Cerium oxide nanoparticles impact on sepsis-induced cerebral injury: Deciphering miRNA / NF-κB/TLR signalling pathway.

Sepsis is regarded as an inflammatory syndrome that consists of complex biochemical and pathophysiological dysregulation, brought on by endogenous factors in response to systemic infection. Sepsis can cause short- and long-term cerebral injury. Cerium oxide nanoparticles (CeO2 NPs) have been reported to possess both anti-inflammatory and antioxidative properties. The current study investigated the potential role of cerium oxide nanoparticles in the management of sepsis-induced brain injury. To achieve this target, forty male albino rats were divided into 4 groups, ten rats each. Group (i) set as a shame group. Group (ii) set as shame group administrated CeO2 NPs. Group (iii) septic group treated with saline and Group (iv) septic group treated with CeO2 NPs. The sepsis model in rats was induced by cecal ligation and puncture (CLP). Results showed CeO2 NPs administration resulted in significant improvement in the survival rate of rats, suppression in serum sepsis biomarkers (CRP, ESM-1, PCT and D- dimer), amelioration of brain inflammatory mediators (TNF-α- IL-6, NF-kB and LTB4) as well as apoptotic markers (Cas-3 and BAX). Furthermore, immunomodulation of miRNAs expression (155,124 and 146a). These findings demonstrate a promising pivotal role of CeO2 NPs treatment in alleviating the deleterious effects induced by sepsis in the brain.

Protective effect of kaempferol glucoside against lipopolysaccharide-caused acute lung injury via targeting Nrf2/NF-κB/NLRP3/GSDMD: Integrating experimental and computational studies.

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-1ß (interleukine-1ß) 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.

Targeting allosteric sites of human aromatase: a comprehensive in-silico and in-vitro workflow to find potential plant-based anti-breast cancer therapeutics.

Recent findings suggested several allosteric pockets on human aromatase that could be utilised for the development of new modulators able to inhibit this enzyme in a new mechanism. Herein, we applied an integrated in-silico-based approach supported by in-vitro enzyme-based and cell-based validation assays to select the best leads able to target these allosteric binding sites from a small library of plant-derived natural products. Chrysin, apigenin, and resveratrol were found to be the best inhibitors targeting the enzyme's substrate access channel and were able to produce a competitive inhibition with IC50 values ranged from 1.7 to 15.8 µM. Moreover, they showed a more potent antiproliferative effect against ER+ (MCF-7) than ER- one (MDA-MB-231) cell lines. On the other hand, both pomiferin and berberine were the best hits for the enzyme's haem-proximal cavity producing a non-competitive inhibition (IC50 15.1 and 21.4 µM, respectively) and showed selective antiproliferative activity towards MCF-7 cell lines.

Peptide substrate screening for the diagnosis of SARS-CoV-2 using fluorescence resonance energy transfer (FRET) assay.

The novel corona (SARS-CoV-2) virus causes a global pandemic, which motivates researchers to develop reliable and effective methods for screening and detection of SARS-CoV-2. Though there are several methods available for the diagnosis of SARS-CoV-2 such as RT-PCR and ELSIA, nevertheless, these methods are time-consuming and may not apply at the point of care. In this study, we have developed a specific, sensitive, quantitative and fast detection method for SARS-CoV-2 by fluorescence resonance energy transfer (FRET) assay. The total extracellular protease proteolytic activity from the virus has been used as the biomarker. The specific peptide sequences from the library of 115 dipeptides were identified via changes in the fluorescence signal. The fluorogenic dipeptide substrates have the fluorophore and a quencher at the N- and the C- terminals, respectively. When the protease hydrolyzes the peptide bond between the two specific amino acids, it leads to a significant increase in the fluorescence signals. The specific fluorogenic peptide (H-d) produces a high fluorescence signal. A calibration plot was obtained from the changes in the fluorescence intensity against the different concentrations of the viral protease. The lowest limit of detection of this method was 9.7 ± 3 pfu/mL. The cross-reactivity of the SARS-CoV-2-specific peptide was tested against the MERS-CoV which does not affect the fluorescence signal. A significant change in the fluorescence signal with patient samples indicates that this FRET-based assay might be applied for the diagnosis of SARS-CoV-2 patients. Graphical abstract.

Untargeted Metabolic Profiling of Extracellular Vesicles of SARS-CoV-2-Infected Patients Shows Presence of Potent Anti-Inflammatory Metabolites.

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this study aimed to perform untargeted metabolomics to identify key metabolites and associated pathways that are present in EVs, isolated from the serum of COVID-19 patients. The results showed the presence of antivirals and antibiotics such as Foscarnet, Indinavir, and lymecycline in EVs from patients treated with these drugs. Moreover, increased levels of anti-inflammatory metabolites such as LysoPS, 7-α,25-Dihydroxycholesterol, and 15-d-PGJ2 were detected in EVs from COVID-19 patients when compared with controls. Further, we found decreased levels of metabolites associated with coagulation, such as thromboxane and elaidic acid, in EVs from COVID-19 patients. These findings suggest that EVs not only carry active drug molecules but also anti-inflammatory metabolites, clearly suggesting that exosomes might play a crucial role in negotiating with heightened inflammation during COVID-19 infection. These preliminary results could also pave the way for the identification of novel metabolites that might act as critical regulators of inflammatory pathways during viral infections.

Evaluation in broilers of aerosolized nanoparticles vaccine encapsulating imuno-stimulant and antigens of avian influenza virus/Mycoplasma gallisepticum.

BACKGROUND: The global prevalence of economic primary infection of poultry by H9N2 virus, including the Lineage A, panzootic group ME1, and associated with secondary infection by Mycoplasma gallisepticum (MG), is alarming to the sustainability of the poultry sector. This research evaluated in broilers the immunity and protection induced by aerosolization of liposomal nanoparticles vaccine, encapsulating antigens of H9N2 virus and MG, with or without the incorporation of Echinacea extract (EE) immuno-stimulant. Six different treatments (TRTs) of broilers were included in the experimental design, with three replicate pens/TRT and stocking of 20 day-old birds/replicate. RESULTS: The tracheobronchial washings of birds subjected to aerosolization of liposomal nanoparticles, encapsulating antigens of H9N2 and MG and EE had the highest significant mean levels of each of IgA and IgG specific to H9N2 and MG, associated with lowest tracheal MG colonization, tracheal H9N2 recovery, tracheal histopathologic lesions, mortality, and best performance in body weight and feed conversion compared to all other challenged birds allocated to different treatments (P < 0.05). However, the control broilers, free from challenge with MG and H9N2, had the lowest mortality and tracheal lesions, and the highest production performance. CONCLUSION: The aerosolization of liposomal nanoparticles, encapsulating antigens of H9N2 and MG and EE resulted in enough local immunity for protection of broilers against infection, and in attaining the highest production performance in challenged birds. The potential implication of vaccinating with safe killed nanoparticle vaccines is of utmost importance to the global poultry sector.

Chitosan Coated Microparticles Enhance Simvastatin Colon Targeting and Pro-Apoptotic Activity.

This work aimed at improving the targeting and cytotoxicity of simvastatin (SMV) against colon cancer cells. SMV was encapsulated in chitosan polymers, followed by eudragit S100 microparticles. The release of SMV double coated microparticles was dependent on time and pH. At pH 7.4 maximum release was observed for 6 h. The efficiency of the double coat to target colonic tissues was confirmed using real-time X-ray radiography of iohexol dye. Entrapment efficiency and particle size were used in the characterization of the formula. Cytotoxicity of SMV microparticles against HCT-116 colon cancer cells was significantly improved as compared to raw SMV. Cell cycle analysis by flow cytomeric technique indicated enhanced accumulation of colon cancer cells in the G2/M phase. Additionally, a significantly higher cell fraction was observed in the pre-G phase, which highlighted enhancement of the proapoptotic activity of SMV prepared in the double coat formula. Assessment of annexin V staining was used for confirmation. Cell fraction in early, late and total cell death were significantly elevated. This was accompanied by a significant elevation of cellular caspase 3 activity. In conclusion, SMV-loaded chitosan coated with eudragit S100 formula exhibited improved colon targeting and enhanced cytotoxicity and proapoptotic activity against HCT-116 colon cancer cells.

Synthesis and in vitro antitumor activity of novel acylspermidine derivative N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide (AAHD) against HepG2 cells.

Naturally occurring polyamines like Putrescine, Spermidine, and Spermine are polycations which bind to the DNA, hence stabilizing it and promoting the essential cellular processes. Many synthetic polyamine analogues have been synthesized in the past few years, which have shown cytotoxic effects on different tumours. In the present study, we evaluated the antiproliferative effect of a novel, acylspermidine derivative, (N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide) (AAHD) on HepG2 cells. Fluorescence staining was performed with nuclear stain (Hoechst 33342) and acridine orange/ethidium bromide double staining. Dose and the time-dependent antiproliferative effect were observed by WST-1 assays, and radical scavenging activity was measured by ROS. Morphological changes such as cell shrinkage & blebbing were analyzed by fluorescent microscopy. It was found that AAHD markedly suppressed the growth of HepG2 cells in a dose- and time-dependent manner. It was also noted that the modulation of ROS levels confirmed the radical scavenging activity. In the near future, AAHD can be a promising drug candidate in chalking out a neoplastic strategy to control the proliferation of tumour cells. This study indicated that AAHD induced anti-proliferative and pro-apoptotic activities on HCC. Since AAHD was active at micromolar concentrations without any adverse effects on the healthy cells (Fibroblasts), it is worthy of further clinical investigations.

Determinants of breast cancer in Saudi women from Makkah region: a case-control study (breast cancer risk factors among Saudi women).

BACKGROUND: There are various factors that play a major role in influencing the overall health conditions of women diagnosed with breast cancer. The population of women in Makkah region are diverse, therefore it is significant to highlight the possible determinants of breast cancer in this population. This is a case-control study that assessed determinants of breast cancer including socioeconomic factors, health-related characteristics, menstrual histories and breastfeeding among postmenopausal women in Makkah region in Saudi Arabia. METHODS: A total of 432 female participants (214 cases and 218 controls) were recruited for this study. A validated questionnaire was completed by trained dietitians at King Abdullah Medical City Hospital in the Makkah region of Saudi Arabia. RESULTS: Results displayed that determinants of breast cancer were associated significantly (P < 0.05) with unemployment, large family size, lack of knowledge and awareness about breast cancer, obesity, sedentary lifestyle, smoking, starting menarche at an early age, as well as hormonal and non-hormonal contraceptive use. There was no effect of diabetes, hypertension, hyperlipidemia, and duration of breastfeeding on the incidence of breast cancer. CONCLUSION: In summary, the results of this study accentuate the possible effect of socioeconomic factors, health-related characteristics and menstrual history on the incidence of breast cancer in postmenopausal women in the Makkah region. Education programs should be applied to increase breast cancer awareness and possibly decrease its incidence.

Hepato-protective effect of Allium sativum against immobilization stress in rats.

The purpose of the current study was to examine immobilization stress-induced antioxidant defense changes and estimation of the antioxidant potential of pre and post stress treatment of aqueous garlic extract in rat's liver. For this purpose, male Albino Wistar rats were treated with aqueous garlic extract both pre and after 6 h of immobilization stress. Pro-oxidant status of rat liver was evaluated by determining the levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), glucose, uric acid and the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST). In response to 6 h of immobilization stress a significant rise in the level of above mentioned liver enzymes were recorded. However, SOD, CAT and GST enzymatic activities showed a sharp decline. The extract treatment before and after stress, almost reverted the activities of studied biochemical parameters towards their control values. Current study highlighted the antioxidant potential of garlic extracts. Based on our study, we recommend the use of garlic extract as nutritional supplement for combating oxidative stress induced damage.

Purification and characterization of cysteine protease from miswak Salvadora persica.

BACKGROUND: Generally, proteases in medicinal plants had different therapeutic effects such as anti-inflammatory effect; modulate the immune response and inhibitory effect toward tumor growth. In this study, protease was purified and characterized from miswak roots, as medicinal plant and natural toothbrush. RESULTS: Physical and chemical characterization of cysteine protease P1 were studied such as pH optimum (6.5), optimum temperature (50 °C), thermal stability (50 °C) and Km (3.3 mg azocasein/ml). The enzyme digested some proteins in the order of caseine > haemoglobin > egg albumin >gelatin > bovine serum albumin. Hg2+ had strong inhibitory effect on enzyme activity compared with other metal ions. Kinetic of inhibition for determination the type of protease was studied. Iodoactamide and p-Hydroximercuribenzaoic acid (p-HMB) caused strong inhibitory effect on enzyme activity indicating the enzyme is cysteine protease. CONCLUSIONS: The biochemical characterization of this enzyme will be display the suitable conditions for using of this enzyme in toothpaste in the future and the enzyme may be used in other applications.

Purification and characterization of α-amylase from Trichoderma pseudokoningii.

BACKGROUND: Previous studies have demonstrated that members of Trichoderma are able to generate appreciable amount of extracellular amylase and glucoamylase on soluble potato starch. In this study the α-amylase was purified and characterized from Trichoderma pseudokoningii grown on orange peel under solid state fermentation (SSF). RESULTS: Five α-amylases A1-A5 from Trichodrma pseudokoningii were separated on DEAE-Sepharose column. The homogeneity of α-amylase A4 was detected after chromatography on Sephacryl S-200. α-Amylase A4 had molecular weight of 30 kDa by Sephacryl S-200 and SDS-PAGE. The enzyme had a broad pH optimum ranged from 4.5 to 8.5. The optimum temperature of A4 was 50 °C with high retention of its activity from 30 to 80 °C. The thermal stability of A4 was detected up to 50 °C and the enzyme was highly stable till 80 °C after 1 h incubation. All substrate analogues tested had amylase activity toward A4 ranged from 12 to 100% of its initial activity. The Km and Vmax values of A4 were 4 mg starch/ml and 0.74 µmol reducing sugar, respectively. The most of metals tested caused moderate inhibitory effect, except of Ca2+ and Mg2+ enhanced the activity. Hg2+ and Cd+ 2 strongly inhibited the activity of A4. EDTA as metal chelator caused strong inhibitory effect. CONCLUSIONS: The properties of the purified α-amylase A4 from T. pseudokoningii meet the prerequisites needed for several applications.

Characterization of a conditional interleukin-1 receptor 1 mouse mutant using the Cre/LoxP system.

IL-1 is a key cytokine known to drive chronic inflammation and to regulate many physiological, immunological, and neuroimmunological responses via actions on diverse cell types of the body. To determine the mechanisms of IL-1 actions as part of the inflammatory response in vivo, we generated a conditional IL-1 receptor 1 (IL-1R1) mouse mutant using the Cre/LoxP system (IL-1R1(fl/fl) ). In the mutant generated, exon 5, which encodes part of the extracellular-binding region of the receptor, is flanked by LoxP sites, thereby inactivating the two previously described functional IL-1R1 gene transcripts after Cre-mediated recombination. Using keratin 14-Cre driver mice, new IL-1R1 deficient (-/-) mice were subsequently generated, in which all signaling IL-1 receptor isoforms are deleted ubiquitously. Furthermore, using vav-iCre driver mice, we deleted IL-1 receptor isoforms in the hematopoietic system. In these mice, we show that both the IL-17 and IL-22 cytokine response is reduced, when mice are challenged by the helminth Trichuris muris. We are currently crossing IL-1R1(fl/fl) mice with different Cre-expressing mice in order to study mechanisms of acute and chronic inflammatory diseases.

The use of flow cytometry to examine calcium signalling by TRPV1 in mixed cell populations.

Flow cytometric analysis of calcium mobilisation has been in use for many years in the study of specific receptor engagement or isolated cell:cell communication. However, calcium mobilisation/signaling is key to many cell functions including apoptosis, mobility and immune responses. Here we combine multiplex surface staining of whole spleen with Indo-1 AM to visualise calcium mobilisation and examine calcium signaling in a mixed immune cell culture over time. We demonstrate responses to a TRPV1 agonist in distinct cell subtypes without the need for cell separation. Multi parameter staining alongside Indo-1 AM to demonstrate calcium mobilization allows the study of real time calcium signaling in a complex environment.

Role of hesperetin in LDL-receptor expression in hepatoma HepG2 cells.

BACKGROUND: High plasma concentration of low-density lipoprotein cholesterol (LDL-c) plays a significant role in the incidence of atherosclerosis and coronary heart diseases. The aim of this study was to investigate the mechanism by which the citrus flavonoid, hesperetin, regulates the LDL receptor (LDLr) gene in the human liver using the human hepatoma cell line, HepG2. METHODS: Luciferase reporter gene assays were performed (in the absence of lipoprotein) to measure the activity of the LDLr promoter and the promoters of the sterol regulatory element binding protein (SREBP) transcription factors that control the LDLr promoter. RESULTS: Only SREBP-1 promoter activity was significantly increased 4 h after exposure to 200 µM hesperetin. However, after 24 h incubation with 200 µM hesperetin, the activities of all the promoter-constructs, SREBP-1a, -1c, -2 and LDLr, were significantly increased. The effects of 200 µM hesperetin on elevating LDLr mRNA levels were possibly due to regulation of LDLr gene transcription by SREBP-la and SREBP-2. CONCLUSIONS: We conclude that 200 µM hesperetin was likely to have stimulated LDLr gene expression in human hepatoma HepG2 cells via increased phosphorylation of PI3K andERK1/2, which increased SREBP-1a and SREBP-2 mRNA levels and enhanced the maturation of the encoded proteins. This may lead to lower plasma LDL cholesterol; therefore, diets supplemented with hesperidin might provide cardio-protective effects and reduce mortality and morbidity from coronary heart diseases.

Design, synthesis, molecular modeling, and biological evaluations of novel chalcone based 4-Nitroacetophenone derivatives as potent anticancer agents targeting EGFR-TKD.

A series of chalcone-based 4-Nitroacetophenone derivatives were designed and synthesized by the single-step condensation method. These compounds were identified by 1H NMR,13C NMR, MS, and FTIR analysis. Further, the derivatives were evaluated against four cancer cell lines H1299, MCF-7, HepG2, and K526. The IC50 value of potent compounds NCH-2, NCH-4, NCH-5, NCH-6, NCH-8, and NCH-10 was 4.5-11.4 µM in H1299, 4.3-15.7 µM in MCF-7, 2.7-4.1 µM in HepG2 and 4.9-19.7 µM in K562. To assess the toxicity against healthy cells all potent molecules were evaluated against the HEK-293T cell line, and IC50 values exhibited by NCH-2, and NCH-3 were 77.8, 74.3, and other molecules showed IC50 values > 100 µM. The EGFR expression was determined by using rabbit anti-EGFR monoclonal antibody and significant EGFR expression was knocked down observed in H1299 treated with NCH-10 as well as erlotinib. The underlying mechanism behind cell death was investigated through bioinformatics. First, the molecules were optimized and docked to the binding site of the EGFR kinase domain. The best complexes were simulated for 100-ns and compounds NCH-2, NCH-4, and NCH-10 achieved stability similar to the erlotinib bound kinase domain. The free energy binding (ΔGbind) of NCH-10 was found to be more negative -226.616 ± 2.148 kJ/mol calculated by Molecular Mechanics Poisson Boltzmann's Surface Area (MM-PBSA) method. Both in vitro and in silico results conclude that the present class of chalcone-based 4-Nitroacetophenone derivatives are potent anti-cancer agents targeting EGFR-TKD and are 39 folds more effective against H1299, MCF-7, HepG2, and K562 carcinoma cell lines than healthy HEK-293T cell lines.Communicated by Ramaswamy H. Sarma.

RETRACTED: Alhakamy et al. Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans. Pharmaceutics 2021, 13, 977.

The journal retracts the article, "Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans" [...].

Capsaicin ameliorate pulmonary fibrosis via antioxidant Nrf-2/ PPAR- γ pathway activation and inflammatory TGF-ß1/ NF-κB/COX II pathway inhibition.

Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis. Therefore, this study aimed to assess the therapeutic potential of Capsaicin as an additional treatment to enhance patient tolerance to Bleomycin compared to the antifibrotic drug Pirfenidone. Pulmonary fibrosis was induced in rats through by a single intratracheal Bleomycin administration in day zero, followed by either Capsaicin or Pirfenidone treatment for 7 days. After the animals were sacrificed, their lungs were dissected and examined using various stains for macroscopic and histopathological evaluation. Additionally, the study assessed various antioxidant, anti-inflammatory, and antifibrotic parameters were assessed. Rats exposed to Bleomycin exhibited visible signs of fibrosis, histopathological alterations, increased collagen deposition, and elevated mucin content. Bleomycin also led to heightened increased inflammatory cells infiltration in the bronchoalveolar lavage, elevated fibrosis biomarkers such as hydroxyproline, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-ß1), increased inflammatory markers including tumor necrosis factor-alpha (TNF-α), interlukine-6 (Il-6), interlukine-1ß (Il-1ß) nuclear factor-kappa B (NF-κB), and Cyclooxygenase-2 (COX-2), and transforming growth factor-beta (TGF-ß1),. Furthermore, it reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), increased oxidative stress biomarkers like nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and protein carbonyl. Bleomycin also decreased the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), reduced glutathione (GSH), total antioxidant capacity, and the activities of catalase and superoxide dismutase (SOD). Treating the animals with Capsaicin and Pirfenidone following Bleomycin exposure resulted in improved lung macroscopic and microscopic characteristics, reduced collagen deposition (collagen I and collagen III) and mucin content, decreased inflammatory cell infiltration, lowered levels of hydroxyproline, α-SMA, and TGF-ß1, decreased TNF-α, Il-6, Il-1ß, NF-κB, and COX-2, increased PPAR-γ and Nrf-2 expression, and improvement improved in all oxidative stress biomarkers. In summary, Capsaicin demonstrates significant antifibrotic activity against Bleomycin-induced lung injury that may be attributed, at least in part, to the antioxidant and anti-inflammatory activities of Capsaicin mediated by upregulation of PPAR-γ and Nrf-2 expression and decreasing. TGF-ß1, NF-κB and COX II proteins concentrations.

Modulation of the crosstalk between Keap1/Nrf2/HO-1 and NF-κB signaling pathways by Tomatidine protects against inflammation/oxidative stress-driven fulminant hepatic failure in mice.

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-1ß, 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-1ß/iNOS signaling pathways.