Annona squamosa Fruit Extract Ameliorates Lead Acetate-Induced Testicular Injury by Modulating JAK-1/STAT-3/SOCS-1 Signaling in Male Rats.

Lead (Pb) is a common pollutant that is not biodegradable and gravely endangers the environment and human health. Annona squamosa fruit has a wide range of medicinal uses owing to its phytochemical constituents. This study evaluated the effect of treatment with A. squamosa fruit extract (ASFE) on testicular toxicity induced in male rats by lead acetate. The metal-chelating capacity and phytochemical composition of ASFE were determined. The LD50 of ASFE was evaluated by probit analysis. Molecular docking simulations were performed using Auto Dock Vina. Forty male Sprague Dawley rats were equally divided into the following groups: Gp1, a negative control group; Gp2, given ASFE (350 mg/kg body weight (b. wt.)) (1/10 of LD50); Gp3, given lead acetate (PbAc) solution (100 mg/kg b. wt.); and Gp4, given PbAc as in Gp3 and ASFE as in Gp2. All treatments were given by oro-gastric intubation daily for 30 days. Body weight changes, spermatological parameters, reproductive hormone levels, oxidative stress parameters, and inflammatory biomarkers were evaluated, and molecular and histopathological investigations were performed. The results showed that ASFE had promising metal-chelating activity and phytochemical composition. The LD50 of ASFE was 3500 mg/kg b. wt. The docking analysis showed that quercetin demonstrated a high binding affinity for JAK-1 and STAT-3 proteins, and this could make it a more promising candidate for targeting the JAK-1/STAT-3 pathway than others. The rats given lead acetate had defective testicular tissues, with altered molecular, biochemical, and histological features, as well as impaired spermatological characteristics. Treatment with ASFE led to a significant mitigation of these dysfunctions and modulated the JAK-1/STAT-3/SOCS-1 axis in the rats.

Urtica pilulifera leaves extract mitigates cadmium induced hepatotoxicity via modulation of antioxidants, inflammatory markers and Nrf-2 signaling in mice.

Introduction: Cadmium (Cd) is a harmful heavy metal that results in many toxic issues. Urtica pilulifera showed potential pharmaceutical applications. This study investigated the possible ameliorative mechanism of Urtica pilulifera leaves extract (UPLE) against hepatotoxicity induced by cadmium chloride (CdCl2) in mice. Methods: In vitro phytochemical screening and the metal-chelating activity of UPLE were ascertained. Four groups of forty male mice were used (n = 10) as follows; Group 1 (G1) was a negative control. G2 was injected i.p., with UPLE (100 mg/kg b. wt) daily. G3 was injected i.p., with Cd (5 mg/kg b. wt) daily. G4 was injected with Cd as in G3 and with UPLE as in G2. On day 11, the body weight changes were evaluated, blood, and serum samples were collected for hematological and biochemical assessments. Liver tissues were used for biochemical, molecular, and histopathological investigations. Results: The results showed that UPLE contains promising secondary metabolites that considerably lessen the negative effects of Cd on liver. Furthermore, UPLE inhibited oxidative stress and inflammation; restored antioxidant molecules; and promoted nuclear-related factor-2 (Nrf-2) expression. Also, UPLE improved the histopathological alterations induced by Cd. Discussion: This study explored the beneficial role of UPLE treatment in Cd-induced liver injury through enhancing Nrf-2 signaling and antioxidant enzyme gene expression in the liver of mice. Therefore, UPLE could have valuable implications against hepatotoxicity induced by environmental cadmium exposure. Which can be used as a chelating agent against Cd.

Artemisia annua Extract Attenuate Doxorubicin-Induced Hepatic Injury via PI-3K/Akt/Nrf-2-Mediated Signaling Pathway in Rats.

Doxorubicin (DOX), which is used to treat cancer, has harmful effects that limit its therapeutic application. Finding preventative agents to thwart DOX-caused injuries is thus imperative. Artemisia annua has numerous biomedical uses. This study aims to investigate the attenuative effect of Artemisia annua leaf extract (AALE) treatment on DOX-induced hepatic toxicity in male rats. A phytochemical screening of AALE was evaluated. Forty male rats were used; G1 was a negative control group, G2 was injected with AALE (150 mg/kg) intraperitoneally (i.p) daily for a month, 4 mg/kg of DOX was given i.p to G3 once a week for a month, and G4 was injected with DOX as G3 and with AALE as G2. Body weight changes and biochemical, molecular, and histopathological investigations were assessed. The results showed that AALE contains promising phytochemical constituents that contribute to several potential biomedical applications. AALE mitigated the hepatotoxicity induced by DOX in rats as evidenced by restoring the alterations in the biochemical parameters, antioxidant gene expression, and hepatic histopathological alterations in rats. Importantly, the impact of AALE against the hepatic deterioration resulting from DOX treatment is through activation of the PI-3K/Akt/Nrf-2 signaling, which in turn induces the antioxidant agents.

Cardioprotective Effect of Flibanserin against Isoproterenol-Induced Myocardial Infarction in Female Rats: Role of Cardiac 5-HT2A Receptor Gene/5-HT/Ca2+ Pathway.

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Serotonin (5-HT) release during myocardial ischemia plays an important role in the progression of myocardial cellular injury. This study was conducted to investigate the possible cardioprotective effect of flibanserin (FLP) against isoproterenol (ISO)-induced MI in rats. Rats were randomly divided into five groups and were treated orally (p.o.) with FLP (15, 30, and 45 mg/kg) for 28 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 27th and 28th days to induce MI. ISO-induced myocardial infarcted rats exhibited a significant increase in cardiac markers, oxidative stress markers, cardiac and serum 5-HT levels, and total cardiac calcium (Ca2+) concentration. ISO-induced myocardial infarcted rats also revealed a remarkable alteration of electrocardiogram (ECG) pattern and significantly upregulated expression of the 5-Hydroxytryptamine 2A (5-HT2A) receptors gene. Moreover, ISO-induced myocardial infarcted rats showed significant histopathological findings of MI and hypertrophic signs. However, pretreatment with FLP significantly attenuated the ISO-induced MI in a dose-dependent manner, as the effect of FLP (45 mg/kg) was more pronounced than that of the other two doses, FLP (15 and 30 mg/kg). The present study provides evidence for the cardioprotective efficacy of FLP against ISO-induced MI in rats.

The Combined Effect of Licorice Extract and Bone Marrow Mesenchymal Stem Cells on Cisplatin-Induced Hepatocellular Damage in Rats.

Drug-induced liver damage is a life-threatening disorder, and one major form of it is the hepatotoxicity induced by the drug cisplatin. In folk medicine, Licorice (Glycyrrhiza glabra (is used for detoxification and is believed to be a potent antioxidant. Currently, the magically self-renewable potential of bone marrow mesenchymal stem cells (BM-MSCs) has prompted us to explore their hepatoregenerative capability. The impact of G. glabra extract (GGE) and BM-MSCs alone and, in combination, on protecting against hepatotoxicity was tested on cisplatin-induced liver injury in rats. Hepatic damage, as revealed by liver histopathology and increased levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and malondialdehyde (MDA), was elevated in rats by received 7 mg/kg of cisplatin intraperitoneally. The combination of GGE and BM-MSCs returned the enzyme levels to near the normal range. It also improved levels of liver superoxide dismutase (SOD) and glutathione (GSH) and reduced MDA levels. Additionally, it was found that when GGE and BM-MSCs were used together, they significantly downregulated caspase9 (Casp9), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and interleukin-1ß (IL-1ß), which are involved in severe proinflammatory and apoptotic signaling cascades in the liver. Moreover, combining GGE and BM-MSCs led to the normal result of hepatocytes in several examined liver histological sections. Therefore, our findings suggest that GGE may have protective effects against oxidative liver damage and the promising regenerative potential of BM-MSCs.

Asian Pigeonwing Plants (Clitoria ternatea) Synergized Mesenchymal Stem Cells by Modulating the Inflammatory Response in Rats with Cisplatin-Induced Acute Kidney Injury.

Acute kidney injury is a heterogeneous set of disorders distinguished by a sudden decrease in the glomerular filtration rate, which is evidenced by an increase in the serum creatinine concentration or oliguria and categorized by stage and cause. It is an ever-growing health problem worldwide, with no reliable treatment. In the present study, we evaluated the role of Clitoria ternatea combined with mesenchymal stem cells in treating cisplatin-induced acute kidney injury in rats. Animals were challenged with cisplatin, followed by 400 mg/kg of Asian pigeonwing extract and/or mesenchymal stem cells (106 cells/150 g body weight). Kidney functions and enzymes were recorded, and histopathological sectioning was also performed. The expression profile of IL-1ß, IL-6, and caspase-3 was assessed using the quantitative polymerase chain reaction. The obtained data indicated that mesenchymal stem cells combined with the botanical extract modulated the creatinine uric acid and urea levels. Cisplatin increased the level of malondialdehyde and decreased the levels of both superoxide dismutase and glutathione; however, the dual treatment was capable of restoring the normal levels. Furthermore, all treatments modulated the IL-6, IL-1ß, and caspase-3 gene expression profiles. The obtained data shed some light on adjuvant therapy using C. ternatea and mesenchymal stem cells in treating acute kidney injury; however, further investigations are required to understand these agents' synergistic mechanisms fully. The total RNA was extracted from the control, the positive control, and all of the therapeutically treated animals. The expression profiles of the IL-6, IL-1ß, and caspase-3 genes were evaluated using the real-time polymerase chain reaction. Cisplatin treatment caused a significant upregulation in IL-6. All treatments could mitigate the IL-6-upregulating effect of cisplatin, with the mesenchymal stem cell treatment being the most effective. The same profile was observed in the IL-1ß and caspase-3 genes, except that the dual treatment (mesenchymal stem cells and the botanical extract) was the most effective in ameliorating the adverse effect of cisplatin; it downregulated caspase-3 expression better than the positive control.

H19 and TUG1 lncRNAs as Novel Biomarkers for Irritable Bowel Syndrome in Diabetic Patients.

Introduction: Irritable bowel syndrome (IBS) is a gastrointestinal disorder due to enteric nervous system impairment that produces different patterns of digestion. IBS is a common finding in diabetic patients. The functions of lncRNAs in IBS are still not clear and need to be further investigated. The aim of this study was to assess the diagnostic roles of lncRNA H19 and TUG1 for IBS associated with diabetes and to evaluate their association with clinical and laboratory findings. Subjects and Methods: Samples from 42 diabetic patients, 42 diabetic patients with IBS, and 42 healthy controls were obtained. The LncRNA H19 and TUG1 expressions were measured by quantitative real-time PCR. Results: The patients with IBS had significantly lower levels of lncRNA H19 and TUG1 expression than the healthy controls and diabetic-only patients (p < 0.001). LncRNA H19 and TUG1 can discriminate between diabetic-only patients and those with IBS (areas under the ROC curves of 0.95 and 0.722, respectively). The TUG1 expression levels were significantly different among types of IBS (IBS-D lower than IBS-M and IBS-C lower than IBS-M; p = 0.0165 and p = 0.043, respectively). H19 and TUG1 were downregulated in patients with poor glycemic control. lncRNA H19 and TUG1 expression in diabetic patients with IBS significantly negatively correlated with the IBS severity scoring system. Both lncRNAs' expression significantly predicted the disease severity. LncRNA H19 expression can be an independent predictor for disease severity (adjusted odds ratio = 0.00001, 95% CI = 0−0.5, p = 0.045). Conclusions: Diabetic patients with IBS had significantly lower levels of lncRNA H19 and TUG1 expression than healthy controls and diabetic-only patients. LncRNA H19 had better diagnostic performance criteria for IBS. LncRNA H19 expression can be an independent predictor for IBS severity.

Anti-Inflammatory, Anti-Apoptotic, and Antioxidant Roles of Honey, Royal Jelly, and Propolis in Suppressing Nephrotoxicity Induced by Doxorubicin in Male Albino Rats.

Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Honey, propolis, and royal jelly were evaluated for their ability to protect against nephrotoxicity caused by DOX. Forty-two adult albino rats were divided into control groups. The DOX group was injected i.p. with a weekly dose of 3 mg/kg of DOX for six weeks. The DOX plus honey treated group was injected with DOX and on the next day, received 500 mg/kg/day of honey orally for 21 days. The DOX plus royal jelly treated group was injected with DOX and on the following day, received 100 mg/kg/day of royal jelly orally for 21 days. The DOX plus propolis treated group received DOX and on the following day, was treated orally with 50 mg/kg/day of propolis for 21 days. The DOX plus combined treatment group received DOX and on the following day, was treated with a mix of honey, royal jelly, and propolis orally for 21 days. Results confirmed that DOX raised creatinine, urea, MDA, and TNF-α while decreasing GPX and SOD. Damages and elevated caspase-3 expression were discovered during renal tissue's histopathological and immunohistochemical studies. Combined treatment with honey, royal jelly, and propolis improved biochemical, histological, and immunohistochemical studies in the renal tissue. qRT-PCR revealed increased expression of poly (ADP-Ribose) polymerase-1 (PARP-1) and a decline of Bcl-2 in the DOX group. However, combined treatment induced a significant decrease in the PARP-1 gene and increased Bcl-2 expression levels. In addition, the combined treatment led to significant improvement in the expression of both PARP-1 and Bcl-2 genes. In conclusion, the combined treatment effectively inhibited nephrotoxicity induced by DOX.

Glycine Betaine Relieves Lead-Induced Hepatic and Renal Toxicity in Albino Rats.

Lead (Pb) is a widespread and nondegradable environmental pollutant and affects several organs through oxidative mechanisms. This study was conducted to investigate the antioxidant protective effect of glycine betaine (GB) against Pb-induced renal and hepatic injury. Male albino rats (n = 45) were divided into three groups: G1 untreated control, G2 Pb-acetate (50 mg/kg/day), and G3 Pb-acetate (50 mg/kg/day) plus GB (250 mg/kg/day) administered for 6 weeks. For G3, Pb-acetate was administered first and followed by GB at least 4 h after. Pb-acetate treatment (G2) resulted in a significant decrease in renal function, including elevated creatinine and urea levels by 17.4% and 23.7%, respectively, and nonsignificant changes in serum uric acid levels. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphates (ALP) activities were significantly increased with Pb treatment by 37.6%, 59.3%, and 55.1%, respectively. Lipid peroxidation level was significantly increased by 7.8 times after 6 weeks of Pb-acetate treatment. The level of reduced glutathione (GSH-R) significantly declined after Pb-acetate treatment. Pb-acetate treatment also reduced the activities of superoxide dismutase (SOD), glutathione-S-transferase (GST), and glutathione peroxidase (GSH-PX) by 74.1%, 85.0%, and 40.8%, respectively. Treatment of Pb-intoxicated rats with GB resulted in a significant reduction in creatinine, urea, ALT, AST, and lipid peroxidation, as well as a significant increase in the level of GSH-R and in the activities of ALP, SOD, GST, and GSH-PX. The molecular interaction between GB and GSH-PX indicated that the activation of GSH-PX in Pb-intoxicated rats was not the result of GB binding to the catalytic site of GSH-PX. The affinity of GB to bind to the catalytic site of GSH-PX is lower than that of H2O2. Thus, GB significantly mitigates Pb-induced renal and liver injury through the activation of antioxidant enzymes and the prevention of Pb-induced oxidative damage in the kidney and liver.

Quercetin mitigates rheumatoid arthritis by inhibiting adenosine deaminase in rats.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and bone destruction. Adenosine deaminase (ADA) is a key inflammatory enzyme that increases joint stiffness and pain in RA. In this study, we evaluated the in-silico, and in vivo inhibitory effect of quercetin isolated from Egyptian Fenugreek on ADA enzyme activity. We also determined the combinatorial effect of quercetin on methotrexate mediated anti-inflammatory efficacy and toxicity. In-silico molecular docking was conducted and confirmed in an in vivo RA rat model. The results showed that the inhibition constant of quercetin on joint ADA by docking and in-vitro was 61.9 and 55.5 mM, respectively. Therefore, quercetin exhibits anti-inflammatory effect in a rat RA model as evidenced by reducing the specific activity of ADA in joint tissues, lower jaw volume, enhance body weight, downregulate ADA gene expression, reduce levels of RA cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α, also, rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide RA biomarker levels. These findings demonstrate that the purified quercetin has a promising anti-inflammatory effect against RA disease through its inhibitory effects on the ADA enzyme. Furthermore, isolated quercetin improved the anti-inflammatory efficacy of methotrexate, reduced its toxic effects by increasing antioxidant enzymes and reducing oxidative stress.

Ameliorative Effect of Citrus Lemon Peel Extract and Resveratrol on Premature Ovarian Failure Rat Model: Role of iNOS/Caspase-3 Pathway.

Premature ovarian failure (POF) is described as a loss of oocytes and the absence of folliculogenesis and is considered an adverse effect of chemotherapeutic drugs, which leads to infertility. Subsequently, the existing inquiry was achieved by exploring the potential suspicious influences of lemon peel extract (LPE), and resveratrol (RES) on cyclophosphamide (CPA) induced-POF. The results showed that CPA-induced POF significantly decreased serum estradiol (E2) and progesterone levels, along with a considerable rise in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Moreover, CPA administration to rats significantly increased the serum level of Malondialdehyde (MDA) and significantly lowered the levels of reduced glutathione (GSH) and superoxide dismutase (SOD); in addition, it increased nuclear factor kappa B (NF-κB) levels, tumor necrosis factor-α (TNF-α), as well as cyclooxygenase 2 (COX-2) with the spread expression of inducible nitric oxide synthase (iNOS) mRNA levels and caspase-3 (Casp3) levels in ovarian tissues versus the control rats. However, treatment with LPE and RES suppressed the triggering of NF- κB pathways, evidenced by a considerable reduction in Casp3 & iNOS mRNA expression level and significant ameliorative effects in all evaluated parameters, as confirmed by the histological and immunohistochemical investigation when comparing the model group. In overall findings, both lemon peel extract and resveratrol can mitigate the adverse effects of CPA-induced POF. Most crucially, its combination therapy is a promising pharmacological agent for this disease.

Metformin Improves Biochemical and Pathophysiological Changes in Hepatocellular Carcinoma with Pre-Existed Diabetes Mellitus Rats.

Hepatocellular carcinoma (HCC) is one of the world's most widely recognized malignant tumors that accounts for 90% of all the primary liver cancers and is a major cause of death from cancer, representing half a million deaths per year. Obesity and associated metabolic irregularities, particularly diabetes mellitus (DM) and insulin resistance, are important risk factors for the advancement of HCC. Recently, retrospective studies showed that metformin (MET) could protect the hepatic tissues in pre-existing diabetes mellitus from HCC. The purpose of this study was to assess the role of MET treatment in the pre-existing diabetic rats before and after HCC induction by diethylnitrosamine (DEN). Thirty-five male Sprague Dawley albino rats were partitioned into the following groups: Group 1 (Gp1) was the control. Gp2 was injected intraperitoneally (i.p) with streptozotocin (STZ) (80 mg/kg) and DEN (50 mg/kg/7 weeks). Gp3, Gp4, and Gp5 were injected as in Gp2 and treated with MET (150 mg/kg) before and/or after HCC induction. Biochemical parameters including liver functions, lipid profile, and oxidative stress biomarkers were determined. Furthermore, histological and immunohistochemical changes were assessed in all groups. Our results illustrated that the group of rats that were treated with STZ and DEN had significant changes in both liver functions and were associated with alterations in the liver histopathological architectures. Treatment with MET before or after HCC induction ameliorated the cellular changes in the liver tissues; however, the utmost protection was found in a group of rats, which were treated with MET before and after HCC induction.

The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice.

One of the activating factors of the cells of the innate immune system is the agonists of toll-like receptors (TLRs). Our earlier publications detailed how poly(I:C), a TLR3 agonist, elevates the NK cell population and the associated antigen-specific CD8+ T cell responses. This study involved a single treatment of the B6 mice with poly(I:C) intraperitoneally. To perform a detailed phenotypic analysis, mononuclear cells were prepared from each of the liver, peripheral blood, and spleen. These cells were then examined for their NK cell population by flow cytometric analysis following cell staining with indicated antibodies. The findings of the study showed that the NK cell population of the liver with an NK1.1highCD11bhighCD11chigh B220+Ly6G- phenotype was elevated following the treatment with poly(I:C). In the absence of CD11b molecule (CR3-/- mice), poly(I:C) can still increase the remained numbers of NK cells with NK1.1+CD11b- and NK1.1+Ly6G- phenotypes in the liver while their numbers in the blood decrease. After the treatment with anti-AGM1 Ab, which induced depletion of NK1.1+CD11b+ cells and partial depletion of CD3+NK1.1+ and NK1.1+CD11b- cell populations, poly(I:C) normalized the partial decreases in the numbers of NK cells concomitant with increased numbers of NK1.1-CD11b+ cell population in both liver and blood. Regarding mice with a TLR3-/- phenotype, their injection with poly(I:C) resulted in the partial elevation in the NK cell population as compared to wild-type B6 mice. To summarise, the TLR3 agonist poly(I:C) results in the elevation of a subset of liver NK cells expressing the two myeloid markers CD11c and CD11b. The effect of poly(I:C) on NK cells is partially dependent on TLR3 and independent of the presence of CD11b.

SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.

AIMS: Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity. RESULTS: SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1ß, an activator of NFκB. This negative modulation was abolished by neutralizing IL1ß in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity. INNOVATION: Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation. CONCLUSION: SIRT1 protein levels are downregulated by IL1ß/NFκB signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Rafael de Cabo, Joaquim Ros, Kalervo Hiltunen, and Neil Kaplowitz. Antioxid. Redox Signal. 28, 1187-1208.

Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state.

The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Off mice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet-Off mouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor-erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer.