Ivermectin ameliorates bleomycin-induced lung fibrosis in male rats by inhibiting the inflammation and oxidative stress.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a pulmonary fibrotic disease characterized by a poor prognosis, which its pathogenesis involves the accumulation of abnormal fibrous tissue, inflammation, and oxidative stress. Ivermectin, a positive allosteric modulator of GABAA receptor, exerts anti-inflammatory and antioxidant properties in preclinical studies. The present study investigates the potential protective effects of ivermectin treatment in rats against bleomycin-induced IPF. MATERIALS AND METHODS: The present study involved 42 male Wistar rats, which were divided into five groups: control (without induction of IPF), bleomycin (IPF-induced by bleomycin 2.5 mg/kg, by intratracheal administration), and three fibrosis groups receiving ivermectin (0.5, 1, and 3 mg/kg). lung tissues were harvested for measurement of oxidative stress [via myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH)] and inflammatory markers (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], and transforming growth factor-ß [TGF-ß]). Histological assessments of tissue damage were performed using hematoxylin-eosin (H&E) and Masson's trichrome staining methods. RESULTS: The induction of fibrosis via bleomycin was found to increase levels of MPO as well as TNF-α, IL-1ß, and TGF-ß while decrease SOD activity and GSH level. Treatment with ivermectin at a dosage of 3 mg/kg was able to reverse the effects of bleomycin-induced fibrosis on these markers. In addition, results from H&E and Masson's trichrome staining showed that ivermectin treatment at this same dose reduced tissue damage and pulmonary fibrosis. CONCLUSION: The data obtained from this study indicate that ivermectin may have therapeutic benefits for IPF, likely due to its ability to reduce inflammation and mitigate oxidative stress-induced toxicity.

Spermidine Exerts Protective Effects in Random-Pattern Skin Flap Survival in Rats: Possible Involvement of Inflammatory Cytokines, Nitric Oxide, and VEGF.

BACKGROUND: Distal necrosis and inflammation are two of the most common health consequences of random-pattern skin flaps survival (SFS). Anti-inflammatory effects of spermidine have been identified in various studies. On the other hand, considering the involvement of the nitric oxide molecule in the spermidine mode of action and also its role in skin tissue function, we analyzed the possible effects of spermidine on the SFS and also, potential involvement of nitrergic pathway and inflammatory cytokine in these phenomena. METHODS: Each rat was pretreated with either a vehicle (control) or various doses of spermidine (0.5, 1, 3, 5, 10 and 30 mg/kg) and then was executed a random-pattern skin flap paradigm. Also, spermidine at the dose of 5 mg/kg was selected and one group rats received spermidine 20 min prior to surgery and one additional dose 1 day after operation. Then, 7 days after operations, interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-gamma (IFN-γ), and nitrite levels were inquired in the tissue samples by ELIZA kit. Vascular endothelial growth factor expression was assessed by DAPI staining and fluorescent microscopes. The concentrations of three polyamines, including spermidine, spermine, and cadaverine, were analyzed using HPLC. RESULTS: Pretreatment with spermidine 5 mg/kg improved SFS considerably in microscopic skin H&E staining analysis and decreased the percentage of necrotic area. Moreover, spermidine exerted promising anti-inflammatory effects via the modulation of nitric oxide and reducing inflammatory cytokines. CONCLUSIONS: Spermidine could improve skin flaps survival, probably through the nitrergic system and inflammation pathways. This preclinical study provides level III evidence for the potential therapeutic effects of spermidine on SFS in rats, based on the analysis of animal models. Further studies are needed to confirm these findings in clinical settings. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Possible Interaction of Opioidergic and Nitrergic Pathways in the Anticonvulsant Effect of Ivermectin on Pentylenetetrazole-Induced Clonic Seizures in Mice.

Ivermectin (IVM) is an antiparasitic drug that primarily works by the activation of GABAA receptors. The potential pharmacological pathways behind the anti-convulsant effect of IVM haven't yet been identified. In this study, intravenous injection of pentylenetetrazole (PTZ)-induced clonic seizure in mice was investigated in order to assess the possible influence of IVM on clonic seizure threshold (CST). We also look at the function of the Opioidergic and nitrergic pathways in IVM anticonvulsant action on clonic seizure threshold. IVM (0.5, 1, 5, and 10 mg/kg, i.p.) raised the PTZ-induced CST, according to our findings. Furthermore, the ineffective dose of nitric oxide synthase inhibitors (L-NAME 10 mg/kg, i.p.), and (7-NI 30 mg/kg, i.p.) or opioidergic system agonist (morphine 0.25 mg/kg, i.p.) were able to amplify the anticonvulsive action of IVM (0.2 mg/kg, i.p.). Moreover, the anticonvulsant effect of IVM was reversed by an opioid receptor antagonist (naltrexone 1 mg/kg, i.p.). Furthermore, the combination of the ineffective dose of morphine as an opioid receptor agonist with either L-NAME (2 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) and with an ineffective dose of IVM (0.2 mg/kg, i.p.) had a significant anticonvulsant effect. Taken together, IVM has anticonvulsant activity against PTZ-induced clonic seizures in mice, which may be mediated at least in part through the interaction of the opioidergic system and the nitric oxide pathway.

Sildenafil improves radiation-induced oral mucositis by attenuating oxidative stress, NF-κB, ERK and JNK signalling pathways.

Radiation-induced oral mucositis is a common and dose-limiting complication of head and neck radiotherapy with no effective treatment. Previous studies revealed that sildenafil, a phosphodiesterase 5 inhibitor, has anti-inflammatory and anti-cancer effects. In this study, we investigated the effect of sildenafil on radiation-induced mucositis in rats. Two doses of radiation (8 and 26 Gy X-ray) were used to induce low-grade and high-grade oral mucositis, separately. A control group and three groups of sildenafil citrate-treated rats (5, 10, and 40 mg/kg/day) were used for each dose of radiation. Radiation increased MDA and activated NF-κB, ERK and JNK signalling pathways. Sildenafil significantly decreased MDA level, nitric oxide (NO) level, IL1ß, IL6 and TNF-α. The most effective dose of sildenafil was 40 mg/kg/day in this study. Sildenafil also significantly inhibited NF-κB, ERK and JNK signalling pathways and increased bcl2/bax ratio. In addition, high-dose radiation severely destructed the mucosal layer in histopathology and led to mucosal cell apoptosis in the TUNEL assay. Sildenafil significantly improved mucosal structure and decreased inflammatory cell infiltration after exposure to high-dose radiation and reduced apoptosis in the TUNEL assay. These findings show that sildenafil can improve radiation-induced oral mucositis and decrease the apoptosis of mucosal cells via attenuation of inflammation and oxidative stress.

The Promising Effect of Colchicine on Random-Pattern Skin Flap Survival in Rats: Glutamate Pathway.

BACKGROUND: Random-pattern skin flap is a conventional procedure in reconstructive surgery, yet partial or complete flap necrosis has remained a major issue. Herein, we investigated the potential effects of colchicine on skin flap survival through the glutamate pathway and N-methyl-D-aspartate (NMDA) receptors. METHODS: Wistar male rats were injected multiple doses of colchicine intraperitoneally (0.02, 0.05, 0.1, and 0.4 mg/kg) before the surgery. MK-801 (a noncompetitive NMDA receptor antagonist) was administered in combination with colchicine to assess the role of glutamate. Histopathological evaluation; quantitative assessment of glutamate, IL-6, and TNF-α; and the expression of NR2A-type NMDA receptors were performed in the skin tissue. RESULTS: Colchicine 0.05 mg/kg could significantly promote flap survival compared to the control group (P < 0.001), while administration of MK-801 (0.05 mg/kg) reversed the effect of colchicine (0.05 mg/kg) (P < 0.001). Levels of IL-6 and TNF-α decreased, and the expression of NR2A-type NMDA receptors was enhanced in the flap tissue of colchicine 0.05 mg/kg group compared to the controls. Also, glutamate level significantly increased after the administration of colchicine 0.05 mg/kg compared to the controls (P < 0.05). CONCLUSIONS: We found that colchicine could improve skin flap survival remarkably in rats that have undergone skin flap surgery through the glutamate pathway and NMDA receptors.

Anti-inflammatory Effects of Ivermectin in the Treatment of Acetic Acid-Induced Colitis in Rats: Involvement of GABAB Receptors.

BACKGROUND: Recent investigations have proposed the potential role of gamma-aminobutyric acid (GABA) in regulating motility and immunity of the gastrointestinal system. AIMS: We aimed to investigate the anti-inflammatory effects of ivermectin (IVM) through GABAB receptors following acetic acid-induced colitis in rats. METHODS: In a controlled experimental study, we enrolled 78 male Wistar rats (13 groups; 6 rats/group). After colitis induction using acetic acid (4%), IVM, baclofen (a standard GABAB agonist) or the combination of both agents was delivered to rats orally (by gavage), with the same dosage continued for 5 days. The control group received the vehicle, and prednisolone (a standard anti-inflammatory agent) was administered in a separate group as the positive control. Colon samples were collected on the sixth day for histopathological evaluations and measurement of myeloperoxidase (MPO) activity, TNF-α levels, and p-NF-ĸB p65, COX-2 and iNOS expression levels. RESULTS: The greatest recovery was found after administering IVM 0.5, baclofen 0.5, or IVM 0.2 + baclofen 0.2 mg/kg/day (ulcer index [UI] = 1.4 ± 0.4, 1.7 ± 0.6, and 1.4 ± 0.3, respectively; p < 0.001 vs. the control [UI = 6.5 ± 0.7]). Histopathological evaluations revealed a significant decrease in the inflammation severity in the three above-mentioned groups. P-NF-ĸB p65, COX-2, and iNOS expression, MPO activity, and TNF-α levels also decreased dramatically following treatment with IVM 0.5, baclofen 0.5, or the combination therapy (p < 0.001 vs. the control). CONCLUSIONS: IVM exerted promising anti-inflammatory effects in treating acetic acid-induced colitis in rats. Its synergistic effect with baclofen also signified the possible involvement of GABAB receptors in this process.

Aquaporins and diseases pathogenesis: From trivial to undeniable involvements, a disease-based point of view.

Aquaporins (AQPs), as transmembrane proteins, were primarily identified as water channels with the ability of regulating the transmission of water, glycerol, urea, and other small-sized molecules. The classic view of AQPs involvement in therapeutic plan restricted them and their regulators into managing only a narrow spectrum of the diseases such as diabetes insipidus and the syndrome of inappropriate ADH secretion. However, further investigations performed, especially in the third millennium, has found that their cooperation in water transmission control can be manipulated to handle other burden-imposing diseases such as cirrhosis, heart failure, Meniere's disease, cancer, bullous pemphigoid, eczema, and Sjögren's syndrome.

Ivermectin Increases Random-Pattern Skin Flap Survival in Rats: The Novel Role of GABAergic System.

BACKGROUND: Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. METHODS: Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5 mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1ß and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. RESULTS: IVM 0.05 mg/kg could significantly increase flap survival compared with the control group (P < 0.001). Subeffective dose of baclofen (0.1 mg/kg) had synergistic effect with the subeffective dose of IVM (0.01 mg/kg) (P < 0.001), whereas bicuculline 1 mg/kg reversed the effect of IVM (0.05 mg/kg) (P < 0.001). IVM 0.05 mg/kg could also decrease the IL-1ß and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. CONCLUSIONS: IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."

Beyond its anti-migraine properties, sumatriptan is an anti-inflammatory agent: A systematic review.

Sumatriptan is the first available medication from triptans family that was approved by the U.S. Food and Drug Administration for migraine attacks and cluster headaches in 1991. Most of its action is mediated by selective 5-HT1B/1D receptor agonism. Recent investigations raised the possibility of repositioning of this drug to other indications beyond migraine, as increasing evidence suggests for an anti-inflammatory property of sumatriptan. We performed a literature search using PubMed, Web of Science, Scopus, and Google Scholar using "inflammation AND sumatriptan" or "inflammation AND 5HT1B/D" as the keywords. Then, articles were screened for their relevance and those directly discussing the correlation between inflammation and sumatriptan or 5HT1B/D were included. Total references reviewed or inclusion/exclusion were 340 retrieved full-text articles (n = 340), then based on critical assessment 66 of them were included in this systematic review. Our literature review indicates that at low doses, sumatriptan can reduce inflammatory markers (e.g., interleukin-1ß, tumor necrosis factor-α, and nuclear factor-κB), affects caspases and changes cells lifespan. Additionally, nitric oxide synthase and nitric oxide signaling seem to be regulated by this drug. It also inhibits the release of calcitonin gene-related peptide. Sumatriptan protects against many inflammatory conditions including cardiac and mesenteric ischemia/reperfusion, skin flap, pruritus, peripheral, and central nervous system injuries such as spinal cord injury, testicular torsion-detorsion, oral mucositis, and other experimental models. Considering the safety and potency of low dose sumatriptan compared to corticosteroids and other immunosuppressive medications, it is worth to take advantage of sumatriptan in inflammatory conditions.

Sodium Valproate Improves Skin Flap Survival via Gamma-Aminobutyric Acid and Histone Deacetylase Inhibitory System.

Sodium valproate interacts with biological systems through different mechanisms such as activation of gamma-aminobutyric acid (GABA)-sensitive chloride channels and inhibition of histone deacetylase. In this study, we examined the effect of sodium valproate in random-pattern skin flap of rats and investigated its mechanisms of action. Different types of experiments were carried out. In acute treatment, different doses of sodium valproate (50, 100, 150, 300 mg/kg) were injected intraperitoneally 1 h before surgery. In chronic treatment, the substance was injected each day for 2 wk. The size of skin necrosis was measured 1 wk after the surgery. The rate of secondary healing, amount of weight gain, hair growth, and wound regeneration were measured 2 wk after operation. In acute treatment, sodium valproate (100 mg/kg) reduced significantly the length of skin necrosis (P < 0.05). Administration of bicuculline (competitive antagonist of GABAA, 20 mg/kg) increased the length of skin necrosis (P < 0.05). In addition, administration of 100 mg/kg of sodium valproate and subeffective dose of bicuculline (10 mg/kg) prevented the protective effect of sodium valproate on skin flap necrosis (P < 0.05). In the chronically treated skin flap group, 100 mg/kg of sodium valproate reduced the length of necrosis (P < 0.01). Weight gain in the valproate group was more than that in the control group (P < 0.05). Skin also healed faster in the sodium valproate group than in the control group (P < 0.001). Combination therapy of sodium valproate and trichostatin A (330 nmol/kg) reversed the effect of valproate (P < 0.05). This study demonstrate that sodium valproate accelerates skin secondary healing in a rat model of skin flap probably through a GABA and histone deacetylase-dependent mechanism.

The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression.

BACKGROUND: Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-macrophage stimulating factor (GM-CSF) could interfere with the induction of IDO in septic patients. We hypothesized that GM-CSF could exert antidepressant effects through IDO downregulation in a model for acute inflammation-induced depression. METHODS: To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. It has been well documented that LPS mediates IDO overexpression through TLR4/NF-ĸB signaling. In the treatment group, mice received GM-CSF (30 µg/kg, i.p.) thirty minutes prior to LPS injection. A validated selective serotonin reuptake inhibitor, fluoxetine (30 mg/kg i.p.), was also administered to an experimental group 30 min prior to LPS. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. To confirm that GM-CSF interferes with IDO induction in LPS treated mice, real-time PCR was used to quantify IDO mRNA expression. Furthermore, in order to study whether GM-CSF inhibits the TLR4/NF-ĸB signaling pathway, we measured levels ofpNF-ĸB and TLR4 by western blotting. RESULTS: GM-CSF demonstrated significant antidepressant activity in the presence of LPS on immobility (p < .001) and latency (p = .010) times in the forced swim test. In contrast, fluoxetine did not show any antidepressant activity on either immobility (p = .918) or latency (p = .566) times. Furthermore, GM-CSF inhibited the increase in IDO mRNA (p = .032) and protein (p = .016) expression as a result of LPS administration. A similar trend was observed for TLR4 (p = .042) and pNF-ĸB (p = .026) expression as both proteins showed reduced expression levels in the GM-CSF-pretreated group compared to the untreated (LPS) group. CONCLUSION: Our results propose a promising antidepressant effect for GM-CSF possibly through the downregulation of IDO expression. This remedying effect of GM-CSF could be attributed to decreased amounts of TLR4 and active NF-ĸB in the treated mice.

Pregnancy outcome in patients with non-alcoholic fatty liver disease: a prospective cohort study.

Aim: The purpose of this investigation was to examine the potential association between non-alcoholic fatty liver disease (NAFLD) and adverse maternal and perinatal outcomes during pregnancy. Background: Gaining insights into the effect of NAFLD on pregnancy outcomes is essential to ensure the health and well-being of mothers and infants. Methods: This prospective cohort study was conducted at Imam Khomeini and Razi hospitals of Ahvaz City in 2022. Totally, 180 pregnant women in the NAFLD group to 180 in the control group. In this study, a researcher-made checklist was used to collect the background information, medical history, and lab data during their initial visit using. Follow-up continued until one week after delivery, with pregnancy outcomes assessed. Statistical analysis used student's t-test and the Chi-Square test for group comparisons. Results: Significant differences were observed between the NAFLD, and control groups in terms of age (P=0.003), BMI (P=0.016), ALT and AST measures (P<0.001), and hypertensive complications (P=0.044). The NAFLD group had higher rates of gestational diabetes (P<0.001) and gestational hypertension (P=0.003). However, no significant differences were found in gestational age at delivery, early postpartum hemorrhage rates, birth weight, and neonatal Apgar scores (P>0.05). Conclusion: The pregnant women with NAFLD may be at risk for various complications during pregnancy, including a higher prevalence of gestational diabetes, elevated liver enzymes, and higher blood pressure compared to healthy pregnant women. However, the research failed to identify any statistically significant disparities between infants born to mothers with NAFLD and those delivered to healthy mothers in relation to birth weight, Apgar scores, or neonatal mortality.

Mechanisms underlying dose-limiting toxicities of conventional chemotherapeutic agents.

Dose-limiting toxicities (DLTs) are severe adverse effects that define the maximum tolerated dose of a cancer drug. In addition to the specific mechanisms of each drug, common contributing factors include inflammation, apoptosis, ion imbalances, and tissue-specific enzyme deficiencies. Among various DLTs are bleomycin-induced pulmonary fibrosis, doxorubicin-induced cardiomyopathy, cisplatin-induced nephrotoxicity, methotrexate-induced hepatotoxicity, vincristine-induced neurotoxicity, paclitaxel-induced peripheral neuropathy, and irinotecan, which elicits severe diarrhea. Currently, specific treatments beyond dose reduction are lacking for most toxicities. Further research on cellular and molecular pathways is imperative to improve their management. This review synthesizes preclinical and clinical data on the pharmacological mechanisms underlying DLTs and explores possible treatment approaches. A comprehensive perspective reveals knowledge gaps and emphasizes the need for future studies to develop more targeted strategies for mitigating these dose-dependent adverse effects. This could allow the safer administration of fully efficacious doses to maximize patient survival.

The dose-limiting toxicity of most anticancer drugs occurs via the activation of inflammatory/apoptosis/ROS pathways.Regarding the dose-limiting toxicity of most anticancer drugs, there is no specific treatment other than discontinuation or dose reduction.Accurately identifying the molecular pathways involved in the dose-limiting toxicity of anticancer drugs can help to identify new treatments.

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.

Therapeutic potential of bromhexine for acute itch in mice: Involvement of TMPRSS2 and kynurenine pathway.

Itching is an unpleasant sensation on the skin that could negatively impact the quality of life. Over the years, many non-pharmacological and pharmacological approaches have been introduced to mitigate this burdensome condition; However, the effectiveness of these methods remains questioned. Bromhexine, derived from the Adhatoda vasica plant, is a safe drug with minimal side effects. It has been widely used in managing respiratory symptoms over the years. The results of our study revealed that bromhexine has the potential to alleviate acute itch induced by Compound 48/80, a known mast cell destabilizer. According to our findings, bromhexine exerts its antipruritic effects primarily by inhibiting the Transmembrane Protein Serine Protease 2 (TMPRSS2) and, to a lesser extent, by decreasing the activation of the Kynurenine Pathway (KP). We further investigated the KP involvement by administrating 1-Methyl Tryptophan (1-MT), a known indoleamine-2,3-dioxygenase (IDO) inhibitor. 1-MT was found to be effective in reducing the itch itself. Moreover, co-administration of bromhexine and 1-MT resulted in synergistic antipruritic effects, suggesting that KP plays a role in acute itch. To conclude, we have presented for the first time a repositioning of bromhexine as a treatment for acute itch. In addition, we addressed the involvement of TMPRSS2 and KP in this process.

Low-dose sumatriptan improves the outcome of acute mesenteric ischemia in rats via downregulating kynurenine.

BACKGROUND: Mesenteric ischemia has remained without effective pharmacological management for many years. Sumatriptan, an abortive medication for migraine and cluster headaches, has potent anti-inflammatory properties and ameliorated organ ischemia in previous animal studies. Similarly, inhibition of the kynurenine pathway ameliorated renal and myocardial ischemia/reperfusion (I/R) in many preclinical studies. Herein, we assessed the effect of sumatriptan on experimental mesenteric I/R and investigated whether kynurenine pathway inhibition is a mechanism underlying its action. METHODS: Ischemia was induced by ligating the origin of the superior mesenteric artery (SMA) and its anastomosis with the inferior mesenteric artery (IMA) with bulldog clamps for 30 min. Ischemia was followed by 1 h of reperfusion. Sumatriptan (0.1, 0.3, and 1 mg/kg ip) was injected 5 min before the reperfusion phase, 1-methyltryptophan (1-MT) (100 mg/kg iv) was used to inhibit kynurenine production. At the end of the reperfusion phase, samples were collected from the jejunum of rats for H&E staining and molecular assessments. RESULTS: Sumatriptan improved the integrity of intestinal mucosa after I/R, and 0.1 mg/kg was the most effective dose of sumatriptan in this study. Sumatriptan decreased the increased levels of TNF-α, kynurenine, and p-ERK but did not change the decreased levels of NO. Furthermore, sumatriptan significantly increased the decreased ratio of Bcl2/Bax. Similarly, 1-MT significantly decreased TNF-α and kynurenine and protected against mucosal damage. CONCLUSIONS: This study demonstrated that sumatriptan has protective effects against mesenteric ischemia and the kynurenine inhibition is potentially involved in this process. Therefore, it can be assumed that sumatriptan has the potential to be repurposed as a treatment for acute mesenteric ischemia.

Emerging roles of long non-coding RNA FTX in human disorders.

Long non-coding RNAs (lncRNAs) are involved the progression of cancerous and non-cancerous disorders via different mechanism. FTX (five prime to xist) is an evolutionarily conserved lncRNA that is located upstream of XIST and regulates its expression. FTX participates in progression of various malignancy including gastric cancer, glioma, ovarian cancer, pancreatic cancer, and retinoblastoma. Also, FTX can be involved in the pathogenesis of non-cancerous disorders such as endometriosis and stroke. FTX acts as competitive endogenous RNA (ceRNA) and via sponging various miRNAs, including miR-186, miR-200a-3p, miR-215-3p, and miR-153-3p to regulate the expression of their downstream target. FTX by targeting various signaling pathways including Wnt/ß-catenin, PI3K/Akt, SOX4, PDK1/PKB/GSK-3ß, TGF-ß1, FOXA2, and PPARγ regulate molecular mechanism involved in various disorders. Dysregulation of FTX is associated with an increased risk of various disorders. Therefore, FTX and its downstream targets may be suitable biomarkers for the diagnosis and treatment of human malignancies. In this review, we summarized the emerging roles of FTX in human cancerous and non-cancerous cells.

Cannabidiol Anticonvulsant Effects Against Lithium-Pilocarpine-Induced Status Epilepticus in Male Rats Are Mediated by Neuroinflammation Modulation and Cannabinoids 1 (CB1), But Not CB2 and GABAA Receptors.

Background: Status epilepticus (SE) is a series of seizures that can lead to serious neurological damages. Cannabidiol (CBD) is extracted from the cannabis plant, which has been approved as an antiseizure medication. This study aimed to determine the efficacy of various doses of CBD on lithium-pilocarpine-induced SE in rats and possible involvement of multiple pharmacological pathways. We hypothesized that cannabinoid receptors type 1 (CB1) and CB2, as well as GABAA receptors, might have important roles in the anticonvulsant effects of CBD against SE by its anti-inflammatory effects. Methods: SE was induced by intraperitoneal (i.p.) injection of lithium (127 mg/kg, i.p.) and pilocarpine (60 mg/kg, i.p., 20 h after lithium). Forty-two male rats were divided into seven groups (including control and sham groups), and the treated groups received different doses of CBD (1, 3, 5, 10, and 25 mg/kg, i.p.). SE score was recorded over the next 2 h following pilocarpine injection. Then, we measured the levels of pro-inflammatory cytokines, including interleukin (IL)-lß and tumor necrosis factor (TNF)-α, using ELISA kits. Also we analyzed the expression of CB1, CB2, and GABAA receptors using the Western blot technique. Results: CBD at 5 mg/kg significantly reduced Racine's scale and duration of seizures, and increased the onset time of seizure. Moreover, CBD 5 mg/kg caused significant reductions in the elevated levels of IL-lß and TNF-α, as well as a significant increase in the decreased level of CB1 receptor expression compared to the control group. In other word, CBD reverted the effects of SE in terms of neuroinflammation and CB1 receptor. Based on the obtained results, CBD was not able to restore the declined levels of CB2 or GABAA receptors. Conclusion: Our study found anticonvulsant effects of CBD on the SE rat model induced by lithium-pilocarpine with probable involvement of CB1 receptors and anti-inflammatory effects by reducing IL-1ß and TNF-α markers independent of CB2 and GABAA receptors.

Functional Roles of lncRNAs in Recurrent Pregnancy Loss: A Review Study.

Recurrent pregnancy loss (RPL) or recurrent miscarriage is the failure of pregnancy before 20-24 weeks that influences around 2-5% of couples. Several genetic, immunological, environmental and physical factors may influence RPL. Although various traditional methods have been used to treat post-implantation failures, identifying the mechanisms underlying RPL may improve an effective treatment. Recent evidence suggested that gene expression alterations presented essential roles in the occurrence of RPL. It has been found that long non-coding RNAs (lncRNAs) play functional roles in pregnancy pathologies, such as recurrent miscarriage. lncRNAs can function as dynamic scaffolds, modulate chromatin function, guide and bind to microRNAs (miRNAs) or transcription factors. lncRNAs, by targeting various miRNAs and mRNAs, play essential roles in the progression or suppression of RPL. Therefore, targeting lncRNAs and their downstream targets might be a suitable strategy for diagnosis and treatment of RPL. In this review, we summarized emerging roles of several lncRNAs in stimulation or suppression of RPL.

The N-methyl-D-aspartate receptor antagonist ketamin exerts analgesic effects via modulation of the nitric oxide pathway.

Ketamine, an NMDA receptor antagonist, has been approved to have analgesic effects. It is known that nitric oxide pathway is involved in antinociception but with dual effects. In this study, we investigated the role of nitric oxide in ketamine-induced analgesia. Ketamine was administered to mice acute and chronically with/without nitric oxide synthase (NOS) inhibitors. Experimental models of nociception pain, including hot plate, tail flick, and formalin tests, were performed. Western blot was used to measure levels of nitric oxide synthase enzymes in the brain. Ketamine doses of 0.03 and 0.3 mg/kg had significant analgesic effects (p < 0.01). High-dose chronic ketamine could induce analgesia in later phases of the treatment in tail flick test (p < 0.01). Pretreatment with various NOS inhibitors decreased the analgesic effect. In western blot analysis, the expression of NOS proteins was decreased. Low-dose ketamine is effective in analgesia induction. The expression of nNOS and iNOS proteins is dependent on the inhibition of the NMDA/NO pathway.