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Dina S El-Agamy,1,2 Khaled M El-Harbi,3 Saad Khoshhal,3 Nishat Ahmed,1 Mohamed A Elkablawy,4,5 Ahmed A Shaaban,2,6 Hany M Abo-Haded3,7 1Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; 3Cardiogenetic Team, Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 4Department of Pathology, Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah 30001, Saudi Arabia; 5Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt; 6Department of Pharmacology, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan; 7Pediatric Cardiology Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt Background/purpose: Pristimerin (Pris) is triterpenoid compound with many biological effects. Until now, nothing is known about its effect on doxorubicin (DOX)-induced cardiotoxicity. Hence, this study investigated the impact of Pris on DOX-induced cardiotoxic effects. Materials and methods: Rats were treated with Pris 1 week before and 2 weeks contaminant with repeated DOX injection. Afterwards, electrocardiography (ECG), biochemical, histopathological, PCR, and Western blot assessments were performed. Results: Pris effectively alleviated DOX-induced deleterious cardiac damage. It inhibited DOX-induced ECG abnormities as well as DOX-induced elevation of serum indices of cardiotoxicity. The histopathological cardiac lesions and fibrosis were remarkably improved in Pris-treated animals. Pris reduced hydroxyproline content and attenuated the mRNA and protein expression of the pro-fibrogenic genes. The antioxidant activity of Pris was prominent through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, Pris enhanced the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway as it increased the mRNA and protein expression of Nrf2 and Nrf2-dependent antioxidant genes (GCL, NQO1, HO-1). Additionally, the anti-inflammatory effect of Pris was obvious through the inhibition of mitogen activated protein kinase (MAPK)/nuclear factor kappa-B (NF-kB) signaling and subsequent inhibition of inflammatory mediators. Conclusion: This study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways. Keywords: doxorubicin, pristimerin, cardiotoxicity, Nrf2, MAPK/NF-kB

Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20 mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75 mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneficial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver., 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 Elsevier B.V. All rights reserved.)

Cholestasis is a hepatobiliary disorder characterized by the excessive accumulation of toxic bile acids in hepatocytes, leading to cholestatic liver injury (CLI) through multiple pathogenic inflammatory pathways. Currently, there are limited therapeutic options for the management of cholestasis and associated CLI; therefore, new options are urgently needed. Pirfenidone (PF), an oral bioavailable pyridone analog, is used for the treatment of idiopathic pulmonary fibrosis. PF has recently demonstrated diverse potential therapeutic activities against different pathologies. Accordingly, the present study adopted the α-naphthyl isothiocyanate (ANIT)-induced CLI model in mice to explore the potential protective impact of PF and investigate the underlying mechanisms of action. PF intervention markedly reduced the serum levels of ALT, AST, LDH, total bilirubin, and total bile acids, which was accompanied by a remarkable amelioration of histopathological lesions induced by ANIT. PF also protected the mice against ANIT-induced redox imbalance in the liver, represented by reduced MDA levels and elevated GSH and SOD activities. Mechanistically, PF inhibited ANIT-induced downregulated expressions of the farnesoid X receptor (FXR), as well as the bile salt export pump (BSEP) and the multidrug resistance-associated protein 2 (MRP2) bile acid efflux channels. PF further repressed ANIT-induced NF-κB activation and TNF-α and IL-6 production. These beneficial effects were associated with its ability to dose-dependently inhibit Wnt/GSK-3β/β-catenin/cyclin D1 signaling. Collectively, PF protects against ANIT-induced CLI in mice, demonstrating powerful antioxidant and anti-inflammatory activities as well as an ability to oppose BA homeostasis disorder. These protective effects are primarily mediated by modulating the interplay between FXR, NF-κB/TNF-α/IL-6, and Wnt/β-catenin signaling pathways., 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 Elsevier Inc. All rights reserved.)

The current study explored the protective potential of kaempferol 3-sophoroside-7-glucoside (KSG) against acute lung injury (ALI). Pre-treatment with KSG effectively secured mice from ALI and showed similar efficaciousness to dexamethasone. KSG markedly increased the survival rate and alleviated lung pathological lesions induced by lipopolysaccharide (LPS). Furthermore, KSG attenuated differential and total cell counts in BALF (bronchoalveolar lavage fluid) and MPO (myeloperoxidase) activity. KSG counteracted the NF-κB (nuclear factor-κB) activation and significantly ameliorated the downstream inflammatory cytokine, TNF-α (tumor necrosis factor-α). Simultaneously, KSG suppressed the over-expression of NLRP3 (NOD-like receptor protein 3 ) , caspase-1, and pro-inflammatory cytokine interleukin IL-1β (interleukine-1β) and prohibited the elevation of the pyroptotic parameter GSDMD-N (N-terminal domain of gasdermin D) induced by LPS challenge. In addition, KSG significantly enhanced Nrf2 (nuclear-factor erythroid-2-related factor) and HO-1 (heme-oxygenase-1) expression. Meanwhile, KSG mitigated lipid peroxidative markers (malondialdehyde, protein carbonyl and 4-hydroxynonenal) and boosted endogenous antioxidants (superoxide dismutase/reduced glutathione/catalase) in lung tissue. In silico analyses revealed that KSG disrupts Keap1-Nrf2 protein-protein interactions by binding to the KEAP1 domain, consequently activating Nrf2. Specifically, molecular docking demonstrated superior binding affinity of KSG to KEAP1 compared to the reference inhibitor, with docking scores of -9.576 and -6.633 Kcal/mol, respectively. Additionally, the MM-GBSA binding free energy of KSG (-67.25 Kcal/mol) surpassed that of the reference inhibitor (-56.36 Kcal/mol). Furthermore, MD simulation analysis revealed that the KSG-KEAP1 complex exhibits substantial and stable binding interactions with various amino acids over a duration of 100 ns. These findings showed the protective anti-inflammatory and anti-oxidative modulatory efficiencies of KSG that effectively counteracted LPS-induced ALI and encouraged future research and clinical applications of KSG as a protective strategy for ALI., Competing Interests: 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., (© 2024 The Author(s).)

APAP (Acetaminophen)-induced hepatic injury is a major public health threat that requires continuous searching for new effective therapeutics. KSG (Kaempferol-3-sophoroside-7-glucoside) is a kaempferol derivative that was separated from plant species belonging to different genera. This study explored the protective effects of KSG on ALI (acute liver injury) caused by APAP overdose in mice and elucidated its possible mechanisms. The results showed that KSG pretreatment alleviated APAP-induced hepatic damage as it reduced hepatic pathological lesions as well as the serum parameters of liver injury. Moreover, KSG opposed APAP-associated oxidative stress and augmented hepatic antioxidants. KSG suppressed the inflammatory response as it decreased the genetic and protein expression as well as the levels of inflammatory cytokines. Meanwhile, KSG enhanced the mRNA expression and level of anti-inflammatory cytokine, IL-10 (interleukin-10). KSG repressed the activation of NF-κB (nuclear-factor kappa-B), besides it promoted the activation of Nrf2 signaling. Additionally, KSG markedly hindered the elevation of ASK-1 (apoptosis-signal regulating-kinase-1) and JNK (c-Jun-N-terminal kinase). Furthermore, KSG suppressed APAP-induced apoptosis as it decreased the level and expression of Bax (BCL2-associated X-protein), and caspase-3 concurrent with an enhancement of anti-apoptotic protein, Bcl2 in the liver. More thoroughly, Computational studies reveal indispensable binding affinities between KSG and Keap1 (Kelch-like ECH-associated protein-1), ASK1 (apoptosis signal-regulating kinase-1), and JNK1 (c-Jun N-terminal protein kinase-1) with distinctive tendencies for selective inhibition. Taken together, our data showed the hepatoprotective capacity of KSG against APAP-produced ALI via modulation of Nrf2/NF-κB and JNK/ASK-1/caspase-3 signaling. Henceforth, KSG could be a promising hepatoprotective candidate for ALI., Competing Interests: 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., (© 2024 The Authors.)

Fulminant hepatic failure (FHF) is the terminal phase of acute liver injury, which is characterized by massive hepatocyte necrosis and rapid hepatic dysfunction in patients without preexisting liver disease. There are currently no therapeutic options for such a life-threatening hepatic failure except liver transplantation; therefore, the terminal phase of the underlying acute liver injury should be avoided. Tomatidine (TOM), asteroidal alkaloid, may have different biological activities, including antioxidant and anti-inflammatory effects. Herein, the lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced FHF mouse model was established to explore the protective potential of TOM and the underlying mechanisms of action. TOM pretreatment significantly inhibited hepatocyte necrosis and decreased serum aminotransferase activities in LPS/D-GalN-stimulated mice. TOM further increased the level of different antioxidant enzymes while reducing lipid peroxidation biomarkers in the liver. These beneficial effects of TOM were shown to be associated with targeting of NF-κB signaling pathways, where TOM repressed NF-κB activation and decreased LPS/D-GalN-induced TNF-α, IL-6, IL-1β, and iNOS production. Moreover, TOM prevented LPS/D-GalN-induced upregulation of Keap1 expression and downregulation of Nrf2 and HO-1 expression, leading to increased Nrf2-binding activity and HO-1 levels. Besides, TOM pretreatment repressed LPS/D-GalN-induced upregulation of proliferating cell nuclear antigen (PCNA) expression, which spared the hepatocytes from damage and subsequent repair following the LPS/D-GalN challenge. Collectively, our findings revealed that TOM has a protective effect on LPS/D-GalN-induced FHF in mice, showing powerful antioxidant and anti-inflammatory effects, primarily mediated via modulating Keap1/Nrf2/HO-1 and NF-κB/TNF-α/IL-6/IL-1β/iNOS signaling pathways., 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 Elsevier B.V. All rights reserved.)

Background and objectives: Oleanolic acid (OA) is a penta-cyclic triterpene with diverse bioactivities such as anticarcinogenic, antiviral, antimicrobial, hepatoprotective, anti-atherosclerotic, hypolipidemic, and gastroprotective. However, its effects on hepatorenal damage remain unclear. The protective activity of OA, separated from Viscum schimperi (Loranthaceae), against TAA (thioacetamide)-produced acute hepatic and renal damage was explored. Materials and Methods: Mice were treated with OA for 7 days before TAA (200 mg/kg, i.p.). Serum indices of hepatorenal injury, pathological lesions, molecular biological indexes, and inflammatory/apoptotic genes were estimated. Results: The tissues of both organs were greatly affected by the TAA injection. That was evident through increased serum markers of hepato-renal injury as well as remarkable histopathological lesions. TAA-induced injury was associated with oxidative and inflammatory responses in both organs as there was an elevation of oxidative stress parameters (4-HNE (4-hydroxy-nonenal), MDA (malondialdehyde), NOx (nitric oxide)), decline of antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC)), and an increase in the gene expression/level of inflammatory mediators (interleukins (1β&6)). The inflammatory response was linked to a significant activation of NF-κB (nuclear-factor kappa-B)/TNF-α (tumor-necrosis factor-alpha) signaling. The inflammatory response in both organs was accompanied by apoptotic changes, including a rise in the gene expression and level of apoptotic parameters (caspase-3 and Bax) along with a decline in Bcl-2 (anti-apoptotic parameter) gene expression and level. These pathogenic events were found to be closely related to the suppression of the antioxidant signaling pathway, Nrf2 (nuclear-factor erythroid 2-related factor-2)/SIRT1 (sirtuin-1)/HO-1 (heme-oxygenase 1). On the other hand, OA significantly ameliorated TAA-induced injury in both organs. On the other hand, OA counterpoised the inflammatory response as it ameliorated NF-κB/TNF-α signaling and cytokine release. OA enhanced Nrf2/SIRT1/HO-1 signaling and counteracted apoptotic damage. Conclusions: OA showed anti-inflammation and antiapoptotic capacities that effectively suppressed TAA-induced acute hepatorenal damage.

Cepabiflas B and C (CBs) are flavonoid dimers separated from Allium cepa . They demonstrated antioxidant and α-glucosidase and protein tyrosine phosphatase 1B inhibition capacities. However, their anti-inflammatory activities and their effects on endotoxemia are unknown. The current study aimed at exploring the protective activities of CBs on lipopolysaccharide (LPS)-induced kidney and liver damage in mice and investigating the possible molecular mechanisms. Mice were orally treated with a low (40 mg/kg) or high (60 mg/kg) dose of CBs for five days prior to a single intraperitoneal injection of LPS (10 mg/kg). Samples of serum and hepatic and kidney tissues were collected 24 h after the LPS challenge. Changes in serum indices of hepatic and renal injury, pathological changes, molecular biological parameters, and proteins/genes related to inflammation and apoptosis of these organs were estimated. LPS injection resulted in deleterious injury to both organs as indicated by elevation of serum ALT, AST, creatinine, and BUN. The deteriorated histopathology of hepatic and renal tissues confirmed the biochemical indices. CBs treated groups showed a reduction in these parameters and improved histopathological injurious effects of LPS. LPS-induced hepatorenal injury was linked to elevated oxidative stress as indicated by high levels of MDA, 4-HNE, as well as repressed antioxidants (TAC, SOD, and GSH) in hepatic and kidney tissues. This was accompanied with suppressed Nrf2/HO-1 activity. Additionally, there was a remarkable inflammatory response in both organs as NF-κB signalling was activated and high levels of downstream cytokines were produced following the LPS challenge. Apoptotic changes were observed as the level and gene expression of Bax and caspase-3 were elevated along with declined level and gene expression of Bcl2. Interestingly, CBs reversed all these molecular and genetic changes and restricted oxidative inflammatory and apoptotic parameters after LPS-injection. Collectedly, our findings suggested the marked anti-inflammatory and anti-apoptotic activity of CBs which encouraged its use as a new candidate for septic patients.

γ-Mangostin (γ-MN) is one of the abundant xanthones separated from Garcinia mangostana (Clusiaceae) pericarps that has been reported to have varied bioactivities such as neuroprotective, cytotoxic, antihyperglycemic, antioxidant, and anti-inflammation. Yet, its effect on cholestatic liver damage (CLI) has not been investigated. This study explored the protective activity of γ-MN against alpha-naphthyl isothiocyanate (ANIT)-induced CLI in mice. The results showed that γ-MN protected against ANIT-induced CLI as indicated by reduced serum levels of hepatic injury parameters (e.g., ALT, AST, γ-GT, ALP, LDH, bilirubin, and total bile acids). ANIT-induced pathological lesions were improved in γ-MN pre-treated groups. γ-MN exerted potent antioxidant effects as it lowered the parameters of lipid peroxidation (4-HNE, PC, and MDA) and intensified the content and activity of antioxidants (TAC, GSH, GSH-Px, GST, and SOD) in the hepatic tissue. Furthermore, γ-MN enhanced the signalling of Nrf2/HO-1 as it augmented the mRNA expression of Nrf2/downstream genes (HO-1/GCLc/NQO1/SOD). The binding capacity and the immuno-expression of Nrf2 were also increased. γ-MN showed anti-inflammatory capacity as it suppressed the activation of NF-κB signalling, it decreased mRNA expression and levels of NF-κB/TNF-α/IL-6 and the immuno-expression of NF-κB/TNF-α. In addition, γ-MN inhibited the activation of NLRP3 inflammasome as it lowered the mRNA expression of NLRP3/caspase-1/IL-1β along with their levels as well as the immuno-expression of caspase-1/IL-1β. γ-MN also reduced the level of the pyroptotic parameter GSDMD. Collectively, this study demonstrated the potent hepatoprotective potential of γ-MN against CLI which was linked to its ability to potentiate Nrf2/HO-1 and to offset NF-κB/NLRP3/Caspase-1/IL-1β/GSDMD. Hence, γ-MN may be suggested as a new candidate for cholestatic patients., Competing Interests: Declaration of competing interest The authors declare no potential competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: The management of hospitalized COVID-19 patients depends largely on controlling the intensified inflammatory response known as the cytokine storm. Candidate inflammatory cytokines can serve as new biomarkers for the management of hospitalized COVID-19 patients., Methods: Patients (80) were recruited into three groups: room air (RA), oxygen (OX) and mechanical ventilator (MV). Blood analysis was performed for RBC, WBC, Hb, Platelets, serum albumin and creatinine, INR, PTT, and hematocrit. ELISA was used to quantify a panel of inflammatory mediators including GM-SCF, IFN-α, IFNγ, IL-1β, IL-1R, IL-2, IL-2Ra, IL-6, IL-8, IL-10, IL-12p70, IL-13, MCP-1, MIP-1a, and TNF-α. Correlations between laboratory results and the levels of circulating inflammation mediators were investigated., Results: Patients on MV had low RBC, Hb, albumin, and HCT and high WBC count, PTT, and INR when compared to RA and OX groups. A statistical positive correlation was found between WBC and the levels of IL-6 and MCP-1. RBCs correlated negatively with IL-6 and IL-10 and positively with IL-8. Higher TNF-α correlated with lower platelet counts while higher levels of IL-1Rα and IL-10 were associated with lower Hb levels. Increases in IFN-γ and TNF-α were indicative of compromised kidney functions as creatinine levels increased significantly. Most significant correlations were found between IL-6 and lab results, showing positive correlation with WBC and INR, and negative correlation with RBC, albumin, and HCT., Conclusions: Having the most significant correlations, IL-6 high levels in mechanically ventilated patients were shown to affect laboratory results, and, therefore, is suggested as a severity biomarker of COVID-19., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

The discovery of natural drug metabolites is a leading contributor to fulfilling the sustainable development goal of finding solutions to global health challenges. Depsidones are a class of polyketides that have been separated from lichens, fungi, sponges, and plants and possess various bioactivities, including cytotoxic, antimicrobial, antimalarial, antituberculosis, acetylcholinesterase and α-glucosidase inhibition, and anti-inflammatory effects. Endocannabinoid receptors (CB1 and CB2) are G-protein-coupled receptors (GPCRs), and their activation mediates many physiological processes. CB1 is the dominant subtype in the central nervous system, while CB2 is mainly expressed in the immune system. The two receptors exhibit high heterogeneity, making developing selective ligands a great challenge. Attempts to develop CB2 selective agonists for treating inflammatory diseases and neuropathic pain have not been successful due to the high homology of the binding sites of the CB receptors. In this work, 235 depsidones from various sources were investigated for the possibility of identifying CB2-selective agonists by performing multiple docking studies, including induced fit docking and Prime/molecular mechanics-generalized Born surface area (MM-GBSA) calculations to predict the binding mode and free energy. Simplicildone J ( 10 ), lobaric acid ( 110 ), mollicellin Q ( 101 ), garcinisidone E ( 215 ), mollicellin P ( 100 ), paucinervin Q ( 149 ), and boremexin C ( 161 ) had the highest binding scores (-12.134 kcal/mol, -11.944 kcal/mol, -11.479 kcal/mol, -11.394 kcal/mol, -11.322 kcal/mol, -11.305 kcal/mol, and -11.254 kcal/mol, respectively) when screened against the CB2 receptor (PDB ID: 6KPF). The molecular dynamic simulation was performed on the compounds with the highest binding scores. The computational outcomes show that garcinisidone E ( 215 ) and paucinervin Q ( 149 ) could be substantial candidates for CB2 receptor activation and warrant further in vivo and in vitro investigations.

Garcinia mangostana L. (Clusiaceae), a popular tropical fruit for its juiciness and sweetness, is an opulent fountain of prenylated and oxygenated xanthones with a vast array of bio-activities. Garcinone E (GE), a xanthone derivative reported from G. mangostana, possesses cytotoxic and aromatase inhibitory activities. The present research endeavors to investigate the hepato-protection efficaciousness of GE on concanavalin-A (Con-A)-instigated hepatitis. Results showed that GE pretreating noticeably diminishes both the serum indices (transaminases, ALP, LDH, and γ-GT) and histopathological lesions of the liver. It counteracted neutrophil and CD4+ infiltration into the liver. GE furthered the Nrf2 genetic expression and its antioxidants' cascade, which resulted in amelioration of Con-A-caused oxidative stress (OS), lipid per-oxidative markers (4-HNE, MDA, PC) reduction, and intensified antioxidants (TAC, SOD, GSH) in the hepatic tissue. Additionally, GE prohibited NF-ĸB (nuclear factor kappa-B) activation and lessened the genetics and levels of downstream cytokines (IL1β and IL6). Moreover, the TNF-α/JNK axis was repressed in GE-treated mice, which was accompanied by attenuation of Con-A-induced apoptosis. These findings demonstrated the protective potential of GE in Con-A-induced hepatitis which may be associated with Nrf2/HO-1 signaling activation and OS suppression, as well as modulation of the NF-κB and TNF-α/JNK/apoptosis signaling pathway. These results suggest the potential use of GE as a novel hepato-protective agent against autoimmune hepatitis.

Alpha-mangostin (α-MN) is a xanthone obtained from Garcinia mangostana that has diverse anti-oxidative and anti-inflammatory potentials. However, its pharmacological activity against autoimmune hepatitis (AIH) has not been investigated before. Concanavalin A (Con A) was injected into mice to induce AIH and two doses of α-MN were tested for their protective effects against Con A-induced AIH. The results demonstrated the potent hepatoprotective activity of α-MN evidenced by a remarkable decrease of serum indices of the hepatic injury and amendment of the histological lesions. α-MN significantly attenuated the level and immuno-expression of myeloperoxidase (MPO) indicating a decrease in the neutrophil infiltration into the liver. Additionally, the recruitment of the CD4+ T cell was suppressed in the α-MN pre-treated animals. α-MN showed a potent ability to repress the Con A-induced oxidative stress evident by the reduced levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and protein carbonyl (PC), as well as the enhanced levels of antioxidants as the reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC). The ELISA, RT-PCR, and IHC analyses revealed that α-MN enhanced the sirtuin1/nuclear factor erythroid 2 related factor-2 (SIRT1/Nrf2) signaling and its downstream cascade genes concurrently with the inhibition of the nuclear factor kappa B (NF-κB) and the inflammatory cytokines (tumor necrosis factor-alpha and interleukine-6) signaling. Taken together, these results inferred that the hepatoprotective activity of α-MN could prevent Con A-induced AIH through the modulation of the SIRT1/Nrf2/NF-κB signaling. Hence, α-MN may be considered as a promising candidate for AIH therapy.

Ethnopharmacological Relevance: Cucurbitacins are highly oxygenated tetracyclic triterpenoids, that represent the major metabolites reported from C. colocynthis (L.) Schrad.. Cucurbitacin E glucoside (CuE) is a tetracyclic triterpene glycoside separated from Cucurbitaceae plants. CuE has potent anti-inflammatory, immunomodulatory, and anti-tumor properties., Aim of the Study: The current study aimed at examining the hepatoprotective effect of CuE against concanavalin A (Con A)-produced hepatitis., Materials and Methods: Mice were intravenously administered Con A (15 mg/kg) to induce AIH. CuE was orally administered at two different doses for five days preceding Con A injection., Results: The results revealed that CuE pretreatment markedly attenuated the serum indices of hepatotoxicity and the severity of hepatic lesions. CuE depressed Con A-provoked increment in CD4 + T-cells in hepatic tissue. The antioxidant activity of CuE was evident through its ability to decrease markers of Con A-induced oxidative stress (malondialdehyde, 4-hydroxyenonanal, and protein carbonyl) and intensified the antioxidants in the hepatic tissue (SOD, GSH, and TAC). CuE increased mRNA expression of SIRT1 and Nrf2 as well as its binding capacity. Subsequently, CuE augmented mRNA expression of Nrf2 targeted genes as NQO1, GCL, and HO-1 and recovered its normal level. CuE inhibited the activation of NF-κB/downstream pro-inflammatory mediators signaling. Furthermore, CuE attenuated the mRNA expression of NLRP3 and its associated genes., Conclusion: Collectively, these results demonstrated the remarkable hepatoprotective potential of CuE towards Con A-induced AIH which was mediated via suppression of oxidative stress, enhancing SIRT1/Nrf2/HO-1, and prohibition of the NF-κB/NLRP3 signaling. CuE could be a candidate for hepatitis patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) is a novel syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with varying clinical features. This study aimed to analyze the expression profiles of cytokines in blood, report the important clinical characteristics, and correlate these with the short- and mid-term outcomes., Methods: This cross-sectional study was conducted on hospitalized children with MIS-C from March 2021 to May 2022. Phenotypes were classified into two groups (A,B) according to the severity of the disease and the need for invasive respiratory support. Clinical features, laboratory parameters, and outcomes were reported., Results: We identified 60 children with MIS-C (mean age of 7.4 ± 3.8 years) compared to 30 age- and sex-matched controls with simple COVID-19. The clinical manifestations of MIS-C patients were fever (100%), respiratory (83.3%), GIT (80%), and conjunctivitis (80%). Twenty-seven MIS-C children (45%) required PICU admission due to shock and needed mechanical ventilation. Anemia, lymphopenia, and elevated levels of inflammatory and tissue injury markers were observed in the MIS-C groups (mainly B). High cytokine levels (IL-1β, IL-6, IFN-α, GM-CSF, and HMGB1) were observed acutely in the MIS-C children, and a persistent elevation of some cytokines were reported at midterm follow-up, especially in Group B., Conclusion: Robust inflammatory response to COVID-19 disease with elevated IL-1β, IL-6, and GM-CSF levels might explain the severity and outcome of the clinical syndrome.

Ethnopharmacological Relevance: Kirenol (Kr) is an ent-pimarane type diterpenoid that has been reported from Siegesbeckiaorientalis, S. pubescens, and S. glabrescens (family Asteraceae). These plants have been used traditionally for treating various ailments such as hypertension, neurasthenia, rheumatoid arthritis, asthma, snakebites, allergic disorders, paralysis, soreness, cutaneous disorders, rubella, menstrual disorders, numbness of limbs, dizziness, headache, and malaria. Importantly, in recent years, Kr has received great attention due to its diversified pharmacological activities., Aim of the Study: The current work aims to give an overview on the reported pharmacological activities of Kr. Furthermore, the findings regarding its methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, identification, semisynthetic analogues, and toxicity are highlighted to provide a reference and perspective for its further investigation., Methods: Electronic databases including ScienceDirect, Web of Knowledge, SCOPUS, Wiley Online Library, Taylor & Francis, PubMed, Springer, JACS, and Google Scholar were searched up to the beginning of 2021 to identify the reported studies., Results: A total of 93 articles have been reviewed. The reported data suggested that Kr possessed various bioactivities including cytotoxic, apoptotic, anticancer, anti-inflammatory, cardio-protective, anti-photo-aging, anti-adipogenic, antimicrobial, muscle function improvement, fracture and wound healing, and anti-arthritic. In addition, studies revealed that the antioxidative and anti-inflammatory activities of Kr may mediate many of its therapeutic potentials as confirmed by several in-vitro and in-vivo studies., Conclusion: This review provides an updated summary of the recent studies on Kr, including methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, and identification, as well as semisynthetic analogues, pharmacological activities, and toxicity. Thus, this work can provide useful considerations for planning and design future research on Kr., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the Aspergillus genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus A. terreus against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes ( HO-1 , NQO1 , and GCLm ). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1β). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.

Sitagliptin is known for its anti-diabetic activity though it has other pleiotropic pharmacological actions. Its effect against concanavalin A (Con A)-induced hepatic fibrosis has not been investigated yet. Our target was to test whether sitagliptin can suppress the development of Con A-induced hepatic fibrosis and if so, what are the mechanisms involved? Con A (6 mg/kg) was injected once weekly to male Swiss albino mice for four weeks. Sitagliptin was daily administered concurrently with Con A. Results have shown the potent hepatoprotective activity of sitagliptin against Con A-induced hepatitis and fibrosis. That was evident through the amelioration of hepatotoxicity serum parameters (ALT, AST, ALP, and LDH) and the increase in the level of serum albumin in sitagliptin treated mice. Simultaneously, there was amendment of the Con A-induced hepatic lesions and repression of fibrosis in sitagliptin-treated animals. Hydroxyproline, collagen content and the immuno-expression of the fibrotic markers, TGF-β and α-SMA were depressed upon sitagliptin treatment. Sitagliptin suppressed Con A-induced oxidative stress and increased antioxidants. RT-PCR analysis showed enhancement of mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes (GCLc, GCLm, NQO-1, HO-1) by sitagliptin. Furthermore, sitagliptin ameliorated the level and immuno-expression of nuclear factor kappa-B (NF-κB) alongside the immuno-expression of the inflammatory cytokine, TNF-α. Taken together, this study demonstrates the hepatoprotective activity of sitagliptin which may be in part related to enhancement of Nrf2 signaling pathway and inhibition of NF-κB which interact inflammatory response in liver. Sitagliptin might be a new candidate to suppress hepatitis-associated fibrosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Euphorbia cuneata (EC; Euphorbiaceae), which widely grows in Saudi Arabia and Yemen, is used traditionally to treat pain and inflammation. This study aimed to evaluate the protective anti-inflammatory effect of a standardized extract of EC against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanism(s) of this pharmacologic activity. ALI was induced in male Balb/c mice using intraperitoneal injection of LPS. A standardized total methanol extract of EC or dexamethasone was administered 5 days prior to LPS challenge. Bronchoalveolar fluid (BALF) and lung samples were collected for analysis. The results demonstrated the protective anti-inflammatory effect of EC against LPS-induced ALI in mice. Standardized EC contained 2 R -naringenin-7- O - β -glucoside ( 1 ), kaempferol-7- O - β -glucoside ( 2 ), cuneatannin ( 3 ), quercetin ( 4 ), and 2 R -naringenin ( 5 ) in concentrations of 6.16, 4.80, 51.05, 13.20, and 50.00 mg/g of extract, respectively. EC showed a protective effect against LPS-induced pulmonary damage. EC reduced lung wet/dry weight (W/D) ratio and total protein content in BALF, indicating attenuation of the pulmonary edema. Total and differential cell counts were decreased in EC-treated animals. Histopathological examination confirmed the protective effect of EC, as indicated by an amelioration of LPS-induced lesions in lung tissue. EC also showed a potent anti-oxidative property as it decreased lipid peroxidation and increased the antioxidants in lung tissue. Finally, the anti-inflammatory activity of EC was obvious through its ability to suppress the activation of nuclear factor-κB (NF-κB), and hence its reduction of the levels of downstream inflammatory mediators. In conclusion, these results demonstrate the protective effects of EC against LPS-induced lung injury in mice, which may be due to its antioxidative and anti-inflammatory activities.

Recently, there is an increasing interest in searching for harmless natural products isolated from plant materials that can be used as beneficial dietary supplements and/or therapeutic drug candidates. The present study aimed to test the potential protective role of Pulicaria petiolaris (PP, Asteraceae) against hepatic and cardiotoxic effects associated with lipopolysaccharide (LPS) injection. PP was given orally for 5 days at two different doses before LPS injection. Results have shown that LPS induced remarkable hepatic and cardiac injurious effects in mice. Hepatic damage was evident through increased serum transaminases, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and activity. Estimation of high levels of serum creatine kinase-MB (CK-MB) and cardiac troponin I indicated cardiac damage. Histopathological examination of liver and heart confirmed the biochemical results. Increase in oxidative stress along with a depressed antioxidant status of liver and heart were observed in LPS-intoxicated animals. Furthermore, LPS induced activation of nuclear factor-κB (NF-κB) and subsequent elevation of inflammatory cytokines (TNF-α, IL-6). On the other hand, PP treatment successfully safeguards both organs against LPS-induced injury as indicated by the improvement of the biochemical and histopathological parameters. These results suggest that PP ameliorates LPS-induced hepatic and cardiac oxidative injurious effects via antioxidant and anti-inflammatory effects.

Tovophyllin A (TA) is a xanthone isolated from Garcinia mangostana L. (GM, Guttiferae) pericarps that possesses various beneficial bioactivities. However, its protective effects on acute lung injury (ALI) and lung carcinoma have not yet been explored. The current work was designed to investigate the protective potential of TA against ALI and explore the possible mechanism of action. Two different doses of TA were tested against lipopolysaccharide (LPS)-induced ALI in mice. Moreover, the cytotoxic potential of TA was assessed in epithelial lung (A549 cells) and breast (MCF7 cells) carcinomas utilizing a sulforhodamine B (SRB) assay. The results revealed that TA possessed the ability to protect against LPS-induced acute lung damage. TA attenuated LPS-induced pulmonary edema, as it lowered the protein content in the bronchoalveolar lavage fluid (BALF) and the lung W/D ratio. In addition, TA counteracted inflammatory cell infiltration into the lung tissue, as shown by the total and differential cell counts in the BALF and histopathological examination of the lungs. The oxidative burden in the pulmonary tissue was ameliorated in TA-treated animals as there were reductions in the malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels in the lung tissue. TA increased the levels of antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in the lungs. Furthermore, TA inhibited the activation of nuclear factor-κB (NF-κB). In addition, TA had potent anti-inflammatory activity as it reduced the immunoexpression and levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Furthermore, TA showed significantly enhanced cytotoxic activity against the MCF-7 and A549 cell lines with IC 50 s of 6.1 and 2.2 µM, respectively, compared to doxorubicin (IC 50 s of 0.41 and 0.74 µM, respectively). In conclusion, TA ameliorates LPS-induced ALI through the suppression of oxidative stress and inflammation. These findings suggest the potential use of this compound as a future treatment for ALI.

Background: Pirfenidone (PFD) is an orally active antifibrotic agent that has anti-inflammatory activity in diverse animal models. Its effect against acute pancreatitis (AP) has not been elucidated. Hence, the present investigation was carried out to assess the potential protective role of PFD against l-arginine-induced AP in mice., Methods: AP was induced in adult male Swiss albino mice via intraperitoneal injections of l-arginine (4 g/kg, twice each 1 h apart). PFD (250 mg/kg, orally) was administered one day before and on the day of l-arginine challenge. Twenty-four hours after l-arginine injection, the severity of AP was evaluated using biochemical and histological analyses. Indices of oxidative stress, inflammation and apoptosis were evaluated using ELISA and immunohistochemistry (IHC)., Results: PFD suppressed the development of l-arginine-induced AP as revealed by the improvement of histopathological lesions of pancreatic specimen and the significant reduction of serum amylase and lipase levels. Notably, PFD reduced the lipid peroxidation and enhanced the antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in pancreatic tissue. Importantly, PFD suppressed AP-associated elevation of inflammatory cytokines along with depression of nuclear factor kappa-B (NF-κB) immuno-expression in pancreatic tissue. Lastly, PFD efficiently ameliorated AP-induced elevation of the pro-apoptotic protein (Bax) and increased AP-induced reduction of the anti-apoptotic protein (Bcl2)., Conclusions: PFD protected against l-arginine-induced AP in mice through anti-oxidative, anti-inflammatory and anti-apoptotic properties., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Endophytic fungi have known as a promising source of secondary metabolites. γ-Butyrolactones are a class of metabolites reported from Aspergillus genus, which attracted much attention for their bioactivities. This study aimed to assess the potential cardioprotective effects of aspernolide F (AF) separated from the endophytic fungus A. terreus against doxorubicin (DOX)-induced cardiotoxic effects in rats. Animals were treated with two different doses of AF for 10 days prior to DOX injection. Electrocardiographic (ECG), biochemical, histopathological and immunohistochemical analyses were performed. Results have shown that AF effectively protected against DOX-induced cardiac damage as AF counteracted DOX-induced ECG abnormalities and attenuated serum markers of cardiotoxicity (creatine kinase-MB, lactate dehydrogenase, troponin I, and troponin T). Histopathological examination of cardiac tissue revealed a remarkable improvement in DOX-induced lesions. In addition, AF ameliorated DOX-induced oxidative damage and increased the levels of antioxidants in cardiac tissues. AF treatment inhibited the activation of nuclear factor-κB (NF-κB) and decreased the immuno-expression of NF-κB in cardiac tissue. Furthermore, AF caused a marked lowering in the level of inflammatory cytokines (nitric oxide, tumor necrosis factor-α, and interleukin-6) in the cardiac tissue. Collectively, this study demonstrates the cardioprotective activity of AF against DOX-induced cardiac damage which may be due to its antioxidant and anti-inflammatory activities., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Vitex agnus-castus (VAC, Verbenaceae) is widely used in Chinese traditional medicine as an antiinflammatory agent. This study aimed to explore the efficacy of the VAC extract to protect against lipopolysaccharide (LPS)-induced acute lung injury. The results have shown that VAC had a potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as there was a significant decrease in lung wet/dry ratio and in protein content. VAC also decreased the lactate dehydrogenase's activity in the bronchoalveolar fluid. VAC ameliorated LPS-induced inflammatory cells infiltration into the lung tissue and reversed the histopathological lesions of the lung. Furthermore, VAC counteracted LPS-induced oxidative stress as it attenuated the lipid peroxidation marker, malondialdehyde, in the lung. VAC increased the antioxidant activity as evident by elevated superoxide dismutase activity and increased reduced glutathione content in the lung tissue. Collectively, VAC has a protective activity against LPS-induced acute lung damage through its antioxidant potential. PRACTICAL APPLICATIONS: Vitex agnus-castus has been used in various traditional medicines for treating various ailments as digestive complains, acne, rheumatic pains, menstrual irregularities, premenstrual syndrome, infertility, and hyperprolactinemia. Its leaves are used as a spice and the fruits are used as a substitute for pepper. VAC food supplements are used by women against psychic and somatic premenstrual symptoms. The findings of this study can demonstrate the potent protective activity of the VAC extract against LPS-induced acute lung damage due to its antioxidative effects. Therefore, VAC could be developed as a health functional food to improve acute lung damage and many diseases caused by oxidative damage., (© 2018 Wiley Periodicals, Inc.)

Valproate is a widely used drug against epilepsy and several other neurological disorders although it has deleterious hepatotoxic side effects. The current study was designed to test if agmatine as nitric oxide modulator has protective effects against valproate-induced hepatic injury. Male Swiss albino mice were treated with sodium valproate (SVP) with or without agmatine for 7 days. Serum and liver samples were collected for analysis. Results have revealed that agmatine exerted hepatoprotective effects against SVP-associated hepatic injury. Agmatine ameliorated SVP-induced elevated serum biochemical markers of hepatic damage such as serum transaminases, alkaline phosphatase, γ-glutamyl transferase, and lactate dehydrogenase. Histopathological examination of the liver showed improvement of hepatic lesions in case of agmatine treatment. Furthermore, agmatine attenuated oxidative stress and enhanced antioxidants in liver tissue. Agmatine inhibited the activation of nuclear factor-κB and ameliorated the immunoexpression of inducible nitric oxide synthetase. This was accompanied by decrease in the level of inflammatory markers as nitrite/nitrate, tumor necrosis factor-α, and interleukin-6. These data provide new evidence of the hepatoprotective activity of agmatine against SVP-induced hepatotoxic effects., (© 2018 Wiley Periodicals, Inc.)

Garcinia mangostana L. (GM, family Guttiferae) is one of the most widely recognized tropical fruits. GM is a wealthy pool of xanthones that exhibit a wide range of bioactivities. Tovophyllin A (TA) separated from GM pericarps was tested for its efficacy to ameliorate acetaminophen (APAP)-induced liver injury. Mice were injected with a single dose of APAP with or without TA pretreatment. The protective effects of TA against APAP-induced liver damage were evident through amelioration of serum indices of hepatotoxicity and improvement of hepatic histopathologic lesions. TA has antioxidant activity because it inhibited APAP-induced lipid peroxidation and improved the antioxidant capacity of the liver. Also, TA enhanced the mRNA expression of nuclear erythroid-related factor 2 (Nrf2) and its target genes. Protein expression of Nrf2 and heme oxygenase-1 was enhanced remarkably in TA-pretreated groups. TA suppressed activation of nuclear factor-kappa B (NF-κB) and the subsequent release of pro-inflammatory cytokines. In conclusion, TA has a marked protective activity against APAP-induced hepatotoxicity which may be linked to its ability to activate Nrf2 and inhibit the NF-κB signaling pathway.

Pristimerin (Pris) is a triterpenoid derivative obtained from Celastraceae and Hippocrateaceae families. This compound has been extensively tested for its potent anti-cancer activity against different types of tumors. However, its effects against acute lung injury (ALI) remain to be investigated. This study explored the efficacy of Pris to protect against lipopolysaccharide (LPS)-induced ALI and its possible pathways. Results have shown that Pris possesses potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as presented by significant decrease in lung W/D ratio and in protein content. Pris attenuated LPS-induced inflammatory cell infiltration into the lung tissue and suppressed the activity of myeloperoxidase in lung. LPS-induced histopathological lesions were significantly improved via Pris pretreatment. Pris exhibited not only inhibition of LPS-induced oxidative stress, but also enhancement of the suppressed antioxidant capacity of the lung tissue. The anti-inflammatory activity of Pris against LPS-induced ALI was clearly evident via attenuation of the levels of pro-inflammatory cytokines namely, tumor necrosis factor-α and interleukin-6. Similarly, Pris inhibited LPS-induced elevation of pro-apoptotic protein, Bax, and caspase-3. Pris also increased the diminished level of Bcl2 induced by LPS. Collectively, Pris exerted protective activity against LPS-induced ALI via anti-oxidant, anti-inflammatory and anti-apoptotic pathways., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Pristimerin (Pris) is bioactive natural quinonoid triterpene that has anti-inflammatory and anti-cancer activities. Meanwhile, its effect against hepatitis needs to be elucidated. This investigation aimed to evaluate the ability of Pris to protect against autoimmune hepatitis (AIH). A mouse model of AIH was established using single concanavalin A (Con A) intravenous injection. Mice were treated with Pris at two different doses (0.4 and 0.8 mg/kg) for 5 days prior to Con A challenge. Markers of hepatic injury, oxidative, inflammatory, and apoptotic damage were estimated. Results have revealed that Pris pretreatment ameliorated Con A-induced hepatic damage. There was decrease in the elevated serum indices of hepatic damage (ALT, AST, ALP, and LDH) and improvement of the histopathological picture of the liver. Pris effectively decreased Con A-induced neutrophil infiltration into the hepatic tissue as presented by amelioration of the level and immuno-expression of myeloperoxidase (MPO). Additionally, Pris attenuated Con A-induced increase in CD4+ T-cells in hepatic tissue. Lipid peroxidation was significantly depressed simultaneously with enhancement of the antioxidant capacity in Pris pretreated animals. Pris also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression and its binding capacity. In addition, Pris increased mRNA expression of heme-oxygenase-1 (HO-1) and restored its normal level. Furthermore, Pris decreased the level and immuno-expression of nuclear factor kappa-B (NF-κB) as well as the downstream inflammatory cascade (TNF-α, IL-6, and IL-1β). Finally, Pris showed inhibitory effect on Con A-induced apoptotic alteration in liver as it decreased the mRNA expression and levels the apoptotic markers (Bax and caspase-3) and increased mRNA expression and level of the anti-apoptotic protein (Bcl2). In conclusion, this study demonstrates the potent hepatoprotective efficacy of Pris against Con A-induced hepatitis which may be related to anti-oxidative, anti-inflammatory, and anti-apoptotic pathways. Pris could serve as a new candidate for the management of hepatitis.

Background/aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways., Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot., Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters., Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug's ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Sodium valproate (VP) is an important antiepileptic drug, although it can produce deleterious hepatotoxic reactions. Diallyl trisulfide (DATS) is the principle component of garlic oil that possesses antioxidant properties. This study explored the potential hepatoprotective activity of DATS against VP-induced hepatic damage and its underlying mechanisms. In addition, the study assessed the effect of DATS on VP antiepileptic activity. Rats were given DATS once daily at two different doses along with VP for 2 weeks. Results have shown the ability of DATS to counteract VP-induced hepatic damage as it decreased elevated serum transaminases (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase. Liver histopathology indicated that DATS preserved the hepatic structural integrity and protected against VP-induced hepatic steatosis and necro-inflammation injury. DATS ameliorated VP-induced oxidative stress and increased the antioxidant capacity of the liver. Immunohistochemical analysis showed activation of nuclear factor kappa-B along with high expression of cyclo-oxygenase-2 (COX-2) upon VP administration. This was accompanied by overproduction of proinflammatory mediators (TNF-α, IL-1β, IL-6). Tracing the apoptotic pathway, VP administration induced marked apoptosis using TUNEL staining. Furthermore, VP-treated animals exhibited high immunoexpression of Bax protein and increased levels of Bax and caspase-3 while level of Bcl2 was significantly decreased in hepatic tissue. However, DATS simultaneous treatment counteracted all of these molecular pathological changes. Using pentylenetetrazole (PTZ)-induced seizures model in mice, the effect of DATS on the anticonvulsant activity of VP was found to be positive, meaning that combination of DATS with VP can confer protection against VP-induced hepatic injurious effects through its antioxidant, antiinflammatory, and antiapoptotic properties without affecting VP antiepileptic activity.

This study targeted to test the potential protective role of lutein against lung and liver damage associated with cyclophosphamide (CP) administration. Lutein was given orally for 5days at two different doses both before and after CP injection. Results have shown that CP administration caused marked pulmonary and hepatic injurious effects in mice. Lung damage was evident through increased lung wet/dry ratio, elevated inflammatory cells infiltration into the pulmonary tissues, increased total protein content and lactate dehydrogenase (LDH) activity in the broncho-alveolar lavage fluid. Estimation of high levels of serum transaminases, alkaline phosphatase and LDH in serum revealed hepatic injury. Histopathological examination of both organs confirmed the biochemical analysis. Elevation of oxidative stress along with depressed anti-oxidant status of lung and liver were evident in CP-intoxicated animals. Furthermore, CP induced elevation of inflammatory cytokines (NOx, TNF-α, IL-6) contaminant with activation of nuclear factor kappa-B (NF-κB) and p38 mitogen activated protein kinase (p38-MAPK). On the other side, lutein treatment successfully protected the lung and the liver as indicated by improvement of the biochemical and histopathological parameters. These results suggest that lutein can ameliorate CP-induced pulmonary and hepatic oxidative injurious effects via inhibition of reactive oxygen species (ROS)/NF-κB/MAPK pathway., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Vardenafil is a selective phosphodiesterase-5 inhibitor used for erectile dysfunction treatment. The hepatoprotective role of vardenafil against acute hepatitis is not reported yet. Hence, this study aims to explore the protective role of vardenafil against concanavalin A (Con A) induced acute liver injury. Mice were pretreated with vardenafil (0.17 mg/kg/day) for seven consecutive days, and then subjected to a single IV injection of Con A. The results demonstrated that the vardenafil pretreatment significantly reduced the elevated serum levels of transaminases and alkaline phosphatase. Histopathological examination showed marked necrosis and inflammation in Con A-treated mice which was significantly ameliorated in vardenafil pretreated animals. Vardenafil pretreatment significantly alleviated the expression of nuclear factor kappa-B and inducible nitric oxide synthase in the hepatic tissue. Additionally, serum levels of nitric oxide and tumor necrosis factor-alpha were decreased in vardenafil pretreated animals compared to the Con A group. Therefore, our results demonstrate that vardenafil has hepatoprotective effect and this could be linked to decrease inflammatory mediators., (© 2016 Wiley Periodicals, Inc.)

Purpose: Cyclophosphamide (CP) is a frequently used anticancer and immunosuppressant although its use has been associated with severe cardiotoxicity. The present study examined the ability of methyl palmitate (MP) to counteract CP-induced cardiotoxicity., Methods: Adult male Wistar rats were divided into four groups. The first one served as control while the second received a single injection of CP (200 mg/kg, i.p.). The other two groups were administered MP at two different dose levels (300, 400 mg/kg) for 10 days before and 7 days after CP single injection., Results: CP injection resulted in marked cardiac injury as presented by ECG abnormal changes, elevation of serum creatine kinase-MB (CK-MB), cardiac troponin I, troponin T and lactate dehydrogenase (LDH) and enormous histopathological lesions. Moreover, CP-induced oxidative stress as it elevated malondialdehyde (MDA) and diminished superoxide dismutase activity and glutathione content in heart tissue. Additionally, CP-induced overexpression of toll-like receptors-4 (TLR-4) and nuclear factor kappa-B (NF-κB) accompanied by overproduction of inflammatory cytokines (TNF-α, NO). CP activated cardiomyocyte apoptosis as it increased apoptosis parameters (Bax and caspase-3) and decreased anti-apoptotic marker (Bcl-2). On the other hand, MP treatment attenuated all of the measured parameters of CP-induced cardiotoxicity. MP counteracted CP-induced oxidative stress and suppressed TLR-4 and NF-κB overexpression. Also, levels of cytokines and apoptotic markers were declined while Bcl-2 was elevated in MP treated animals., Conclusions: MP may serve as a new cardioprotective candidate. The cardioprotective effects of MP may be attributed to its ability to suppress oxidative stress and interrupt TLR4/NF-κB signaling pathway with subsequent amelioration of apoptosis.

Objectives: This study aimed to evaluate the potential protective effects of pirfenidone (PFD) against concanavalin A (Con A)-induced hepatitis in mice., Methods: Autoimmune model of hepatitis was established using single intravenous injection of Con A. Mice were randomly assigned into four groups as follows: control group; Con A group; and two groups, receiving PFD in two dose levels (200, 300 mg/kg) for 5 days before Con A administration. Extent of hepatitis was studied using biochemical, histopathological and immunohistochemical estimations., Key Findings: Hepatitis was clearly evident through extensive hepatocellular lesions and elevated levels of serum transaminases, alkaline phosphatase and lactate dehydrogenase. Con A induced an imbalance between oxidant and antioxidant status in the hepatic tissue. Furthermore, Con A significantly elevated hepatic nuclear factor kappa B (NF-κB) expression and inflammatory cytokines levels (tumour necrosis factor-alpha, interleukin-6 and nitric oxide). PFD pretreatment potently ameliorated all these pathological changes., Conclusions: Pirfenidone hepatoprotective activity may be mediated through its antioxidant ability that suppresses NF-κB activation signalling pathways suggesting that PFD may be a new candidate for treatment of acute hepatitis., (© 2016 Royal Pharmaceutical Society.)

There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo- and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factor-alpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicin-induced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis., (© 2016 by the Society for Experimental Biology and Medicine.)

Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D-galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 μg/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS-induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-α production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases.

The present study was undertaken to investigate the effect of the new formyl peptide receptor 2/lipoxin A4 receptor agonist BML-111 on acetaminophen (APAP)-induced liver injury in mice and explore its possible mechanism(s). Male Swiss albino mice were intraperitoneally injected with BML-111 (1 mg/kg) twice daily for five consecutive days prior to a single intraperitoneal injection of APAP (500 mg/kg). Results have shown that APAP injection caused liver damage as indicated by significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Liver histopathological examination revealed marked necrosis and inflammation. Additionally, APAP decreased activities of hepatic glutathione (GSH) and superoxide dismutase (SOD) with significant increase in the hepatic malondialdehyde (MDA) content. Furthermore, APAP increased serum nitrite/nitrate (NO(2) (-)/NO(3) (-)) level and hepatic tumor necrosis factor alpha (TNF-α). Pretreatment with BML-111 significantly reversed all APAP-induced pathological changes. BML-111 prevented the increase of AST, ALT, and ALP. Also, BML-111 markedly attenuated APAP-induced necrosis and inflammation. It decreased MDA with increase in SOD and GSH. Importantly, BML-111 decreased NO(2) (-)/NO(3) (-) level and TNF-α. These findings suggest that BML-111 has hepatoprotective effects against APAP-induced liver injury in mice. Its protective effect may be attributed to its ability to counteract the inflammatory ROS generation and regulate cytokine effects.

While propolis is known to have abundant bioactive constituents and a variety of biological activities, it is not clear whether propolis has beneficial effects on high glucose-mediated vascular endothelial impairment. The aim of the present study was to investigate the potential protective effect of propolis extract against the acute vascular endothelial dysfunction resulting from exposure to high glucose load and to elucidate its underlying mechanism. Rat aortic rings were incubated with normal glucose (11 mM), high glucose (44 mM), or mannitol (44 mM) for 3 h with or without propolis extract (400 μg/ml). Contraction to phenylephrine (Phe, 10(-9)-10(-5) M) and relaxation to acetylcholine (ACh, 10(-9)-10(-5) M) and sodium nitroprusside (SNP, 10(-9)-10(-5) M) were measured before and after incubation. Changes in malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were also measured. Phe-induced contraction was impaired by high glucose as the E(max) decreased from 138.87 ± 11.43 to 103.65 ± 11.5 %. In addition, ACh-induced relaxation was impaired as the E(max) decreased from 99.80 ± 7.25 to 39.20 ± 6.5 %. SNP-induced relaxation was not affected. Furthermore, high glucose decreased the levels of both SOD (by 6 U/ml) and GSH (by 68 %) and increased levels of MDA (by 85 %). Propolis extract prevented high glucose-induced impairment of Phe and ACh responses and increased both SOD and GSH, leading to decreased MDA levels. In conclusion, propolis can protect against high glucose-induced vascular dysfunction by reducing oxidative stress.

Silicosis is one of the most prevalent chronic occupational pulmonary diseases worldwide. The present study aimed to investigate the effects of methyl palmitate on silica-induced lung fibrosis in rats and explore the possible mechanisms. Male Sprague-Dawley rats were divided into 3 groups: group I served as control and group II served as positive control where rats were intranasally instilled with a single dose of silica suspension (50mg in 0.1ml saline/rat). Rats of group III received methyl palmitate (300mg/kg, I.P. three times per week at alternating days) for 60days after instillation of silica. At the end of the treatment period, animals were sacrificed then biochemical parameters and histopathology were assessed. Treatment with methyl palmitate attenuated silica-induced lung inflammation and fibrosis, as it significantly decreased lactate dehydrogenase (LDH) activity and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid (BALF). Methyl palmitate significantly reduced collagen deposition as indicated by a decrease in lung hydroxyproline content and marked attenuation in silica-induced lung fibrosis in histopathological results. In addition, methyl palmitate significantly increased superoxide dismutase (SOD) and reduced glutathione (GSH) activities with a significant decrease in the lung malondialdehyde (MDA) content. Methyl palmitate also reduced silica mediated overproduction of pulmonary nitrite/nitrate (NO2(-)/NO3(-)). Importantly, methyl palmitate decreased the level of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the lung. Taken together, these results demonstrate the potent protective effects of methyl palmitate against silica-induced lung fibrosis. This effect can be attributed to methyl palmitate's ability to counteract the inflammatory cells' infiltration and hence reactive oxygen species (ROS) generation and regulate cytokine effects., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study aimed to assess the effects of thymoquinone (TQ) on pyrogallol-induced endothelial dysfunction in isolated rabbit aorta. The protective effects of TQ were examined by incubating aortic rings in TQ concomitant with pyrogallol. The results revealed that pyrogallol produced significant enhancement of phenylephrine-induced contraction and impairment of acetylcholine-induced relaxation. Pyrogallol caused a significant increase in lipid peroxidation and reduction in the level of superoxide dismutase and reduced glutathione in the aortic homogenates. In addition, pyrogallol produced a significant decrease in nitrite/nitrate concentrations (NOx), constitutive nitric oxide synthase (cNOS) activity and an increase in inducible nitric oxide synthase (iNOS) activity in the aortic homogenates. These changes were counteracted by TQ co-incubation as TQ attenuated pyrogallol-induced impairment in vascular reactivity in a dose-dependent manner. Furthermore, TQ showed potent antioxidant activity as well as causing a significant increase in NOx and cNOS activity, and depression in iNOS activity. These results suggest that TQ can protect against pyrogallol-induced endothelial dysfunction which probably results from its potent antioxidant capacity that leads to an increase in NO production as well as its ability to enhance the generation and bioavailability of NO.

Sitagliptin, a new oral glucose lowering medication, is used for treatment of type 2 diabetes mellitus. The anti-inflammatory property of sitagliptin is reported, yet no studies have been done on asthma. In the present study, the effect of sitagliptin on allergic asthma was investigated using ovalbumin (OVA)-induced asthma model in mice. Swiss male albino mice sensitized and challenged to ovalbumin were treated with sitagliptin (8 mg/kg administered orally twice a day). Drug treatment was done on each day from days 16 to 23, 1 h before the challenge on the days of challenge. Sitagliptin treatment markedly decreased inflammatory cell accumulation in bronchoalveolar lavage (BAL) fluid and in the lungs, as revealed by histopathological examination. Furthermore, the levels of interleukin (IL)-13 in BAL fluid, total and OVA specific immunoglobulins (Ig)-E in serum, were significantly reduced as compared to the OVA group. In addition, sitagliptin significantly increased superoxidase dismutase (SOD) and reduced glutathione (GSH) activities with significant decrease in malondialdehyde (MDA) content in the lung. Importantly, sitagliptin decreased mRNA expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and transforming growth factor-β(1) (TGF-β(1)) in lung tissues as compared to the OVA group. Moreover, nitric oxide content as well as the mRNA expression of inducible nitric oxide synthase (iNOS) was remarkably decreased by sitagliptin treatment. Sitagliptin attenuates the allergic airway inflammation suggesting that sitagliptin may have applications in the treatment of bronchial asthma.

Nilotinib is a new orally bioavailable potent tyrosine kinase inhibitor that is used for the treatment of BCR-ABL-positive chronic myelogenous leukemia. However, its effect on mast cell-mediated anaphylactic reaction is still not known. The present study aimed to investigate the effect of nilotinib on the anaphylactic allergic reaction and study its possible mechanism(s) of action. Nilotinib administration prevented systemic anaphylaxis in mice, mediated by compound 48/80, in a dose- and time-dependent manner. Also, nilotinib significantly inhibited (P<0.05) allergic paw edema in rats. Furthermore, nilotinib significantly decreased (P<0.05) the IgE-mediated passive cutaneous anaphylaxis in a dose dependent manner. In addition, nilotinib dose-dependently reduced histamine release from the rat peritoneal mast cells activated either by compound 48/80 or by ovalbumin. Moreover, nilotinib attenuated the secretion of pro-inflammatory cytokine, tumor necrosis factor (TNF)-α expression in the rat peritoneal mast cells. These findings provide evidence that nilotinib inhibits mast cell-derived immediate-type allergic reactions and so it could be a candidate as an anti-allergic agent., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The present study was designed to examine the potential preventive and curative effects of curcumin, resveratrol, imatinib, rosiglitazone, losartan and bosentan (BOS) on Schistosoma mansoni-induced liver fibrosis in mice. Induction of liver fibrosis was produced in male Swiss mice by subcutaneous injection of S. mansoni cercariae per mouse. Mice were left for 28 days before starting the experiment then mice were divided into two main groups. The first group was further subdivided into experimental groups and started drug treatment at day 28 after infection and continued for 2 weeks in order to evaluate the potential preventive effects of the mentioned drugs on S. mansoni-induced liver fibrosis. The second group of mice were left for 2 weeks and then treated with praziquantel for two consecutive days to eradicate the worms and so stop egg disposition and further fibrosis development. Mice were then subdivided into the experimental groups and drug treatment was started for 2 weeks to evaluate their efficacy to decrease the developed fibrosis. At the end of the experiment period, mice were killed and serum was collected for the estimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and albumin. Liver tissue was taken for the estimation of hepatic hydroxyproline content and histopathological examination to confirm the biochemical results. Results of the study indicate that curcumin and imatinib have potent antifibrotic activity both in suppressing and reversing S. mansoni-induced liver fibrosis, while resveratrol has beneficial effects only in suppressing the development of S. mansoni-induced liver fibrosis.