) and 5 g (ED 50 ≈ 16.5 mg/kg) in the PTZ test were the most potent compounds among the designed compounds. In the MES test, the observed ED 50s 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 GABA A 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 GABA A receptors and possess no affinity for α5-containing receptors. The newly designed compounds could be considered as leading compounds in synthesizing novel GABA A receptor agonists with minimum side effects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: 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., Methods: 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., Results: Dexamethasone (2 mg/kg) or risperidone (2, 4 and 6 mg/kg) improved acetic acid-induced macroscopic ( p  < .001) and microscopic lesions. Additionally, risperidone (2, 4 and 6 mg/kg) inhibited the activity of MPO and TNF-α ( p  < .01, p  < .001) in the colon tissue compared to acetic acid group. Furthermore, bothdexamethasone and risperidone (2, 4 and 6 mg/kg) significantly reduced acetic acid-induced expression of TLR4and pNF-kB proteins ( p  < .05 , p  < .01 , p  < .001)., Conclusion: 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.

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.

Aim: The aim of the present study was to evaluate the anti-inflammatory effect of thymol in acetic acid-induced rat colitis through inhibiting the NF-κB signaling pathway., Methods: Colitis was induced by intra-rectal administration of 2 mL of diluted acetic acid (4%) solution using a flexible plastic rubber catheter in Wistar rats. Colitis was induced on the first day and all treatments were applied 5 days after the induction of colitis. Thymol was dissolved in 0.2% tween 80 in saline and administered orally at doses of 10, 30, and 100 mg/kg per day. Macroscopic and histopathologic investigations were done. The expression of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) was determined by immunohistochemistry (IHC) assay. The protein expression level of pNF-κB p65 was measured by the Western blot technique., Results: Treatment with thymol reduced mucosal and histological damages compared to the acetic acid group. Our results showed that thymol markedly inhibited the production of MPO and TNF-α in the colon tissue of the acetic acid-induced group. In addition, thymol decreased acetic acid-induced up-regulation of pNFκB p65 protein., Conclusions: The results of our study suggest that thymol exerts an anti-inflammatory effect in acetic acid-induced rat colitis by inhibiting the NF-κB signaling pathway and downregulating TNF-α and MPO expressions.

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. Methods: Acute colitis was produced by intra-rectal instillation of 2 mL of 4% acetic acid diluted in normal saline. Then, two hours after induction of colitis, DMSO as vehicle, dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) were given to the animals intraperitoneally (i.p.) and continued for five following days. Evaluation of macroscopic and microscopic damages were done. Myeloid peroxidase enzyme (MPO) activity was measured by a biochemical technique. Moreover, tumor necrosis factor-α (TNF-α) activity was identified by ELISA, and the expression level of pNF-kB protein was evaluated by immunohistochemistry (IHC). Results: Dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) decreased the macroscopic and microscopic damages compared with acetic acid group ( p  ˂ .001). Additionally, these agents decreased the activity of MPO ( p  ˂ .001), TNF-α ( p  ˂ .001) and the expression level of p-NF-kB ( p  ˂ .001) in rat colon tissue compared with the acetic acid group. Conclusion: It is proposed that the anti-inflammatory activity of dapsone on acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: 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., Methods: 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., Results: 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., Conclusions: 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 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.