Role of gambogenic acid in regulating PI3K/Akt/NF-kβ signaling pathways in rat model of acute hepatotoxicity

ABSTRACT The purpose of this study is to investigate the protective effect of gambogenic acid (GA) in acetaminophen (APAP)-induced hepatotoxicity in rat models. GA (10 mg/kg) was administered intraperitoneal (i.p.) to rats for 7 consecutive days followed by APAP (500 mg/kg) single dose (i.p.) on the final day after GA administration. The levels of MDA, GSH, SOD, CAT, GPx, GST, ALP, AST, ALT, proinflammatory cytokines (TNF-α, IL-1β, IL-6), apoptosis markers (caspase-3 and -9, Bax, Bcl-2), 4-hydroxynonenal (4-HNE), and prostaglandin E2 (PGE2) were evaluated. Results exhibited protective effects of GA by inhibiting inflammation, preventing oxidative stress and apoptosis in APAP-induced liver. Histopathological changes caused by APAP were attenuated, protein expressions of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) were upregulated, and nuclear factor–kappa β (NF-kβ) was downregulated by GA. In summary, GA significantly exerted anti-inflammatory and antiapoptotic effects against APAP-induced hepatotoxicity potentially through regulation of PI3K/Akt and NF-kβ signaling pathways.

Download Full-text

Improved protective effects of American ginseng berry against acetaminophen-induced liver toxicity through TNF-α-mediated caspase-3/-8/-9 signaling pathways

Phytomedicine ◽

10.1016/j.phymed.2018.09.234 ◽

2018 ◽

Vol 51 ◽

pp. 128-138 ◽

Cited By ~ 10

Author(s):

Xing-Yue Xu ◽

Zi Wang ◽

Shen Ren ◽

Jing Leng ◽

Jun-nan Hu ◽

...

Keyword(s):

Signaling Pathways ◽

Caspase 3 ◽

Liver Toxicity ◽

American Ginseng ◽

Protective Effects ◽

Tnf Α

Download Full-text

Platycodon grandiflorum Saponins Ameliorate Cisplatin-Induced Acute Nephrotoxicity through the NF-κB-Mediated Inflammation and PI3K/Akt/Apoptosis Signaling Pathways

Nutrients ◽

10.3390/nu10091328 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1328 ◽

Cited By ~ 21

Author(s):

Weizhe Zhang ◽

Jingang Hou ◽

Xiaotong Yan ◽

Jing Leng ◽

Rongyan Li ◽

...

Keyword(s):

Protective Effect ◽

Signaling Pathways ◽

Kidney Injury ◽

Dependent Manner ◽

Protective Effects ◽

Phosphatidylinositol 3 Kinase ◽

Platycodon Grandiflorum ◽

Tnf Α ◽

Factor Α ◽

Oxide Synthase

Although cisplatin is a potent chemotherapeutic agent against cancers, its clinical application is seriously limited by its severe side effects of nephrotoxicity. Previous studies reported that saponins isolated from the roots of Platycodon grandiflorum (PGS) exerted protective effects in various animal models of renal injury, with no confirmation on cisplatin-induced injury. This study was designed to investigate the protective effect of PGS (15 and 30 mg/kg) on cisplatin-induced kidney injury in mice. The levels of serum creatinine (CRE) and blood urea nitrogen (BUN), and renal histopathology demonstrated the protective effect of PGS against cisplatin-induced kidney injury. PGS exerted anti-inflammation effects via suppressing nuclear factor-kappa B (NF-κB) activation and alleviating the cisplatin-induced increase in inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in kidney tissues. The expressions of phosphorylation of phosphatidylinositol 3-kinase/protein kinase B and its downstream apoptotic factors, such as Bcl-2 and caspase families were regulated by PGS in a dose-dependent manner. In conclusion, PGS exerted kidney protection effects against cisplatin-induced kidney injury by inhibiting the activation of NF-κB and regulating PI3K/Akt/apoptosis signaling pathways in mice.

Download Full-text

Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats

Open Life Sciences ◽

10.1515/biol-2021-0012 ◽

2021 ◽

Vol 16 (1) ◽

pp. 128-141

Author(s):

Gang Xiao ◽

Mei Zhang ◽

Xing Peng ◽

Guangyuan Jiang

Keyword(s):

Signaling Pathways ◽

Cerebral Aneurysm ◽

Protocatechuic Acid ◽

Inflammatory Responses ◽

Dependent Manner ◽

Nuclear Factor ◽

Protective Effects ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Abstract Our current research aims to examine whether protocatechuic acid (PCA) can be used as a therapeutic agent for the development of cerebral aneurysm (CA) and to elucidate the mechanisms behind this. We assessed the effects of PCA at 50 and 100 mg/kg on the activation of signaling pathways for tissue necrosis factor (TNF)-α/nuclear factor (NF)-κB/nuclear factor erythroid 2 (Nrf-2) on progression and development in an elastase-induced CA model, accompanied by a high-salt diet to induce hypertension. The expression of inflammatory cytokines, chemokines, tumor necrosis factor-α, interleukins (IL)-8, IL-17, IL-6, IL-1β, and matrix metalloproteinase (MMP)-2 and MMP-9 was analyzed by ELISA, western blot, and reverse transcriptase quantative polymerase chain reaction. The expression levels of antioxidant enzymes and translocation of Nrf-2 were also determined. The group treated with PCA demonstrated a significant (P < 0.05) decrease in the aneurysmal size in rats compared to the CA-induced group. We found that PCA treatment suppressed the invasion of macrophage and activation of TNF-α/NF-κB/Nrf-2 signaling pathways. There was a significant decrease (P < 0.05) in pro-inflammatory cytokine and chemokine levels in a dose-dependent manner. We found that PCA treatment exerts protective effects by suppressing the development and progression of CA through the inhibition of inflammatory responses in macrophages via TNF-α/NF-κB/Nrf-2 signaling pathways, thus demonstrating that PCA can act as a treatment for CA.

Download Full-text

Protective Effects of Taraxasterol against Ethanol-Induced Liver Injury by Regulating CYP2E1/Nrf2/HO-1 and NF-κB Signaling Pathways in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8284107 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Lu Xu ◽

Yifan Yu ◽

Rui Sang ◽

Jinxia Li ◽

Bingjie Ge ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathways ◽

Heme Oxygenase 1 ◽

Intragastric Administration ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Histopathological Changes ◽

Liver Index ◽

Liver Tissues

Taraxasterol, a pentacyclic-triterpene compound, is one of the main active components isolated from the traditional Chinese medicinal herb Taraxacum. The objective of this study is to evaluate the protective effects of taraxasterol and its possible underlying mechanisms against ethanol-induced liver injury in mice. ICR mice were fed with Lieber-DeCarli diet containing 5% ethanol for 10 d and then challenged with a single dose of 20% ethanol (5 g/kg BW) by intragastric administration. The mice were intragastrically treated daily with taraxasterol (2.5, 5, and 10 mg/kg). Tiopronin was used as a positive control. The liver index was calculated, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in sera were detected. The contents of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) and the activity of superoxide dismutase (SOD) in the livers were measured. The histopathological changes of liver tissues were observed by hematoxylin and eosin (H&E) staining. The protein expression levels of hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant protein heme oxygenase-1 (HO-1), and nuclear factor-kappa B (NF-κB) signaling pathway in liver tissues were detected by immunohistochemistry and Western blot methods. Taraxasterol significantly reduced the ethanol-induced increases of liver index, ALT, AST, and TG levels in sera and TG and MDA contents in the livers and hepatic ROS production and suppressed the ethanol-induced decreases of hepatic GSH level and SOD activity. Taraxasterol also significantly inhibited the secretion of proinflammatory cytokines TNF-α and IL-6 induced by ethanol. In addition, taraxasterol improved the liver histopathological changes in mice with ethanol-induced liver injury. Further studies revealed that taraxasterol significantly inhibited the ethanol-induced upregulation of CYP2E1, increased the ethanol-induced downregulation of Nrf2 and HO-1, and inhibited the degradation of inhibitory kappa Bα (IκBα) and the expression level of NF-κB p65 in liver tissues of ethanol-induced mice. These findings suggest that taraxasterol possesses the potential protective effects against ethanol-induced liver injury in mice by exerting antioxidative stress and anti-inflammatory response via CYP2E1/Nrf2/HO-1 and NF-κB signaling pathways.

Download Full-text

Dietary Oleocanthal Supplementation Prevents Inflammation and Oxidative Stress in Collagen-Induced Arthritis in Mice

Antioxidants ◽

10.3390/antiox10050650 ◽

2021 ◽

Vol 10 (5) ◽

pp. 650

Author(s):

Tatiana Montoya ◽

Marina Sánchez-Hidalgo ◽

María Luisa Castejón ◽

María Ángeles Rosillo ◽

Alejandro González-Benjumea ◽

...

Keyword(s):

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Protective Effects ◽

Collagen Induced Arthritis ◽

Neuroprotective Effects ◽

Tnf Α ◽

Protein Expressions ◽

Ifn Γ ◽

Preventive Role

Oleocanthal (OLE), a characteristic and exclusive secoiridoid of Oleoaceae family, is mainly found in extra virgin olive oil (EVOO). Previous studies have reported its antioxidant, anti-inflammatory, antimicrobial, anticancer and neuroprotective effects. Since the pathogenesis of rheumatoid arthritis (RA) involves inflammatory and oxidative components, this study was designed to evaluate the preventive role of dietary OLE-supplemented effects in collagen-induced arthritis (CIA) murine model. Animals were fed with a preventive OLE-enriched dietary during 6 weeks previous to CIA induction and until the end of experiment time. At day 43 after first immunization, mice were sacrificed: blood was recollected and paws were histological and biochemically processed. Dietary OLE prevented bone, joint and cartilage rheumatic affections induced by collagen. Levels of circulatory matrix metalloproteinase (MMP)-3 and pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, IL-17, IFN-γ) were significantly decreased in secoiridoid fed animals. Besides, dietary OLE was able to diminish COX-2, mPGES-1 and iNOS protein expressions and, also, PGE2 levels. The mechanisms underlying these protective effects could be related to Nrf-2/HO-1 axis activation and the inhibition of relevant signaling pathways including JAK-STAT, MAPKs and NF-κB, thus controlling the production of inflammatory and oxidative mediators. Overall, our results exhibit preliminary evidences about OLE, as a novel dietary tool for the prevention of autoimmune and inflammatory disorders, such as RA.

Download Full-text

The Impact of Royal Jelly against Hepatic Ischemia/Reperfusion-Induced Hepatocyte Damage in Rats: The Role of Cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α Signaling Pathways

Current Molecular Pharmacology ◽

10.2174/1874467213666200514223829 ◽

2020 ◽

Vol 14 (1) ◽

pp. 88-100

Author(s):

Fares E.M. Ali ◽

Heba M. Saad Eldien ◽

Nashwa A.M. Mostafa ◽

Abdulrahman H. Almaeen ◽

Mohamed R.A. Marzouk ◽

...

Keyword(s):

Signaling Pathways ◽

P38 Mapk ◽

Royal Jelly ◽

Ischemia Reperfusion ◽

Histopathological Changes ◽

Down Regulation ◽

Hepatic Ischemia ◽

Tnf Α ◽

Hepatic Ischemia Reperfusion ◽

The Impact

Objective: The present study was conducted to elucidate the underlying molecular mechanism as well as the potential hepatoprotective effects of royal jelly (RJ) against hepatic ischemia/reperfusion (IR) injury. Methods: Rats were assigned into four groups; sham (received vehicle), IR (30 minutes ischemia and 45 minutes reperfusion), sham pretreated with RJ (200 mg/kg P.O.), and IR pretreated with RJ (200 mg/kg P.O.). The experiment has lasted for 28 days. Results: Hepatic IR significantly induced hepatic dysfunctions, as manifested by elevation of serum transaminases, ALP and LDH levels. Moreover, hepatic IR caused a significant up-regulation of P38-MAPK, NF-κB-p65, TNF-α and MDA levels along with marked down-regulation of Nrf-2, HO-1, COX-4, cytoglobin, IκBa, IL-10, GSH, GST and SOD levels. Additionally, marked histopathological changes were observed after hepatic IR injury. On the contrary, pretreatment with RJ significantly improved hepatic functions along with the alleviation of histopathological changes. Moreover, RJ restored oxidant/antioxidant balance as well as hepatic expressions of Nrf-2, HO-1, COX-4, and cytoglobin. Simultaneously, RJ significantly mitigated the inflammatory response by down-regulation of P38-MAPK, NF-κB-p65, TNF-α expression. Conclusion: The present results revealed that RJ has successfully protected the liver against hepatic IR injury through modulation of cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α signaling pathways.

Download Full-text

NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis

Gastroenterology Research and Practice ◽

10.1155/2010/367694 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 39

Author(s):

Shin Maeda

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathways ◽

Inflammatory Cell ◽

Prognostic Markers ◽

Tumor Promotion ◽

Neoplastic Cell ◽

Nuclear Factor ◽

Tlr Signaling ◽

The Third

Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. The role of molecular changes in HCC have been used to identify prognostic markers and chemopreventive or therapeutic targets. It seems that toll-like receptors (TLRs) as well as the nuclear factor (NF)-κB, and JNK pathways are critical regulators for the production of the cytokines associated with tumor promotion. The cross-talk between an inflammatory cell and a neoplastic cell, which is instigated by the activation of NF-κB and JNKs, is critical for tumor organization. JNKs also regulate cell proliferation and act as oncogenes, making them the main tumor-promoting protein kinases. TLRs play roles in cytokine and hepatomitogen expression mainly in myeloid cells and may promote liver tumorigenesis. A better understanding of these signaling pathways in the liver will help us understand the mechanism of hepatocarcinogenesis and provide a new therapeutic target for HCC.

Download Full-text