Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway.

OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway. MATERIAL AND METHODS: Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription -3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule -1(ICAM-1) and caspase-3 genes were measured in tissue. RESULTS: Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group. CONCLUSION: It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers.

Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho- or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3- and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr)4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.

Trifluoperazine mitigates cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in mice by modulating the AKT/mTOR-driven autophagy and Nrf2/HO-1 signaling cascades.

AIM: This study aims to investigate the hepatoprotective effect of the antipsychotic drug trifluoperazine (TFP) against cyclophosphamide (CPA)-induced hepatic injury by exploring its effect on autophagy and the Nrf2/HO-1 signaling pathway. MAIN METHODS: The hepatotoxicity of CPA was assessed by biochemical analysis of the serum hepatotoxicity markers (ALT, AST, and direct bilirubin), histopathological examination, and ultrastructure analysis by transmission electron microscopy (TEM). The ELISA technique was used to assess the hepatic content of oxidative stress (MDA and SOD) and inflammatory markers (IL-1ß and TNF-α). Immunohistochemical assessment was used to investigate the hepatic expression of NF-κB, Nrf2, caspase-3, as well as autophagy flux markers (p62 and LC3B). The mRNA expression of HO-1 was assessed using RT-qPCR. Western blot assay was used to determine the expression of p-AKT and p-mTOR. KEY FINDINGS: TFP improved CPA-induced hepatotoxicity by reducing the elevated hepatotoxicity markers, and alleviating the histopathological changes with improving ultrastructure alterations. It also reduced oxidative stress by reducing MDA content and upregulating SOD activity. In addition, it exhibited anti-inflammatory and anti-apoptotic effects by decreasing NF-κB expression, IL-1ß, TNF-α levels, and caspase-3 expression. Furthermore, TFP-induced hepatoprotection was mediated by favoring Nrf2 expression and increasing the mRNA level of HO-1. As well, it improved autophagy by increasing LC3B expression concurrently with reducing p62 expression. Moreover, TFP modulated the AKT/mTOR pathway by reducing the expression of p-AKT and p-mTOR. SIGNIFICANCE: TFP significantly protected against CPA-induced hepatotoxicity by upregulating Nrf2/HO-1 signaling along with enhancement of protective autophagy via inhibition of the AKT/mTOR signaling pathway.

The emerging role of α7nAChRs/caspase-3/Nrf-2 signaling pathway in citicoline improved autistic behavior induced by thimerosal in mice.

AIMS: Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD. MATERIALS AND METHODS: The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 µg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers. KEY FINDINGS: Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1ß). The drug also increased the brain GPx activity. SIGNIFICANCE: Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

Potential Antitumor Activity of Combined Lycopene and Sorafenib against Solid Ehrlich Carcinoma via Targeting Autophagy and Apoptosis and Suppressing Proliferation.

An FDA-approved kinase inhibitor called sorafenib (SOR) is used to treat primary kidney and liver cancer as well as to stop the spread of advanced breast cancer. Side effects from SOR, such as palmar-plantar erythrodysesthesia syndrome, can negatively impact an individual's quality of life. There are a lot of data supporting the importance of lycopene (LYC) in preventing cancer. The antitumor properties of the combination of sorafenib and lycopene were examined in this study. A viability test against MDA-MB-231 was used to assess the anticancer efficacy of sorafenib, lycopene, and their combination in vitro. Moreover, a cell cycle analysis and Annexin-V/PI double staining were performed by using flow cytometry. In addition, the protein level of JNK-1, ERK-1, Beclin-1, P38, and P53 of the MDA-MB-231 cell line was estimated using ELISA kits. In addition, mice with SEC were divided into four equal groups at random (n = 10) to investigate the possible processes underlying the in vivo antitumor effect. Group IV (SEC-SOR-LYC) received SOR (30 mg/kg/day, p.o.) and LYC (20 mg/kg/day, p.o.); Group I received the SEC control; Group II received SEC-SOR (30 mg/kg/day, p.o.); and Group III received SEC-LYC (20 mg/kg/day, p.o.). The findings demonstrated that the combination of sorafenib and lycopene was superior to sorafenib and lycopene alone in causing early cell cycle arrest, suppressing the viability of cancer cells, and increasing cell apoptosis and autophagy. Likewise, the combination of sorafenib and lycopene demonstrated inhibition of the levels of Bcl-2, Ki-67, VEGF, IL-1ß, and TNF-α protein. Otherwise, the quantities of the proteins BAX, P53, and caspase 3 were amplified. Furthermore, the combined treatment led to a substantial increase in TNF-α, caspase 3, and VEGF gene expression compared to the equivalent dosages of monotherapy. The combination of sorafenib and lycopene enhanced apoptosis and reduced inflammation, as seen by the tumor's decreased weight and volume, hence demonstrating its potential anticancer effect.

Evaluation of the effect of direct-acting antiviral agents on melatonin level and lipid peroxidation in chronic hepatitis C patients.

Background: Oxidative stress and its end products, such as malondialdehyde (MDA) play a leading role in the pathogenesis of hepatitis C. Melatonin is a hormone that helps regulate circadian rhythms, which likely play a role in infectious diseases in terms of susceptibility, clinical expression, and outcome. Objective: The present study was conducted to assess serum malondialdehyde and melatonin levels in patients with chronic hepatitis C infection before and after the intake of direct-acting antivirals. Method: Forty hepatitis C patients were the subjects of this study. While ten healthy volunteers who matched in age and socioeconomic status served as the control subjects. Malondialdehyde and melatonin were assayed in the serum of the three groups, and the results were statistically analyzed. Results: Hepatitis C patients had significantly higher malondialdehyde (p < 0.001) but significantly lower melatonin (p < 0.001) as compared to the healthy controls. After 12 weeks of treatment with direct-acting antivirals, the malondialdehyde level decreased significantly (p < 0.001) and the melatonin level increased significantly (p < 0.001). A significant negative correlation between malondialdehyde and melatonin was observed. Conclusion: The present findings suggest that treatment of hepatitis C patients with Direct-acting antivirals improves liver function parameters and antioxidant profiles.

Protective role of naftidrofuryl against methotrexate-induced testicular damage via the amelioration of the p53/miRNA-29a/CDC42 apoptotic pathway, inflammation, and oxidative stress.

This study aimed to assess the possible protective effects of naftidrofuryl (Naf) against methotrexate (MTX)-induced testicular toxicity in rats. Male rats were randomly distributed into four groups: control, Naf, MTX, and MTX+Naf groups. MTX administration induced oxidative stress, inflammation, and apoptosis in the testicular tissue, while pretreatment with Naf attenuated these pathways. Naf pretreatment significantly decreased malondialdehyde and interleukin-6 contents, microRNA-29a (miRNA-29a) expression level, and nuclear factor kappa B and p53 immunostaining in the testicular tissues compared to the MTX group. Conversely, it significantly increased Johnsen's score, serum testosterone level, serum total antioxidant capacity, testicular superoxide dismutase activity, testicular catalase activity, and testicular cell division cycle 42 (CDC42) expression compared to the MTX group. In conclusion, Naf exerted a significant protective effect against MTX-induced testicular toxicity via antioxidant and anti-inflammatory mechanisms and modulating the p53/miRNA-29a/CDC42 apoptotic pathway.

Dapagliflozin mitigates ovalbumin-prompted airway inflammatory-oxidative successions and associated bronchospasm in a rat model of allergic asthma.

BACKGROUND: Asthma is a chronic inflammatory lung disease that universally affects millions of people. Despite numerous well-defined medications, asthma is poorly managed. This study aims to clarify the potential therapeutic effect of Dapagliflozin (DAPA) against lung inflammation, oxidative stress, and associated bronchospasm in OVA-sensitized rat asthma model. RESEARCH DESIGN AND METHODS: Twenty-five rats were allocated into (Control, Asthma, DEXA, DAPA, and DAPA+DEXA). All treatments were administered orally once a day for two weeks. The BALF levels of IL-17, TNFα, IL-1ß, and MCP-1 were determined to assess airway inflammation. For oxidative stress determination, BALF MDA levels and TAC were measured. The BALF S100A4 level and NO/sGC/cGMP pathway were detected. Lung histopathological findings and immunohistochemical investigation of eNOS and iNOS activities were recorded. RESULTS: DAPA significantly reduced (p < 0.001) airway inflammatory-oxidative markers (IL-17, TNFα, IL-1ß, MCP1, and MDA), but increased (p < 0.001) TAC, and mitigated bronchospasm by activating NO/sGC/cGMP and reducing S100A4 (p < 0.001). The biochemical and western blot studies were supported by histopathological and immunohistochemical investigations. CONCLUSIONS: DAPA presents a new prospective possibility for future asthma therapy due to its anti-inflammatory, anti-oxidant, and bronchodilator properties. DAPA has the property of reducing Dexamethasone (DEXA)-associated unfavorable effects during asthma treatment.

Dipyridamole induces the phosphorylation of CREB to promote cancer cell proliferation.

Dipyridamole, a traditional anti-platelet drug, has been reported to inhibit the proliferation of cancer cells. The present study aimed to investigate the possibility of dipyridamole as an adjuvant of chemotherapy by enhancing the cytotoxicity of an anti-cancer drug. The cytotoxicity of colorectal cancer cells (HCT-8), CD133+/CD44+ stem-like subpopulation of HCT-8 cells and lymphoma cells (U937) to dipyridamole and/or doxorubicin was evaluated using MTT proliferation and colony forming assays. The expression levels of phosphorylated cAMP-regulatory element-binding protein (pCREB) and poly(ADP-ribose) polymerase-1 (PARP-1) in cells were analyzed via western blotting and immunofluorescence. The present study reported controversial data regarding the anti-cancer effect of dipyridamole. Dipyridamole increased, rather than inhibited, the proliferation of HCT-8 and U937 cells in a dose-dependent manner. Furthermore, it was found that dipyridamole significantly increased the expression levels of pCREB and PARP-1. However, the combined usage of dipyridamole significantly enhanced the cytotoxicity of doxorubicin to HCT-8 cells at particular doses. Based on the current findings, dipyridamole likely induces the phosphorylation of CREB to promote the proliferation of cancer cells, but may enhance the cytotoxicity of anti-cancer drugs at particular doses.

Nicaraven prevents the fast growth of inflamed tumors by an anti-inflammatory mechanism.

Inflammatory microenvironment is known to accelerate the progression of malignant tumors. We investigated the possible anti-inflammatory effect of nicaraven on slowing tumor growth. Tumor-bearing mice randomly received nicaraven injection (50 mg/kg daily, i.p, n = 8) or placebo treatment (n = 8) for 10 days, and then sacrificed for evaluations. Nicaraven administration effectively inhibited the fast growth of tumor, as a large tumor (> 1.0 g) developed finally in three of the eight mice received placebo treatment. Cytokines/chemokines array indicated that nicaraven reduced the levels of CXCL10 and SDF-1 in the tumor as well as the levels of IL-2 and MIP-2 in serum. Immunofluorescence staining showed that nicaraven significantly reduced the recruitment of macrophages and neutrophils in the tumor. Interestingly, western blot indicated that the expression of CD86, CD206, and NIMP-R14 was especially enhanced in the three large-size tumors, suggesting the potential role of nicaraven in preventing the hyper-inflammatory tumor microenvironment. Moreover, the expression of PARP-1 was downregulated, but the expression of phospho-p38 MAPK, phospho-MKK-3/6, and phospho-MSK-1 was upregulated in the large-size tumors, suggesting the involvement of p38 MAPK pathway in the anti-inflammatory effect of nicaraven. Taken together, our study suggests that nicaraven may effectively prevent the fast growth of inflamed tumors by an anti-inflammatory mechanism.

Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti-inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra-rectal administration of oxazolone in the 5th and 7th days after pre-sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-13, signal transducer and activator of transcription-3 (STAT-3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL-10, tight junction protein zonula occludens (ZO-1), and caspase-3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL-13, IL-6, TNF-α, STAT-3, caspase-3, and MPO activity and significantly increased IL-10, ZO-1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti-inflammatory effects possibly by restoring IL-10 and ZO-1 levels and limiting IL-6/STAT-3 trans-signaling.

Role of allopurinol and febuxostat in the amelioration of dextran-induced colitis in rats.

Ulcerative colitis is a chronic auto-inflammatory disorder confined to the colorectal region. It is challenging to find an absolute treatment and current therapy aims to ameliorate symptoms, decrease relapses and prevent prognosis of colorectal cancer. In the present study, we investigated the possible action of xanthine oxidase inhibitors in murine colitis model by measuring different indicative parameters and comparing the results to those of the reference sulfasalazine. Also, we compared the effects of combining sulfasalazine and allopurinol to each drug alone. Dextran Sodium Sulfate (DSS) is used in this study to induce ulcerative colitis in male wistar rats as it is known to be the closest model that mimics human ulcerative colitis. Allopurinol was given prior to colitis induction by four days and febuxostat for six days before induction with DSS (5% w/v) and continue to give them concomitantly during the induction.Il-1ß, malondialdehyde, reduced glutathione (GSH), xanthine oxidase, and superoxide dismutase were measured in colonic tissue. We also measured concentrations of IL-1ß, Il-6 and uric acid in serum. Allopurinol dose-dependently ameliorated biochemical injuries. Febuxostat has shown better results than allopurinol and sulfasalazine, and this is the first study to demonstrate this.

Evaluation of salicylic acid peeling in comparison with topical tretinoin in the treatment of postinflammatory hyperpigmentation.

BACKGROUND: Postinflammatory hyperpigmentation (PIH) is an acquired hyperpigmentation that involves areas of prior cutaneous inflammation. In addition to prevention, there are a variety of medications and procedures used to treat PIH. AIM OF THE WORK: The aim of this work was to evaluate the efficacy, tolerability, and safety of salicylic acid peeling in comparison with topical tretinoin in the treatment of PIH. PATIENTS AND METHODS: This study included forty-five patients with PIH lesions. The patients were divided into three groups, group I was treated with salicylic acid peeling 20-30%, group II was treated with topical tretinoin 0.1%, and group III was treated with combination of salicylic acid peel and topical tretinoin. The patients were assessed clinically to evaluate the efficacy, tolerability, and safety of the treatment. Dermoscopy was carried out to the recurrent or nonimproved cases only. RESULTS: Combination of salicylic acid peel and topical tretinoin treatment showed significant clinical improvement of PIH than each treatment alone with no complications. There was no significant difference in the recurrence rate between the three groups. There was nonsignificant difference between the efficacy of the treatment and the PIH type in the studied groups. There was nonsignificant difference between the efficacy of the treatment and the duration of the PIH except for group III. CONCLUSION: Combination treatment modality is believed to be preferred in the treatment of PIH due to its higher efficacy than single treatment alone, with well tolerability, less side effects, and low recurrence rate.

Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocin-induced diabetic model.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-ß 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N=48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-ß1, IL-1ß, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-ß1, IL-1ß, Proteinuria and AGEPs and significant increase in SOD and NO. The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.

Bone marrow mononuclear cells enhance anti-inflammatory effects of pravastatin against isoproterenol-induced myocardial infarction in rats.

The current study investigated the combinatorial effect of pravastatin (PRAV) and bone marrow mononuclear cells (BM-MNC) on acute myocardial infarction (AMI) induced experimentally in rats. After induction of MI, rats were given oral PRAV (20 mg/kg/day) for 28 days or a bolus intravenous injection (via lateral vein) of a total of 14 × 10(6) autologous BM-MNC or a combination of both. Serum brain natriuretic peptide (BNP) and histologic changes in cardiac tissues were assessed. Cardiac contents of lipid peroxides, superoxide dismutase (SOD) and inflammatory biomarkers including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß as well as vascular endothelial growth factor (VEGF) and nitric oxide (NO) were also measured. Combined PRAV and BM-MNC treatment significantly suppressed serum BNP. Cardiac cell apoptosis and inflammatory cell infiltration in heart tissue decreased significantly in both the PRAV and the PRAV + BM-MNC groups. Cardiac lipid peroxides along with TNFα and IL-1ß levels were significantly reduced in both the PRAV and PRAV + BM-MNC hosts with an increase in SOD levels. However, the combined treatment increased cardiac NO levels and did not modify cardiac VEGF levels. The current results indicated that administration of BM-MNC improved the therapeutic efficacy of PRAV treatment by improving the morphology of infarcted hearts as well as decreasing inflammation in a host, but did not do so by inducing therapeutic angiogenesis.

Histamine protects against the acute phase of experimentally-induced hepatic ischemia/re-perfusion.

Histamine, involved in many inflammatory reactions and immune responses, is reported to suppress--via H4R stimulation--injury concomitant with the late phase of warm hepatic ischemia/re-perfusion (I/R). The current study investigated the possible effects of histamine on the acute phase of hepatic I/R injury, and the possible underlying mechanisms like oxidative stress and release of inflammatory cytokines (e.g., tumor necrosis factor (TNF)-α nd interleukin [IL]-12). Rats were divided into naïve, sham-operated, and I/R groups. The I/R group was divided into sub-groups and pre-treated with histaminergic ligands before induction of ischemia. Anesthetized rats were subjected to warm ischemia for 30 min by occlusion of the portal vein and hepatic artery, then re-perfused for 90 min. Rats in the control I/R group showed significant increases in hepatic malondialdehyde (MDA), TNFα, and IL-12 contents, and in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, along with significant decreases in hepatic reduced glutathione (GSH) content and marked diffuse histopathologic damage. Pre-treatment with histamine resulted in significant mitigation of each of these end-points. The protective effect of histamine was not antagonized by pre-treatment with mepyramine (H1R antagonist) or ranitidine (H2R antagonist) and completely reversed by pre-treatment with thioperamide (H3R and H4R antagonist). In addition, the histamine protective effect was mimicked by pre-treatment of rats with clozapine (H4R agonist). These observations strongly suggested that histamine has a protective effect against hepatic I/R-mediated tissue injury during the acute phase, and this effect was mediated through an H4R stimulation that led to a decrease in IL-12 and TNFα production--outcomes that consequently decreased localized oxidative stress and afforded hepatic protection in general.