"Niclosamide: A potential antipruritic agent by modulating serotonin pathway through metabotropic glutamate receptors (mGluRs)".

Pruritus is an uncomfortable sensation induced by various pruritogens, including serotonin. Serotonin, acting as an inflammatory mediator, can activate a histamine-independent pathway. Consequently, many anti-pruritus medications, such as antihistamines, are not effective in adequately relieving patient symptoms. Niclosamide, an anthelmintic drug, has recently demonstrated an affinity for Metabotropic glutamate receptors (mGluRs). mGluRs are a group of receptors activated by glutamate, and they are involved in regulating neuronal excitability. In this study, we utilized mouse models of serotonergic itch and administered different doses of Niclosamide to examine the expression of mGluR1, mGluR5, and 5-HT2. The administration of 5 mg/kg Niclosamide successfully suppressed pruritus in the mice. Additionally, the levels of mGluR1, mGluR5, 5-HT2, and TRPV1 were significantly reduced. These findings suggest that Niclosamide holds promise as a potential antipruritic drug.

Sex Dimorphism in Pain Threshold and Neuroinflammatory Response: The Protective Effect of Female Sexual Hormones on Behavior and Seizures in an Allergic Rhinitis Model.

Our previous research demonstrated that allergic rhinitis could impact behavior and seizure threshold in male mice. However, due to the complex hormonal cycles and hormonal influences on behavior in female mice, male mice are more commonly used for behavioral tests. In this study, we aimed to determine whether these findings were replicable in female mice and to explore the potential involvement of sexual hormones in regulating neuroinflammation in an allergic model. Our results indicate that pain threshold was decreased in female mice with allergic rhinitis and the levels of IL-23/IL-17A/IL-17R were increased in their Dorsal root ganglia. However, unlike males, female mice with AR did not display neuropsychological symptoms such as learning and memory deficits, depression, and anxiety-like behavior. This was along with decreased levels of DNA methyl transferase 1 (DNMT1) and inflammatory cytokines in their hippocampus. Ovariectomized mice were used to mitigate hormonal effects, and the results showed that they had behavioral changes and neuroinflammation in their hippocampus similar to male mice, as well as increased levels of DNMT1. These findings demonstrate sex differences in how allergic rhinitis affects behavior, pain sensitivity, and seizure thresholds. Furthermore, our data suggest that DNMT1 may be influenced by sexual hormones, which could play a role in modulating inflammation in allergic conditions.

Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System.

Status epilepticus (SE) is a critical medical emergency marked by persistent or rapidly repeating seizures, posing a threat to life. Using the lithium-pilocarpine-induced SE model, we decide to evaluate the anti-seizure effects of ivermectin as a positive allosteric modulator of GABAA receptor and the underlying mechanisms involved. Lithium chloride was injected intraperitoneally at a dose of 127 mg/kg, followed by the administration of pilocarpine at a dose of 60 mg/kg after a 20-h interval in order to induce SE. Subsequently, the rats received varying amounts of ivermectin (0.3, 1, 3, 5, and 10 mg/kg, i.p.) 30 min before the onset of SE. To study the underlying molecular mechanisms, we had pharmacological interventions of diazepam (1 mg/kg), glibenclamide and nicorandil as ATP-sensitive potassium channel blocker and opener (both 1 mg/kg, i.p.), naltrexone and morphine, as opioid receptor antagonist and agonist (1 mg/kg and 0.5 mg/kg, i.p., respectively). In addition, three nitric oxide inhibitors, namely, L-NAME (10 mg/kg, i.p.), 7-NI (30 mg/kg, i.p.), and aminoguanidine (100 mg/kg, i.p.), were administered to the rats in the experiment. Finally, we use ELISA and western blotting, respectively, to examine the amounts of pro-inflammatory cytokines (TNF-α and IL-1ß), nitrite, and GABAA receptors in the rat hippocampal tissue. The study found that ivermectin, at doses of 3, 5, and 10 mg/kg, exerts anti-seizure effects and decrease Racine's scale SE score. Interestingly glibenclamide and naltrexone reduced the anti-seizure effects of ivermectin, and from other hand diazepam, nicorandil, morphine, L-NAME, 7-NI, and aminoguanidine, enhance the effects when co-administrated with subeffective dose of ivermectin. Additionally, the study found that ivermectin decreased the elevated levels of TNF-α and IL-1ß following SE, while increased the reduced expression of GABAA receptors. Overall, these findings suggest that ivermectin has anti-seizure effects in a SE seizure which may be mediated by the modulation of GABAergic, opioidergic, and nitrergic pathways and KATP channels.

Characterization and in vivo evaluation of a fabricated absorbable poly(vinyl alcohol)-based hernia mesh.

The most widely taken medical approach toward hernia repair involves the implementation of a prosthetic mesh to cover the herniated site and reinforce the weakened area of the abdominal wall. Biodegradable meshes can serve as biocompatible grafts with a low risk of infection. However, their major complication is associated with a high rate of degradation and hernia recurrence. We proposed a facile and cost-effective method to fabricate a poly(vinyl alcohol)-based mesh, using the solution casting technique. The inclusion of zinc oxide nanoparticles, citric acid, and three cycles of freeze-thaw were intended to ameliorate the mechanical properties of poly(vinyl alcohol). Several characterization, cell culture, and animal studies were conducted. Swelling and water contact angle measurements confirmed good water uptake capacity and wetting behavior of the final mesh sample. The synthesized mesh acquired a high mechanical strength of 52.8 MPa, and its weight loss was decreased to 39 %. No cytotoxicity was found in all samples. In vivo experiments revealed that less adhesion and granuloma formation, greater tissue integration, and notably higher neovascularization rate were resulted from implanting this fabricated hernia mesh, compared to commercial Prolene® mesh. Furthermore, the amount of collagen deposition and influential growth factors were enhanced when rats were treated with the proposed mesh instead of Prolene®.

Therapeutic potential of infliximab for pruritus in mice model of cholestasis induced by bile duct ligation: Possible involvement of IL-31.

BACKGROUND: Cholestatic pruritus is a distressful sensation that can cause a massive desire of scratching skin. Despite maximum medication therapy, some patients still experience pruritus. In this study, we evaluated the effect of infliximab on cholestatic pruritus induced in mice by bile duct ligation. METHODS: Twenty-four balb/c mice were randomly assigned to three groups; sham, control, and treatment. The bile duct ligation procedure was performed on mice in the control and treatment groups. After six days, mice in the treatment group received subcutaneous administration of infliximab, and the next day all mice were subjected to the scratching behavior test. Skin, dorsal root ganglia (DRG), and blood samples of mice were collected and evaluated by histopathological, molecular, and biochemical tests. RESULTS: The scratching behavior has significantly decreased in mice with cholestasis after the administration of infliximab. The levels of TNFα, TNFR1, TNFR2, NF-κB, and IL-31were higher in control mice compared to sham. In addition, expression levels of TNFR1, NF-κB, and IL-31 were decreased in the treatment group compared to the controls in skin and DRG, while TNFR2 levels were decreased only in DRG. CONCLUSION: Infliximab can block TNFα interaction with receptors and inhibit further inflammatory response. Also, our results suggested that infliximab can suppress IL-31 expression indirectly, which is a well-known cytokine in pruritus pathophysiology Infliximab can be a potential therapeutic approach in resistant pruritus in cholestatic disorders.

Evaluation of colonic anastomosis healing using hybrid nanosheets containing molybdenum disulfide (MOS2) scaffold of human placental amniotic membrane and polycaprolactone (PCL) in rat animal model.

Anastomosis is a standard technique following different conditions such as obstruction, tumor, and trauma. Obstruction, adhesion, or anastomosis leakage can be some of its complications. To improve healing and prevent postoperative complications, we design a hybrid scaffold containing acellular human amniotic membranes and polycaprolactone-molybdenum disulfide nanosheets for colon anastomosis. The animal model of colocolonic anastomosis was performed on two groups of rats: control and scaffold. The hybrid scaffold was warped around the anastomosis site in the scaffold group. Samples from the anastomosis site were resected on the third and seventh postoperative days for histopathological and molecular assessments. Histopathologic score and burst pressure had shown significant improvement in the scaffold group. No mortality and anastomosis leakage was reported in the scaffold group. In addition, inflammatory markers were significantly decreased, while anti-inflammatory cytokines were increased in the scaffold group. The result indicates that our hybrid scaffold is a proper choice for colorectal anastomosis repair by declining postoperative complications and accelerating healing.

Allergic rhinitis in BALB/c mice is associated with behavioral and hippocampus changes and neuroinflammation via the TLR4/ NF-κB signaling pathway.

BACKGROUND: Allergic rhinitis is a systemic disease with high prevalence, which some of its neuropsychological problems have been reported. The primary pathophysiology and mechanism of the neuropsychological dysfunction of AR patients have not been described yet, so here we subjected an animal model of AR to identify any behavioral or seizure threshold changes and to assess the pathophysiology of the disease. METHODS: Eighty male BALB/C mice were randomly divided into the allergic rhinitis group and controls. Allergic rhinitis was induced in the first group by administering OVA and aluminum hydroxide intraperitoneally and then nasal injection of OVA for 14 consecutive days. Both groups were subjected to different tests for assessing depressive-like behavior, anxiety, spatial and contextual memory, and learning and seizure threshold. Hippocampus and plasma samples of mice were subjected for analyzing cytokines and immune modulators and for pathology and immunohistochemistry evaluation. RESULTS: The depressive and anxiety-like behavior were increased in AR, and the spatial learning and memory were disturbed in the AR group. Also, AR mice had lower seizure thresholds compared to controls. Lab data suggested that TLR4, NF-κB, IL-1ß, and TNFα expressions were increased in the AR hippocampus as well as their plasma proinflammatory cytokines. Likewise, demyelination, cell death, and M1 macrophage aggregation were increased in the AR hippocampus. CONCLUSION: Behavioral and cognitive problems should be taken seriously in patients with AR or other atopic diseases, and more investigating is required to clear the pathophysiology behind it and its treatment.

Safety and efficacy of aprotinin versus tranexamic acid for reducing absolute blood loss and transfusion in pediatric patients undergoing craniosynostosis surgery: a randomized, double-blind, three-arm controlled trial.

OBJECTIVE: Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to adults, excessive blood loss may quickly lead to hypovolemic shock. Therefore, reducing blood loss is important in craniosynostosis surgery. This study was conducted to evaluate the efficacy of aprotinin or tranexamic acid (TXA) in blood loss reduction in these patients. METHODS: In the current randomized controlled trial, 90 eligible pediatric patients with craniosynostosis were randomly divided into three groups to receive either aprotinin, TXA, or no intervention. The absolute blood loss and transfusion amount were assessed for all patients both intraoperatively and 2 and 8 hours postoperatively. RESULTS: Although crude values of estimated blood loss were not significantly different between groups (p = 0.162), when adjusted to the patient's weight or EBV, the values reached the significance level (p = 0.018), particularly when the aprotinin group was compared to the control group (p = 0.0154). The EBV losses 2 hours and 8 hours postoperatively significantly dropped in the TXA and aprotinin groups compared to the control group (p = 0.001 and p < 0.001, respectively). Rates of postoperative blood transfusion were significantly higher in the control group (p = 0.024). Hemoglobin and hematocrit 8 hours postoperatively were lower in the control group than in the TXA or aprotinin treatment groups (p < 0.002 and p < 0.001, respectively). There were no serious adverse events associated with the interventions in this study. CONCLUSIONS: Aprotinin and TXA can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric patients undergoing craniosynostosis surgery.

Autoimmunity and cytokines in Guillain-Barré syndrome revisited: review of pathomechanisms with an eye on therapeutic options.

Guillain-Barré syndrome (GBS) is the most common cause of acute paralysis in the United States. Campylobacter jejuni is a common trigger for GBS, igniting autoimmunity as a result of molecular mimicry between C. jejuni lipooligosaccharide (LOS) and host gangliosides. Evidence also suggests an active role for cell-mediated and innate immunity in pathogenesis of GBS. Infection alone is not enough for GBS to develop, infection with the same strain might yield different outcomes in different patients. C. jejuni strains with low to absent molecular mimicry to self-antigens can cause full-blown GBS with positive autoantibodies. A role for T helper 17 and IL-17 in acute phase of GBS is also identified. Currently, no biological treatment is validated for severe, ventilation-dependent patients with GBS, who might not benefit from either IVIG or plasma exchange therapy. Use of biologic agents in treatment-resistant GBS, especially anti-IL-17 agents, such as secukinumab, ixekizumab, and brodalumab, is to be hoped. This review covers up-to-date knowledge on autoimmune mechanisms responsible in different subtypes of GBS: acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy; as well as the experimental autoimmune neuritis (EAN), a commonly used animal model of GBS.

Novel evaluation of sevoflurane anesthetic exposure on the testicular germ cells of neonatal male mice.

Background: Inhalatory anesthetics may impact spermatogenesis and sexual behavior. Comprehensive evaluation should be conducted to screen the effect of inhalatory anesthetics on the sperm and semen quality. This experimental research was organized to assess the impacts of sevoflurane during the period of neonatal spermatogenesis. Materials and methods: Twenty-one pregnant mice were obtained from the Pasteur Institute. After birth, neonates were categorized based on exposure to Monitored Anesthesia Care (MAC) of sevoflurane into three groups: experimental 1, experimental 2 and control. In order to investigate the testicular condition, a histological evaluation, including apoptosis study and immunohistochemistry, was performed. Not only apoptotic target genes such as Bax and Bcl-2, but also microRNA17-92, were investigated in testicular samples via real-time polymerase chain reaction (real-time PCR). Results: The outcomes of this work indicated the effects of sevoflurane on spermatogonial and germ cells in testicular tissue via stimulating apoptotic target genes and microRNA-17-92. The proportion of Bax/Bcl-2 in the experimental group was 8.318699 ± 1.093, and the proportion of Bax/Bcl-2 in the control group was 2.631 ± 0.079. There was a significant (p ≤ 0.002) difference among the control group and both experimental groups. Conclusion: Sequential sevoflurane exposure during the neonatal period may create testicular dysfunction due to the high level of apoptosis in spermatogonial cells. Also, sevoflurane may affect spermatogenesis by influencing other biomarkers, such as microRNA.

Different Behavior and Response of Staphylococcus Epidermidis and Streptococcus Pneumoniae to a Ventriculoperitoneal Shunt: An in vitro Study.

BACKGROUND: Pneumococcal shunt infection is a rare event. There is no consensus on the therapeutic management of this kind of shunt infection according to literature reviews, and it seems to be different from infection with Staphylococcus epidermidis. We studied 2 shunted patients with pneumococcal meningitis, both of whom were treated with only antibiotics. The management of these cases seems to be different from that of shunt catheter infection due to these bacteria. We conducted a laboratory study to show the different behavior of pneumococcus compared to S. epidermidis regarding shunt catheter colonization. MATERIALS AND METHODS: S. epidermidis and Streptococcus pneumoniae bacteria isolated from the cerebrospinal fluid of meningitis patients were incubated in sterile media. Forty-five segments of shunt catheter from silicone material were placed in 45 separate media of S. epidermidis and pneumococcus. Then each catheter was washed and cultured in blood chocolate agar growth medium in separate petri dishes via the roll plate method. The dishes were extracted from the incubator and the colony count was calculated after 72 h. RESULTS: The colony count was obviously different between the 2 bacteria groups, with a higher count related to S. epidermidis dishes. The colony count of the pneumococcal petri dishes was 25-35,000 (mean 14,337) and for dishes with S. epidermidis it was 14,000-100,000 (mean 50,125) (p = 0.001). CONCLUSION: The adherence of pneumococcus to shunt catheters seems to be much less than that of S. epidermidis, which produced a very low colony count when incubated with the catheter in the medium culture. S. pneumoniae meningitis in shunted patients can be managed successfully with only antibiotics. This approach can prevent problems related to the several additional surgeries required for shunt removal, a new shunt insertion, and the management of high intracranial pressure.