Renoprotective effect of diacetylrhein on diclofenac-induced acute kidney injury in rats via modulating Nrf2/NF-κB/NLRP3/GSDMD signaling pathways.

Diclofenac (DF)-induced acute kidney injury (AKI) is characterized by glomerular dysfunction and acute tubular necrosis. Due to limited treatment approaches, effective and safe drug therapy to protect against such AKI is still needed. Diacetylrhein (DAR), an anthraquinone derivative, has different antioxidant and anti-inflammatory properties. Therefore, the aim of the current study was to investigate the renoprotective effect of DAR on DF-induced AKI while elucidating the potential underlying mechanism. Our results showed that DAR (50 and 100 mg/kg) markedly abrogated DF-induced kidney dysfunction decreasing SCr, BUN, serum NGAL, and serum KIM1 levels. Moreover, DAR treatment remarkably maintained renal redox balance and reduced the levels of pro-inflammatory biomarkers in the kidney. Mechanistically, DAR boosted Nrf2/HO-1 antioxidant and anti-inflammatory response in the kidney while suppressing renal TLR4/NF-κB and NLRP3/caspase-1 inflammatory signaling pathways. In addition, DAR markedly inhibited renal pyroptosis via targeting of GSDMD activation. Collectively, this study confirmed that the interplay between Nrf2/HO-1 and TLR4/NF-κB/NLRP3/Caspase-1 signaling pathways and pyroptotic cell death mediates DF-induced AKI and reported that DAR has a dose-dependent renoprotective effect on DF-induced AKI in rats. This effect is due to powerful antioxidant, anti-inflammatory, and anti-pyroptotic activities that could provide a promising treatment approach to protect against DF-induced AKI.

Inhibitory effect of diacerein on diclofenac-induced acute nephrotoxicity in rats via modulating SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

The aim of this study is to explore the potential of repurposing the antiarthritic drug diacerein (DCN) against diclofenac (DCF)-induced acute nephrotoxicity in rats. Rats were divided into four groups: Group I (CTRL) served as the negative control; Group II (DCF) served as the positive control and was injected with DCF (50 mg/kg/day) for three consecutive days (fourth-sixth) while being deprived of water starting on day 5; Group III (DCF + DCN50) and Group IV (DCF + DCN100) were orally administered DCN (50 and 100 mg/kg/day, respectively) for six days and injected with DCF, while being deprived of water as described above. Changes in kidney function biomarkers were assessed. Levels of MDA and GSH along with NO content in kidney tissues were measured as indicators of oxidative stress status. Histopathological changes of the renal cortex and medulla were evaluated. Changes in renal NF-κB and SIRT-1 levels were immunohistochemically addressed. Western blotting was used to estimate the relative expressions of HIF-1α, p53, and active caspase-3. Our results showed that DCN inhibited kidney dysfunction and suppressed oxidative stress, which were reflected in improved kidney architecture, including less tubular degeneration and necrosis in the cortex and medulla. Interestingly, DCN reduced renal HIF-1α, p53, and active caspase-3 expression and NF-κB activation while increasing renal SIRT1 expression. In conclusion, for the first time, DCN counteracts acute kidney injury induced by DCF in rats by its anti-oxidative, anti-inflammatory, antinecrotic, and anti-apoptotic effects in a dose-dependent manner, which are mainly via targeting SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

Tiron ameliorates acetic acid-induced colitis in rats: Role of TGF-ß/EGFR/PI3K/NF-κB signaling pathway.

BACKGROUND: Ulcerative colitis (UC), an ongoing inflammatory disorder of the colon, is marked by persistent mucosal surface irritation extending from the rectum to the near-proximal colon. Tiron is a synthetic analogue of vitamin E which is known to have antioxidant and anti-inflammatory effects in various animal models, so the goal of this study was to find out whether Tiron had any preventive impacts on UC inflicted by acetic acid (A.A) exposure in rats. METHOD: Tiron (235 and 470 mg/kg) was administered intra-peritoneally for 2 weeks, and A.A (2 ml, 3 % v/v) was injected intra-rectally to cause colitis. Colon tissues and blood samples were then collected for measurement of various inflammatory and oxidative stress biomarkers. RESULTS: Tiron administration significantly diminished lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon as compared to A.A-injected rats. Additionally, Tiron attenuated oxidative stress biomarkers. Tiron also enforced the levels of Glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3), while it greatly lowered the expression of nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interferon-γ (IFN-γ), and transforming growth factor-1(TGF-ß1), phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic cellular structures. Furthermore, colonichistopathologic damages, revealed by hematoxylin and eosin (H&E) and Alcian Blue stain, were significantly decreased upon Tiron administration. CONCLUSION: Tiron prevented A.A-induced colitis in rats via modulating inflammatory pathway TGF-ß1/P-EGFR/PI3K/AKT/NF-κB, alongside managing the oxidant/antioxidant equilibrium, and boosting the reliability of the intestinal barrier.

Artificial neural network approach for prediction of AuNPs biosynthesis by Streptomyces flavolimosus, characterization, antitumor potency in-vitro and in-vivo against Ehrlich ascites carcinoma.

Gold nanoparticles (AuNPs) have emerged as promising and versatile nanoparticles for cancer therapy and are widely used in drug and gene delivery, biomedical imaging, diagnosis, and biosensors. The current study describes a biological-based strategy for AuNPs biosynthesis using the cell-free supernatant of Streptomyces flavolimosus. The biosynthesized AuNPs have an absorption peak at 530-535 nm. The TEM images indicate that AuNPs were spherical and ranged in size from 4 to 20 nm. The surface capping molecules of AuNPs are negatively charged, having a Zeta potential of - 10.9 mV. FTIR analysis revealed that the AuNPs surface composition contains a variety of functional groups as -OH, C-H, N-, C=O, NH3+, amine hydrochloride, amide group of proteins, C-C and C-N. The bioprocess variables affecting AuNPs biosynthesis were optimized by using the central composite design (CCD) in order to maximize the AuNPs biosynthesis. The maximum yield of AuNPs (866.29 µg AuNPs/mL) was obtained using temperature (35 °C), incubation period (4 days), HAuCl4 concentration (1000 µg/mL) and initial pH level 6. Comparison was made between the fitness of CCD versus Artificial neural network (ANN) approach based on their prediction and the corresponding experimental results. AuNPs biosynthesis values predicted by ANN exhibit a more reasonable agreement with the experimental result. The anticancer activities of AuNPs were assessed under both in vitro and in vivo conditions. The results revealed a significant inhibitory effect on the proliferation of the MCF-7 and Hela carcinoma cell lines treated with AuNPs with IC50 value of 13.4 ± 0.44 µg/mL and 13.8 ± 0.45 µg/mL for MCF-7 and Hela cells; respectively. Further, AuNPs showed potential inhibitory effect against tumor growth in tumor-bearing mice models. AuNPs significantly reduced the tumor volume, tumor weight, and decreased number of viable tumor cells in EAC bearing mice.

Eicosapentaenoic acid mitigates ulcerative colitis-induced by acetic acid through modulation of NF-κB and TGF-ß/ EGFR signaling pathways.

BACKGROUND: Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine that mostly affects the rectum and colon. The absence of safe and effective therapeutic agents encourages the discovery of novel therapeutic agents to effectively treat UC and its complications. The purpose of this research was to examine the protective impact of Eicosapentaenoic acid (EPA) in rats with UC induced by acetic acid (AA). METHOD: AA (2 ml, 3 % v/v) was injected intrarectally to cause UC. Before administering AA, EPA (300 and 1000 mg/kg) was given orally for 28 days. RESULTS: EPA inhibited AA-induced UC by enhancing colonic histopathological changes like inflammation, goblet cell loss, glandular hyperplasia and mucosal ulceration, concomitant with a reduction in colon weight, colon weight/length ratio, C-reactive protein (CRP), and serum lactate dehydrogenase (LDH). EPA also effectively restored the imbalance between oxidants and antioxidants caused by AA. In addition, EPA increased the levels of trefoil factor-3 (TFF-3) and glucagon-like peptide-1 (GLP-1), while significantly reducing the expression of nuclear factor kappa B (NF-κB), interferon-γ (IFN-γ), and interleukin-6 (IL-6), transforming growth factor-1(TGF-ß1), and phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic tissues. CONCLUSION: EPA inhibited AA-induced UC in rats by modulating the TGF-ß/P-EGFR and NF-κB inflammatory pathways, regulating the oxidant/antioxidant balance, and enhancing the colon barrier integrity.

TLR4-IN-C34 protects against acute kidney injury via modulating TLR4/MyD88/NF-κb axis, MAPK, and apoptosis.

Objectives: Acute kidney injury (AKI) is a major component of isoproterenol (ISO) induced cardiorenal syndrome. In this study, we investigated the effect of TLR4-IN-C34 as a toll-like receptor (TLR)-4 inhibitor on ameliorating ISO-induced AKI and the possible molecular underlying pathways. Materials and Methods: The study included 4 groups: control group, ISO group (rats received 100 mg/kg ISO in 2 doses 24 hr apart, SC), ISO+C341 and ISO+C343 groups (rats received 1 or 3 mg/kg TLR4-IN-C34 respectively twice one hour before each ISO injection, IP). Results: Obtained results showed that TLR4-IN-C34 injection prior to ISO decreased serum creatinine level (P<0.05). Renal tissue histopathologic changes were markedly decreased by TLR4-IN-C34. Renal relative expression of MAPK and MyD88 mRNA decreased significantly in both ISO+C341 and ISO+C343 groups compared with the ISO group (P<0.05). Furthermore, TLR-IN-C34 lowered the inflammatory cytokines IL-8, IL-1ß, and IL-12 renal levels (P<0.05). Immunostained kidney sections showed a marked decrease in NF-κb positive cells in addition to the apoptotic marker Bax (P<0.05) by the two tested doses of TLR4-IN-C34. On the other hand, the expression of the antiapoptotic marker Bcl-2 by renal cells was markedly increased. Conclusion: It can be concluded that TLR4-IN-C34 ameliorates ISO-induced AKI through anti-inflammatory anti-apoptotic effects and modulation of TLR4 signaling pathways.

Dose-dependent renoprotective impact of Lactoferrin against glycerol-induced rhabdomyolysis and acute kidney injury.

Acute kidney injury (AKI) is a clinical disorder with a serious impact on the quality of patients' lives. Considering its increased worldwide prevalence, investigating novel therapeutic approaches for the management of AKI has been inevitable. Lactoferrin (LF), a glycoprotein belonging to the transferrin family, is known to play an important role in regulating iron homeostasis. This study aimed to evaluate the renoprotective effect of LF (30, 100, and 300 mg/kg orally) against glycerol (GLY)-induced rhabdomyolysis (RM) in rats. RM was induced by a single intramuscular injection of GLY 50% (10 mL/kg) after 24-h water deprivation in male Sprague-Dawley rats. LF administration conferred significant dose-dependent renoprotective impact against GLY-induced RM as evidenced by the decreased renal/somatic index and the significant improvement in renal functions as confirmed by the significant increase in creatinine clearance, decrease in serum creatinine and blood urea nitrogen, and improvement in albuminuria and proteinuria. Redox homeostasis was significantly restored in a dose-dependent manner as well. Moreover, serum interleukin-1ß (IL-1ß) was significantly decreased with a parallel significant decrease in renal NOD-like receptor family pyrin domain containing 3 (NLRP3) and thioredoxin interacting protein (TXNIP), kidney injury molecule-1 (KIM-1), caspase-3 expression, nuclear factor kappa B (NF-κB), cluster of differentiation (CD68) expression, and a significant increase in renal nuclear factor erythroid 2-related factor 2 (NRF2) expression. Ultimately, LF administration was associated with a significant amelioration of GLY-induced renal necrotic and inflammatory alterations. In conclusion, the observed dose-dependent nephroprotective effect of LF can be attributed to its modulatory impact on inflammatory/apoptotic/oxidative signaling.

Indapamide Increases IRS1 Expression and Modifies Adiponectin/NLRP3/PPARγ Crosstalk in Type 2 Diabetic Rats.

The current study aimed to evaluate the anti-diabetic effects of canagliflozin (CANA) and indapamide (INDA) and their impacts as adiponectin modulators in experimentally induced type 2 diabetes mellitus (T2DM). T2DM was associated with a significant rise in blood glucose level and HbA1C%, andreduced adiponectin and insulin secretions. Moreover, the malondialdehyde (MDA) contents in both the epididymal adipocytes and soleus muscle significantly escalated, while the total antioxidant capacity (TAC) and epididymal adipocyte Nrf2 expression significantly declined. Moreover, serum TNF-α, epididymal adipocyte's NOD-like receptor protein 3, NLRP3, NF-κB and CD68 expressions markedly escalated, and serum IL-10 significantly declined. Furthermore, there was a significant escalation in PPARγ expression in epididymal adipocytes, with a significant reduction in soleus muscle's expression of IRS1. CANA and INDA treatments markedly reduced blood glucose levels, increased adiponectin and insulin secretion, enhanced anti-oxidant defenses, and reduced oxidative burden, with marked anti-inflammatory impact. Interestingly, the impact of indapamide on DM indices and oxidative and inflammatory changes was comparable to that of canagliflozin. Nevertheless, indapamide had a superior effect compared to canagliflozin on HbA1c%, expression of IRS1 and reduction of NF-κB and CD68 expressions. INDA could be effective in regulating T2DM, with underlined anti-diabetic, antioxidant, and anti-inflammatory properties. INDA increased IRS1 expression and modified adiponectin/NLRP3/PPARγ crosstalk. The impacts of INDA are comparable to those of the standard anti-diabetic drug CANA.

Diacerein versus adipoRon as adiponectin modulators in experimentally-induced end-stage type 2 diabetes mellitus in rats.

The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.

Nifuroxazide mitigates cholestatic liver injury by synergistic inhibition of Il-6/Β-catenin signaling and enhancement of BSEP and MDRP2 expression.

Cholestasis is a complex hepatic disorder underlined with retention of the highly toxic bile components within the hepatocytes. Nifuroxazide (NIF); a nitrofuran derivative, is widely used drug for treatment of acute and chronic diarrhea. The current study was performed to investigate the curative effect of NIF (25 and 50 mg/kg) on lithocholic acid (LCA)-induced cholestasis and compare the observed impact to that of ursodeoxycholic acid (UDCA). Intriguingly, NIF significantly attenuated LCA-induced cholestatic injury. NIF successfully reversed cholestatic injury to a similar extent compared to the mainstay drug, UDCA. NIF administration remarkably attenuated liver/body index and restored liver functions. Moreover, it restored the disrupted balance in oxidative homeostasis. On the other hand, NIF induced a marked improvement in histopathological and immuno-histochemical analysis of liver specimens. Ultimately, NIF mitigated inflammatory response and proliferative ability of hepatocytes with significant reduction in hepatic expression of proliferatingcellnuclearantigen(PCNA), cluster of differentiation 68 (CD68), interlukin-6 (Il-6) and ß-catenin. Interestingly, NIF successfully increased bile transformation with increased the hepatic expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MDRP2). Nevertheless, molecular docking of NIF with ß-catenin and BSEP showed a better alignment inside the pocket with strong interaction for both protein binding sites. In conclusion, NIF attenuated experimentally-induced cholestatic dysfunction with an underlined synergistic inhibition of Il-6/Β-catenin pathways and direct enhancement of bile acids transporters gene expression.

Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling.

AIM: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis. MATERIALS AND METHODS: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis. RESULTS: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, ß-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3ß. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation. CONCLUSION: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation.

Graviola mitigates acetic acid-induced ulcerative colitis in rats: insight on apoptosis and Wnt/Hh signaling crosstalk.

In this study, we elucidated the potential protective effects of graviola leaves, compared with sulfasalazine, against acetic acid (AA)-induced ulcerative colitis (UC) in rats. Twenty-eight mature male rats were divided into four groups, Sham, Colitis, Colitis/Sulfa, and Colitis/Graviola, and were treated orally with either saline, saline, sulfasalazine (100 mg/kg/day), or graviola (100 mg/kg/day), respectively, for 7 days. On the 4th day, UC was induced by transrectal administration of 4% AA. Colon tissues were excised for macroscopic and histopathological evaluation and immunohistochemical analysis of caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax). Also, levels of oxidative mediators, Wnt family member1 (Wnt1), smoothened (Smo), and glioblastoma-1 (Gli1) were evaluated. Macroscopic and histopathological examination revealed that both graviola and sulfasalazine significantly mitigated colonic damage. Besides, both treatments significantly alleviated AA-induced oxidative stress, as evidenced by reduced nitric oxide (No) and malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity and raised reduced glutathione (GSH) content. Both treatments significantly attenuated AA-induced apoptosis via downregulating the expression of Bax and caspase-3 and upregulating the expression of the anti-apoptotic protein, Bcl-2. Furthermore, downregulation of mRNA expression of Wnt1 with concomitant upregulation of Smo and Gli1 was observed in rats treated with either sulfasalazine or graviola. Based on these observations, graviola may attenuate AA-induced UC, at least partially, by modulating apoptosis and Wingless/Int1 (Wnt) and hedgehog (Hh) signaling crosstalk.

Potential anti-inflammatory effect of dapagliflozin in HCHF diet- induced fatty liver degeneration through inhibition of TNF-α, IL-1ß, and IL-18 in rat liver.

Non-alcoholic fatty liver (NAFLD) is accompanied by an increased expression of oxidative stress parameters, in addition to the inflammatory cytokines; tumor necrosis factor alpha (TNF-α), interleukin type 1beta (IL-1ß), and interleukin type 18 (IL-18). The aim of this study is to investigate the effect of dapagliflizon (DAPA) on high carbohydrate-high fat (HCHF) diet-induced expression of inflammatory cytokines in rat liver. NAFLD was induced by feeding the rats HCHF diet (consist of animal fat tallow and standard show pellets) and the consumption of fructose in drinking water (10%) for 12 or 18 weeks. The oral administration of DAPA (1 mg/kg/day) from 13th week to 18th week significantly improved NAFLD as indicated by a significant reduction in liver aminotransferases in addition to a significant decrease of serum MDA, cholesterol, triglyceride and LDL-cholesterol with concomitant significant elevation of HDL-cholesterol. DAPA-treated animals showed a significant reduction of liver homogenate content of TNF-α, IL-1ß, and IL-18. These results indicate that the administration of DAPA may be beneficial against HCHF diet-induced NAFLD. Histopathological examination of liver specimens supported the conclusion that DAPA improves steatohepatitis induced by HCHF diet.

Irbesartan mitigates acute liver injury, oxidative stress, and apoptosis induced by acetaminophen in mice.

Hepatotoxicity induced by acetaminophen (APAP)-overdose is a major concern in clinical practice. In the present work, the detoxifying effect of irbesartan (Irb) on the APAP-induced acute liver injury was evaluated in mice. Induction of acute liver injury in mice was established by a single intraperitoneal (IP) injection of APAP (0.5 g/kg), then mice were injected with Irb (50 or 75 mg/kg, IP), each given twice at 1 and 12 hours post APAP injection. Liver functions, hepatic oxidative and nitrosative stress markers, and liver histopathology were determined after 24 hours. Hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) levels were also estimated. Immunohistochemical evaluations of hepatic expression of phosphorylated NF-kB and active caspase-3 were assigned. Irb treatment attenuated APAP-induced acute liver injury. Irb suppressed APAP-caused elevation of liver enzymes as well as oxidative and nitrosative stress in liver tissues as evidenced by the decrease in hepatic CYP2E1 expression and hepatic levels of malondialdehyde and nitric oxide in addition to the elevated hepatic superoxide dismutase activity and reduced glutathione concentration. Also, Irb mitigated APAP-induced inflammation in liver tissues via decreasing the expression of hepatic NF-κB, phosphorylated NF-κB and TNF-α, and attenuated hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 expression and activation. Also, Irb mitigated the APAP-induced histopathological changes in liver specimens. These data suggested that Irb ameliorates APAP-induced acute liver injury through antioxidant, anti-inflammatory, and antiapoptotic activities.

Krill oil alleviates oxidative stress, iron accumulation and fibrosis in the liver and spleen of iron-overload rats.

Krill oil (KO) is a recent supplement which is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids are found in both krill oil and fish oil. In krill oil, they esterified to phospholipids, but in fish oil, they are esterified to triacylglycerols. The target of this study was to investigate whether KO could help against iron overload-induced toxicity in liver and spleen. Rats were randomly assigned into 3 categories: control rats, rats received iron in a drinking water for 8 weeks followed by either vehicle or KO (40 mg/kg) treatment for an extra 8 weeks. Extent of hepatic and splenic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. KO effectively improved the microscopic features of liver and spleen. Moreover, it decreased the increased levels of serum transaminases, ALP, LDH, iron, and ferritin and increased albumin serum level as well. In addition, it restored the balance between oxidants and antioxidants in the hepatic and splenic tissues. Furthermore, it decreased HO-1 levels, upregulated the production of Nrf2, and limited the expression of MMP9. These findings altogether suggest that KO might be a new candidate for treatment of iron overload-induced toxicity. Graphical abstract Graphical abstract.

Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4.

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.