Nicorandil attenuates lithocholic acid-induced hepatotoxicity in mice through impeding oxidative stress, inflammation and apoptosis.

This study was performed to explore the beneficial protective impact of nicorandil (Nico) against lithocholic acid (LCA)-induced hepatotoxicity. MATERIALS AND METHODS: Mice received Nico (50 and 100 mg/kg. orally) for 7 days and LCA (125 mg/kg, i.p.) was injected for the last 4 days two times daily. RESULTS: Nico improved both structural and functional abnormalities induced by LCA. Nico significantly decreased serum levels of transaminases, ALP, GGT and markedly elevated albumin levels. Additionally, Nico mitigated oxidative stress; it decreased contents of MDA and NO and increased GSH level and SOD activity. Moreover, Nico markedly decreased the elevated levels of TNF-α, JNK, Bax, Caspase-3 and iNOS, and increased the levels of eNOS in hepatic tissues. Furthermore, Nico substantially decreased the expression of NFκBp65 in hepatic tissues. Histopathological and transmission electron microscopy findings further supported these biomarkers. CONCLUSION: Nico might be used as an adjuvant medication to prevent LCA-induced hepatotoxicity, pending further clinical research, through impeding oxidative stress, inflammation and apoptosis.

Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways.

The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKß, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1ß. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.

Suppression of NLRP3 inflammasome orchestrates the protective efficacy of tiron against isoprenaline-induced myocardial injury.

The major contribution of myocardial damage to global mortalities raises debate regarding the exploration of new therapeutic strategies for its treatment. Therefore, our study investigated the counteracting effect of tiron against isoprenaline (ISO)-mediated cardiac infarction in mice. Tiron was administered to mice for 7 days prior to two consecutive injections of ISO on days 8 and 9 of the treatment protocol. Tiron significantly reduced the levels of CK-MB, LDH, and AST in serum samples of ISO-challenged mice. A considerable increase in the cardiac antioxidant response was observed in tiron-treated mice, as indicated by depletion of MDA and enhancement of antioxidant activities. Furthermore, tiron induced a marked decrease in NLRP3, ASC, and caspase-1 levels accompanied by weak immune reactions of IL-1ß, NF-κB, TLR4, and iNOS in the infarct cardiac tissues. Histopathological screening validated these variations observed in the cardiac specimens. Thus, tiron clearly mitigated the oxidative and inflammatory stress by repressing the NLRP3 inflammasome and the TLR4/NF-κB/iNOS signaling cascade.

Tiron enhances the anti-cancer activity of doxorubicin in DMBA-induced breast cancer: Role of Notch signaling/apoptosis/autophagy/oxidative stress.

Existing work intended to investigate the outcomes of the localized mitochondrial antioxidant tiron (TR) alone or in combination with doxorubicin (DOX) in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats and the mechanistic pathways behind these effects. Also, to examine the preventive role of TR against DOX-related cardiotoxicity. 64 female Sprague-Dawley rats were randomly assigned into 8 groups: CTRL, DOX, TR, DMBA, DMBA + DOX, DMBA + TR100, DMBA + TR200, and DMBA + DOX + TR200. Rats received TR (100 and 200 mg/kg), DOX (2mg/kg), and DMBA (7.5 mg/kg) for four consecutive weeks. TR alone or combined with DOX not only inhibited oxidative status-related parameters and Notch pathway proteins but also attenuated proliferation markers, and enhanced apoptosis, and autophagy-related genes. Consistently, the histopathological analysis showed better scores in mammary tissues isolated from groups treated with TR only or combined with DOX. Additionally, TR dramatically decreased relative heart weight, myocardial injury biomarkers, and heart oxidative stress parameters while maintaining the myocardial histological integrity. Here we provided evidence that TR acts via modulating Notch signaling/apoptosis/autophagy/oxidative stress to elicit anti-tumor activity and combination with DOX revealed a higher efficacy as a novel anticancer strategy. Moreover, TR could be a potential cardio-protective candidate during DOX-chemotherapy, possibly via its antioxidant activity.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators.

BACKGROUND: Diabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. METHODS: Sprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. RESULTS: PPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1ß and ICAM-1). CONCLUSION: Collectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

Levocetrizine attenuates cyclophosphamide-induced lung injury through inhibition of TNF-α, IL-1ß, TGF-ß and MMP-9.

Cyclophosphamide (CP) is an antineoplastic drug commonly used worldwide. Despite its spread, it causes fatal organ toxicity. Lung toxicity is a serious side effect of CP. Actually, in the past three years the world has been facing an un-predicted crisis following COVID-19 pandemic and the associated high-mortality rates attributed to respiratory distress. Accordingly; this study aimed to probe the potential prophylactic role of levocetrizine against CP-induced lung injury. Animals were allocated into three sets; control; CP and CP/Levo. CP was intraperitoneally injected in rats 150 mg/kg once on day 7. Levocetrizine was given orally for 14 days starting 7 days before CP injection. On the last day, all rats were sacrificed and lung tissues were kept for analysis. CP significantly elevated lung/body weight index, inflammatory cell counts, LDH, total protein, TNF-α, IL-1ß, TGF-ß and histamine levels in bronchoalveolar lavage (BAL). Moreover, it markedly increased expression of MMP-9 and contents of MDA, hydroxyproline, collagen and NOx besides decreasing GSH level and SOD activity in lung tissues. These biochemical results were further confirmed by histopathological examination. In contrast, treatment with levocetrizine significantly attenuated CP-induced pathological alterations. These findings propose that levocetrizine can attenuate CP-induced lung injury via exerting antioxidant, anti-inflammatory and anti-fibrotic effects.

Diacerein mitigates adenine-induced chronic kidney disease in rats: Focus on TLR4/MYD88/TRAF6/NF-κB pathway.

Chronic kidney disease (CKD) is a serious problem which negatively affects human health. AIMS: The purpose of this investigation was to explore the possible beneficial impacts of diacerein on adenine-induced CKD in rats. MAIN METHODS: 32 male Sprague Dawley rats were allocated into 4 groups; normal, diseased (200 mg/kg adenine, orally) and diacerein (25 and 50 mg/kg, orally). KEY FINDINGS: Adenine produced marked reduction in rats' body weights and a substantial increase in kidney/body weight index. Additionally, adenine significantly increased serum creatinine and BUN levels besides proteinuria levels, and also reduced creatinine clearance. Adenine induced oxidative stress as evidenced by increased MDA content and diminished GSH concentration in renal tissues. These biochemical measurements were confirmed by the morphological and histopathological results. Moreover, adenine revealed substantial elevation in renal level and expression of MYD88, TRAF6 and TNF-α, and renal level of IL-1ß in addition to increased expression of TLR4, NF-κB p65 and p-NF-κB p65 while reduced the expression of IκB-α. Diacerein in a dose-dependent manner effectively ameliorated adenine-induced alterations. SIGNIFICANCE: Diacerein could be used as a therapeutic agent to attenuate CKD after further clinical studies.

Tenofovir alone or combined with doxorubicin abrogates DMBA-induced mammary cell carcinoma: An insight into its modulatory impact on oxidative/Notch/apoptotic signaling.

AIMS: Breast cancer incidence keeps on growing and emerging as one of the major global challenges, therefore, the introduction of new approaches is of great demand. Drug repurposing is crucial to faster and cheaper discovery of anti-cancer drugs. The antiviral tenofovir disproxil fumarate (TF) was reported to decrease hepatocellular carcinoma risk by interfering with cell cycle and proliferation. This study aimed to scrutinize the role of TF alone or combined with doxorubicin (DOX) in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinoma rat model. MATERIALS AND METHODS: Breast carcinoma was induced by DMBA (7.5 mg/kg, twice/week, subcutaneous into mammary gland) for 4 successive weeks. TF (25 and 50 mg/kg/day) was given orally and DOX (2 mg/kg) was injected once/week by tail vein starting from day 1. KEY FINDINGS: The anti-cancerous effect of TF was mediated by suppression of oxidative stress markers and Notch signaling proteins (Notch1, JAG1, and HES1), attenuation of tumor proliferation markers (cyclin-D1 and Ki67), and boosting of apoptosis (P53 and Caspase3) and autophagy biomarkers (Beclin1 and LC3). In parallel, histopathological assessment displayed that mammary glands from animals treated with TF alone or combined with DOX showed better histopathological scores. Interestingly, TF and DOX co-treatment markedly decreased myocardial injury markers (AST, LDH, and CK-MB), restored the balance between GSH and ROS, prohibited lipid peroxidation, and preserved microscopic myocardial architecture. SIGNIFICANCE: TF elicited antitumor activity via multiple molecular mechanisms. Moreover, combining TF with DOX might be a potential novel strategy to enhance DOX-anticancer activity and decrease its cardiac side effects.

Epigallocatechin-3-gallate in combination with corticosteroids mitigates heat stress-induced acute kidney injury through modulating heat shock protein 70 and toll-like receptor 4-dependent pathways.

Recently, recurrent heat stress (HS) and dehydration have been exhibited to give rise to kidney disease epidemic in hot regions. The current study was carried out to estimate a possible renoprotective effect of dexamethasone (Dexa) and epigallocatechin-3-gallate (EGCG) as a heat shock protein (HSP)-70 inhibitor on HS-induced nephropathy. In total, five groups of rats were used: control group, HS group (exposed to heat for 40 min), Dexa+HS group (rats were injected with Dexa i.p.15 mg/kg/day for 3 days followed by HS), EGCG+HS group (rats received EGCG 100 mg/kg/day, orally, for 7 days followed by HS), and EGCG+ Dexa +HS group (rats received EGCG 100 mg/kg/day, orally, for 7 days and injected Dexa as described along the last 3 days followed by HS). Kidney sections were stained with H&E and scored for tubular injury. A marked increase in creatinine, urea, malondialdehyde (MDA), monocyte chemoattractant protein (MCP)-1, HSP-70, nuclear factor kappa B (NF-κB), toll-like receptor 4 (TLR-4) and Caspase-3 expression was observed after HS induction (p < 0.001). Treatment with EGCG combined with Dexa notably reduced tubular injury, MCP-1, HSP-70, NF-κB, and TLR-4 levels (p < 0.001). Moreover, it increased IL-10, antioxidant capacity and Bcl-2 expression levels in the kidney (p < 0.001). This renoprotective impact might be attributed to anti-inflammatory, antioxidant, and anti-apoptotic mechanisms besides interfering with TLR-4-mediated NF-κB activation pathway.

Ameliorative effect of desloratadine against cisplatin-induced renal and testicular toxicity in rats: Attention to TLR4/NLRP3 inflammasome signaling pathway.

Cisplatin (CIS) is a potent anticancer drug that is used in the treatment of different types of cancer. Owing to its serious side effects, its clinical use is considerably limited. AIMS: This study was mapped to investigate the potential effects of desloratadine (DES) against CIS-induced nephrotoxicity and testicular injury. MAIN METHODS: DES (5 and 10 mg/kg) was orally administered for 10 days, and CIS was injected once (10 mg/kg, i.p.) in adult male rats on day 9 to induce both renal and testicular toxicity. KEY FINDINGS: DES significantly attenuated CIS-induced alterations in histopathology and biomarkers. DES resulted in a significant reduction in serum levels of creatinine (Cr), urea, and blood urea nitrogen (BUN), in addition to a marked decrease in urinary levels of albumin and total protein. Additionally, DES efficiently reinstated the oxidative balance by preventing the elevation of malondialdehyde (MDA) and enhancing superoxide dismutase (SOD) activity, and increasing glutathione (GSH) levels. Moreover, DES produced a profound decrease in renal and testicular levels of nucleotide-binding domain-(NOD) like receptor 3 (NLRP3), interleukin (IL)-1ß, and caspase-1 when compared to the CIS group. Furthermore, DES significantly decreased CIS-induced elevation in toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) levels in both renal and testicular tissues. SIGNIFICANCE: DES can be used as adjuvant therapy with CIS in cancerous cases, pending further clinical studies.

Naringenin mitigates thioacetamide-induced hepatic encephalopathy in rats: targeting the JNK/Bax/caspase-8 apoptotic pathway.

Hepatic encephalopathy (HE) is a serious neurological disorder which is related to liver dysfunction. HE was induced by thioacetamide (TAA) injection (350 mg kg-1, i.p.) for 3 consecutive days. This study was performed to investigate the prophylactic impact of naringenin against TAA-induced HE. Naringenin (100 mg kg-1) was orally administered for 7 days starting 4 days prior to TAA injection. Naringenin effectively mitigated TAA-induced behavioural, structural and functional alterations. Naringenin ameliorated TAA-induced cognitive impairment as evidenced by the increase in the fall-off time in the rotarod test, decrease in the escape latency in the Morris water maze test and increase in the time spent in the center and in the number of rearing in the open field test. Additionally, naringenin significantly decreased the serum levels of transaminases, alkaline phosphatase, gamma-glutamyl transferase, bile and ammonia. Moreover, naringenin succeeded in reducing the levels of hepatic and cerebral c-Jun N-terminal kinases (JNK) as well as hepatic SORT1 levels. In addition, naringenin successfully elevated the levels of hepatic and cerebral pro-brain-derived neurotrophic factor (pro-BDNF) and BDNF in addition to the cerebral SORT1 level. Finally, naringenin markedly decreased the expression of Bax and caspase-8 as presented by the immunohistochemical results. Collectively, the ameliorative effect of naringenin on the development of HE might be attributed to the modulation of the JNK/Bax/caspase-8 apoptotic pathway.

Empagliflozin mitigates methotrexate-induced hepatotoxicity: Targeting ASK-1/JNK/Caspase-3 pathway.

Methotrexate (MTX) administration causes hepatotoxicity, a serious side effect limiting its clinical use. Therefore, this study was performed to investigate the beneficial effect of empagliflozin (Empa) against MTX-induced hepatotoxicity. Adult male albino mice were pre-treated with Empa (at 10 or 25 mg/kg/d, orally) for 6 days and then received a single MTX injection (at 20 mg/kg, intraperitoneally). Empa effectively ameliorated MTX-induced structural and functional alterations. It significantly decreased transaminase, alkaline phosphatase, and gamma-glutamyl transferase levels and increased albumin levels in the serum. Moreover, Empa restored the oxidant/antioxidant balance as indicated by reduced malondialdehyde and total nitrite/nitrate contents and elevated reduced glutathione level and superoxide dismutase activity. Additionally, Empa (10 and 25 mg/kg) markedly suppressed the elevated levels of tumor necrosis factor-alpha, interleukin-6, apoptosis signal-regulating kinase1, c-Jun N-terminal kinase, BCL2 associated X protein, and Caspase-3 in hepatic tissues and increased the hepatic interleukin-10 levels. Furthermore, Empa substantially decreased nuclear factor kappa B expression in hepatic tissues. These biochemical findings were further confirmed by histopathological and transmission electron microscopy observations. Therefore, Empa might be used as an adjuvant to ameliorate MTX-induced hepatotoxicity after further clinical evaluation.

Hepatoprotective effect of nicorandil against acetaminophen-induced oxidative stress and hepatotoxicity in mice via modulating NO synthesis.

Acetaminophen (APAP) overdose can produce hepatotoxicity and consequently liver damage. This study investigated the hepatoprotective impacts of nicorandil on hepatic damage induced by APAP. Nicorandil was administered orally (100 mg/kg) for seven days before APAP challenge (500 mg/kg, ip). Pretreatment with nicorandil reduced serum levels of aminotransferases, bilirubin, GGT and LDH, and increased serum level of albumin. Moreover, nicorandil inhibited the increase in liver MDA levels and reversed the decline in GSH content and SOD activity. Besides, it notably alleviated APAP-induced necrosis observed in histopathological findings. Additionally, nicorandil alleviated APAP-induced NO overproduction and iNOS expression; however, the protein expression of eNOS was significantly increased. Moreover, nicorandil markedly reduced hepatic TNF-α and NF-κB levels, in addition to decreasing the protein expression of MPO in hepatic tissues. Furthermore, flow cytometry (annexin V-FITC/PI) displayed a significant decline in late apoptotic and necrotic cells, and an increase in viable cells in nicorandil group. Also, nicorandil caused a significant boost in hepatic antiapoptotic marker bcl-2 level. The presented data proposed that the protective effect of nicorandil might be attributed to its antioxidant, its impact on NO homeostasis, and its anti-inflammatory properties. Therefore, nicorandil may be a promising candidate for protection from liver injury induced by APAP.

Hepatoprotective and cognitive-enhancing effects of hesperidin against thioacetamide-induced hepatic encephalopathy in rats.

Hepatic encephalopathy (HE) is a serious neurological disorder which might occur in both acute and chronic liver injury. AIMS: This study was carried out to explore the protective effects of hesperidin against experimentally induced HE. MAIN METHODS: Rats were sorted into four groups each of six; Normal group, TAA group: rats were administered 350 mg/kg of TAA i.p. from day 5 to day 7. TAA+ Hesp 100 group: rats were administered hesperidin 100 mg/kg/day orally for 7 days along with i.p TAA injection 350 mg/kg from day 5 to 7. TAA+ Hesp 200 group: rats were administered hesperidin 200 mg/kg/day orally for 7 days along with i.p TAA injection 350 mg/kg from day 5 to 7. Liver function, oxidative stress biomarkers, behavioral tests in addition to histopathological examination were assessed. KEY FINDINGS: Hesperidin efficiently mitigated TAA-induced HE as evidenced by significant reduction in liver enzymes, bile and ammonia levels in serum. Moreover, hesperidin restored oxidant/antioxidant balance as manifested by reduction in MDA content in both cerebral and hepatic tissues. Additionally, hesperidin improved motor and cognitive abilities besides tissues' architecture as demonstrated by behavioral tests and histopathology results, respectively. Hesperidin also decreased levels of NLRP3 and increased levels of Sirt1 and FOXO in both cerebral and hepatic tissues. Finally, hesperidin markedly decreased the expression of IL-1ß and caspase-1 as shown by immunohistochemical results. SIGNIFICANCE: Taken together, the hepatoprotective impact of hesperidin and its ameliorative effect on the progression of HE appear to be mediated by its modulatory influence on NLRP3/Sirt1/FOXO signaling.

Calycosin modulates NLRP3 and TXNIP-mediated pyroptotic signaling and attenuates diabetic nephropathy progression in diabetic rats; An insight.

Diabetic nephropathy [DN] is one of the most prevalent microvascular complications of diabetes mellitus [DM] and it is considered a leading cause of kidney failure. In this study calycosin, an isoflavone that constitutes the major constituent in Radix Astragali with numerous pharmacological merits was investigated as reno-protective agent against DN and also the potential underlying mechanisms were investigated. Streptozotocin (STZ) (40 mg/kg) was injected in the peritoneal cavity of male Sprague-Dawely rats to induce DM. For ten weeks, calycosin (5 and 10 mg/kg), and NAC (500 mg/kg) were orally administered and they significantly lowered blood glucose levels, but significantly increased insulin levels. Calycosin improved the deteriorated kidney functions as evidenced in retracted serum creatinine, albuminuria, blood urea nitrogen, and proteinuria levels. Meanwhile, urine creatinine clearance significantly escalated. Furthermore, biomarkers of cell injury; LDH activity, significantly declined and kidney content of NO markedly decreased as well. Inflammation, fibrosis and oxidative stress were manifested by increased serum levels of IL-1ß, renal NF-κBp65, NLRP3, TXNIP and MDA contents with declined levels of IL-10 and TAC and decreased Nrf2 expression. The above-mentioned biomarkers were significantly improved with calycosin treatment which modulated NF-κB/p65/NLRP3/TXNIP signaling, oxidative stress, inflammatory cytokines and fibrotic processes; Thus, implying a reno-protective impact. This was associated with improvement in renal histopathological and immune-histopathological parameters; H&E, Masson Trichrome and Nrf-2. Based on these findings, calycosin can be presumed to be a promising drug for hindering the development of DN through modulation of NF-κB/p65/NLRP3/TXNIP inflammasome signaling pathway.

Pimitespib, an HSP90 inhibitor, augments nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop in rats with bleomycin-challenged lungs: Evolutionary perspective in managing pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-ß. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis.

Ameliorative effect of montelukast against carbon tetrachloride-induced hepatotoxicity: Targeting NLRP3 inflammasome pathway.

AIMS: Montelukast, a selective antagonist of type 1 cysteinyl-leukotriene receptors, has antioxidant and anti-inflammatory abilities. This study aimed to explore its hepatoprotective impact against CCl4-induced hepatotoxicity compared to a standard hepatoprotective agent, silymarin. MAIN METHODS: Twenty-four albino mice were used in this study, CCl4 (1 mL/kg of 1:1 v/v CCl4:olive oil) was singly injected in mice, and montelukast was administered in a dose of 10 mg/kg. KEY FINDINGS: Results revealed that montelukast significantly improved CCl4-induced alterations in both structure and function of the liver, verified respectively through histopathology and by the reduced levels of ALT, AST, ALP, and GGT upon comparison with CCl4. Also, montelukast prevented the induction of oxidative stress via decreasing hepatic MDA content and enhancing GSH levels. Moreover, montelukast produced a profound decrease in the levels of hepatic NLRP3 and its adaptor protein, ASC, and a reduction in the pro-inflammatory markers, NF-κB, IL-1ß, TNF-α, and IL-6. In addition, montelukast markedly reduced liver fibrosis, as illustrated by Masson Trichrome, and the decreased hepatic levels of TGF-ß and α-SMA. Furthermore, montelukast efficiently decreased apoptosis as manifested by the decreased hepatic level of Caspase 3. SIGNIFICANCE: Montelukast protected against CCl4-induced hepatotoxicity via exerting antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.

Renoprotective effect of empagliflozin in cafeteria diet-induced insulin resistance in rats: Modulation of HMGB-1/TLR-4/NF-κB axis.

AIM: Cafeteria diet (CAF) is a well-established model used to mimic what occurs in human upon eating junk and ultra-processed food. This study aimed to investigate the possible protective impact of empagliflozin (EMPA) against CAF-induced insulin resistance (IR) in rats and the possible underlying mechanisms. MAIN METHODS: Rats were fed on CAF diet for 12 weeks while treatment with EMPA (10 & 30 mg/kg/day, orally) and/or metformin (MET) (100 mg/kg/day, orally) started at day 29. KEY FINDINGS: Oral administration of EMPA and/or MET significantly and dose-dependently succeeded to attenuate CAF-induced obesity which was evidenced by decreased oral glucose tolerance test (AUCOGTT), insulin tolerance test (AUCITT) and decreased fasting serum insulin level besides improving the histopathological alterations induced by CAF. Moreover, EMPA significantly mitigated CAF-induced elevation in serum levels of creatinine urea, transaminases (ALT and AST), and increased albumin level as well as improving dyslipidemia and oxidative stress. Furthermore, EMPA markedly reduced renal levels of high mobility group box 1 (HMGB-1), toll like receptor4 (TLR-4) and nuclear factor κB (NF-κB) as well as decreasing the expression of tumor necrosis factor α (TNF-α) and Caspase 3. Combining EMPA30 with MET synergistically improved dyslipidemia, oxidative stress and enhanced kidney function. SIGNIFICANCE: EMPA administration could confer protection against CAF-induced IR and its complications through its hypoglycemic, insulin-sensitizing, hypolipidemic, hepatoprotective, renoprotective, anti-inflammatory, anti-oxidant and anti-apoptotic properties. Also, our findings highlighted the synergistic effect of combining EMPA30 with MET so this combination might be promising in treatment of IR.

Hepatoprotective effect of Baicalin against thioacetamide-induced cirrhosis in rats: Targeting NOX4/NF-κB/NLRP3 inflammasome signaling pathways.

AIM: Liver cirrhosis is the result of a vicious cycle of both chronic oxidative stress and inflammation. NADPH oxidase-4 (NOX4) and its companion, NOD-like receptor protein 3 (NLRP3) inflammasome, are emerging as therapeutic targets of liver fibrosis. MAIN METHODS: Baicalin (BA), a natural flavone, has been investigated for its therapeutic potential against cirrhosis induced by thioacetamide (TAA) (200 mg/kg, twice/week) for 12 weeks in Sprague-Dawley rats. Two doses of BA were administered (25 and 75 mg/kg/day, orally, a week after TAA was stopped and continued for 4 weeks). KEY FINDINGS: BA was able to reduce fibrosis visualized by Masson trichrome and immunohistochemical staining of the hepatic α-smooth muscle actin (α-SMA) and transforming growth factor-ß1. Moreover, BA was able to ameliorate inflammation by reducing hepatic NLRP3 inflammasome subunits, NLRP3 and caspase-1, both parts of the complex responsible for the activation of different interleukins (IL), measured as IL-1ß. In addition, BA was able to reduce hepatic nuclear factor kappa B (NF-κB)-driven inflammation through IL-6. BA targeted inflammation through its anti-oxidant ability evidenced by the enhancement of the hepatic superoxide dismutase (SOD) and reduced glutathione (GSH) activity and level, respectively, and the reduction of both hepatic malondialdehyde (MDA) and nitric oxide (NOx) contents. Treatment with BA significantly decreased TAA-induced elevation in hepatic NOX4, a key enzyme for reactive oxygen species (ROS) generation, as well as, inducible nitric oxide synthase (iNOS). SIGNIFICANCE: therefore, the study could conclude, the anti-fibrotic effect of BA through TGF- ß1/NOX4/NF-κB/NLRP3 pathway, exerting both anti-inflammatory and anti-oxidant effects.