Hepatic TNF-α Research Articles

Total saponins from Panax japonicus attenuate acute alcoholic liver oxidative stress and hepatosteatosis by p62-related Nrf2 pathway and AMPK-ACC/PPARα axis in vivo and in vitro

Ethnopharmacological relevancePanax japonicus (T. Nees) C.A. Mey. (PJ) has been used as a tonic traditional Chinese medicine (TCM) for years. Based on its meridian tropism in liver, spleen, and lung, PJ was popularly used to enhance the function of these organs. It is originally recorded with detoxicant effect on binge drink in Ben Cao Gang Mu Shi Yi, a persuasive Chinese materia medica. And binge dink has a close relationship with alcoholic liver disease (ALD). Hence, it's meaningful to investigate whether PJ exerts liver protection against binge drink toxicity. Aim of the studyThis investigation was carried out not only to emphasize the right recognition of total saponins from PJ (SPJ), but also to study on its sober-up effectiveness and defensive mechanism against acute alcoholic liver injury in vivo and in vitro. Materials and methodsSPJ constituents were verified by HPLC-UV analysis. In vivo, acute alcoholic liver oxidative stress and hepatosteatosis were established by continuous ethanol gavage to C57BL/6 mice for 3 days. SPJ was pre-administered for 7 days to investigate its protective efficacy. Loss of righting reflex (LORR) assay was employed to assess anti-inebriation effect of SPJ. Transaminases levels and hematoxylin and eosin (H&E) staining were measured to indicate the alcoholic liver injury. Antioxidant enzymes were measured to evaluate the oxidative stress degree in liver. Measurement of hepatic lipid accumulation was based on Oil Red O staining. Levels of inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). In vitro, HepG2 cells were treated with ethanol for 24 h, and SPJ was pre-administered for 2 h. 2,7-dichlorofluorescein diacetate (DCFH-DA) was used as a probe to indicate reactive oxygen species (ROS) generation. Nrf2 activation was verified by the favor of specific inhibitor, ML385. The nuclear translocation of Nrf2 was indicated with immunofluorescence analysis. Proteins expressions of related pathways were determined by Western blotting. ResultsOleanane-type saponins are the most abundant constituents of SPJ. In this acute model, SPJ released inebriation of mice in a dose dependent manner. It decreased levels of serum ALT and AST, and hepatic TG. Besides, SPJ inhibited CYP2E1 expression and reduced MDA level in liver, with upregulations of antioxidant enzymes GSH, SOD and CAT. p62-related Nrf2 pathway was activated by SPJ with downstream upregulations of GCLC and NQO1 in liver. AMPK-ACC/PPARα axis was upregulated by SPJ to alleviate hepatic lipidosis. Hepatic IL-6 and TNF-α levels were downregulated by SPJ, which indicated a regressive lipid peroxidation in liver. In HepG2 cells, SPJ reduced ethanol-exposed ROS generation. Activated p62-related Nrf2 pathway was verified to contribute to the alleviation of alcohol-induced oxidative stress in hepatic cells. ConclusionThis attenuation of hepatic oxidative stress and steatosis suggested the therapeutic value of SPJ for ALD.

Investigation of the anti-oxidative and anti-inflammatory effects of melatonin on experimental liver damage by radiation.

Radiotherapy is one of the inevitable treatment approaches for several types of cancer. We aimed to show the protective and therapeutic effects of daily use of melatonin on liver tissues subjected to a single dose of 10Gy (gamma-ray) total body radiation. Rats were divided into 6 groups, of which 10 were in each: control, sham, melatonin, radiation, radiation+melatonin, and melatonin+radiation. The rats received 10 Gy of external radiation throughout their entire bodies. The rats were given 10 mg/kg/day of melatonin intraperitoneally before or after radiation treatment, depending on the group. Histological methods, immunohistochemical analysis (Caspase-3, Sirtuin-1, α-SMA, NFΚB-p65), biochemical analysis by ELİSA (SOD, CAT, GSH-PX, MDA, TNF-α, TGF-β, PDGF, PGC-1α) and the Comet assay as a marker of DNA damage were applied to the liver tissues. Histopathological examinations showed structural changes in the liver tissue of the radiation group. Radiation treatment increased the immunoreactivity of Caspase-3, Sirtuin-1 and α-SMA, but these effects were relatively attenuated in the melatonin-treated groups. The melatonin+radiation group had statistically significant results close to those of the control group, in terms of Caspase-3, NFΚB-p65 and Sirtuin-1 immunoreactivity. In melatonin treated groups, hepatic biochemical markers, MDA, SOD, TNF-α, TGF-β levels, and DNA damage parameters were decreased. Administration of melatonin before and after radiation has beneficial effects, but using it before radiation may be more efficient. Accordingly, daily melatonin usage could mitigate ionizing radiation induced damage.

Sulfated Chinese Yam Polysaccharides Alleviate LPS-Induced Acute Inflammation in Mice through Modulating Intestinal Microbiota.

This study aimed to test the preventive anti-inflammatory properties of Chinese yam polysaccharides (CYP) and sulfated Chinese yam polysaccharides (SCYP) on LPS-induced systemic acute inflammation in mice and investigate their mechanisms of action. The results showed that SCYP can efficiently reduce plasma TNF-α and IL-6 levels, exhibiting an obvious anti-inflammation ability. Moreover, SCYP reduced hepatic TNF-α, IL-6, and IL-1β secretion more effectively than CYP, and significantly altered intestinal oxidative stress levels. In addition, a 16S rRNA gene sequencing analysis showed that CYP regulated the gut microbiota by decreasing Desulfovibrio and Sutterella and increasing Prevotella. SCYP changed the gut microbiota by decreasing Desulfovibrio and increasing Coprococcus, which reversed the microbiota dysbiosis caused by LPS. Linear discriminant analysis (LDA) effect size (LEfSe) revealed that treatment with CYP and SCYP can produce more biomarkers of the gut microbiome that can promote the proliferation of polysaccharide-degrading bacteria and facilitate the intestinal de-utilization of polysaccharides. These results suggest that SCYP can differentially regulate intestinal flora, and that they exhibit anti-inflammatory effects, thus providing a new reference to rationalize the exploitation of sulfated yam polysaccharides.

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver-derived TNF-alpha in senescence-accelerated mice.

Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice. A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations. In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group. The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.

The effects of camelina sativa oil and high-intensity interval training on liver function and metabolic outcomes in male type 2 diabetic rats.

The purpose of this study was to evaluate the independent and combined effects of camelina sativa oil and high-intensity interval training (HIIT) on liver function, and metabolic outcomes in streptozotocin-induced diabetic rats. Forty male Wistar rats were randomly assigned to five equal groups (8 per group): Normal control (NC), diabetic control (DC), diabetic + camelina sativa oil (300 mg/kg by oral gavage per day; D + CSO), diabetic + HIIT (running on a treadmill 5 days/week for 8 weeks; D + HIIT), diabetic + camelina sativa oil + HIIT (D + CSO + HIIT). In all three intervention groups (D + CSO, D + HIIT, and D + CSO + HIIT) compared to the DC, hepatic TNF-α, MDA, and histopathology markers, decreased and hepatic PGC-1α, and PPAR-γ increased (p < 0.05). However, the effect of D + CSO was greater than D + HIIT alone. Hepatic TG decreased significantly in D + HIIT and D + CSO + HIIT compared to other groups (p < 0.001). Fasting plasma glucose in all three intervention groups (D + CSO, D + HIIT, and D + CSO + HIIT) and HOMA-IR in D + CSO and D + CSO + HIIT were decreased compared to DC (p < 0.001). Only hepatic TAC and fasting plasma insulin remained unaffected in the three diabetic groups (p < 0.001). Overall, D + CSO + HIIT had the largest effect on all outcomes. At the doses and treatment duration used in the current study, combination of CSO and HIIT was beneficial for reducing liver function and metabolic outcomes other than CSO and HIIT alone.

Hepatic-Modulatory Effects of Chicken Liver Hydrolysate-Based Supplement on Autophagy Regulation against Liver Fibrogenesis

Chicken-liver hydrolysates (CLHs) have been characterized as performing several biofunctions by our team. This study aimed to investigate if a CLH-based supplement (GBHP01TM) can ameliorate liver fibrogenesis induced by thioacetamide (TAA) treatment. Our results showed that the TAA treatment caused lower body weight gains and enlarged livers, as well as higher serum ALT, AST, and ALP levels (p < 0.05). This liver inflammatory and fibrotic evidence was ameliorated (p < 0.05) by supplementing with GBHP01TM; this partially resulted from its antioxidant abilities, including decreased TBARS values but increased TEAC levels, reduced GSH contents and catalase/GPx activities in the livers of TAA-treated rats (p < 0.05). Additionally, fewer nodules were observed in the appearance of the livers of TAA-treated rats after supplementing with GBHP01TM. Similarly, supplementing GBHP01TM decreased fibrotic scars and the fibrotic score in the livers of TAA-treated rats (p < 0.05). Moreover, the increased hepatic IL-6, IL-1β, and TNF-α levels after TAA treatment were also alleviated by supplementing with GBHP01TM (p < 0.05). Meanwhile, GBHP01TM could decrease the ratio of LC3B II/LC3B I, but upregulated P62 and Rab7 in the livers of TAA-treated rats (p < 0.05). Taking these results together, the CLH-based supplement (GBHP01TM) can be characterized as a natural agent against liver fibrogenesis.

Hepatic regenerative response to long-term consumption of cinnamon-rich diet in aged rats.

The present study aimed to investigate the impact of cinnamon on liver regeneration in a rat model of partial hepatectomy (PH). Thirty-two old male Sprague-Dawley rats (12 weeks old) were randomly divided into two equal groups (n=16). One group was fed with a standard diet (control) while the other group was fed with the same diet containing 1% cinnamon for 41 weeks. Then, all animals were subjected to the PH procedure and their livers were studied on postoperative days 2, 10 and 28. The liver contents of hepatic growth factor (HGF), insulin, malondialdehyde (MDA), nitric oxide metabolites (NOx), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, the serum levels of liver function markers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), MDA, NOx and SOD activity were measured. The regenerated liver weight was significantly higher in cinnamon-treated animals than the controls on both day 10 and 28 post hepatectomy. The hepatic MDA levels in the cinnamon-treated animals were significantly lower than the control rats. Cinnamon led to a significant increase of SOD on day 2 after hepatectomy in serum and liver content. The basal level of HGF in the liver of cinnamon-consuming rats was significantly higher than in the control rats. Hepatic insulin level was significantly increased relative to baseline and control on day 2 in the cinnamon-consuming rats. Hepatic TNF-α levels dramatically decreased on postoperative days (POD) 2 relative to baseline in the control and cinnamon-treated rats. Long-term cinnamon consumption enhanced liver regeneration outcomes in old rats.

Pediococcus pentosaceus PR-1 modulates high-fat-died-induced alterations in gut microbiota, inflammation, and lipid metabolism in zebrafish.

Obesity is a health issue worldwide. This study aimed to evaluate the beneficial effects of Pediococcus pentococcus PR-1 on the modulating of gut microbiota, inflammation and lipid metabolism in high-fat-diet (HFD)-fed zebrafish. Adult zebrafish were fed a commercial (C), high fat (H, 25% fat), probiotic (P, 106 CFU/g), or high fat with probiotic (HP) diets twice daily for 5 weeks. Gut microbiota were analysed using 16S rRNA gene sequencing. Gene expressions of intestinal cytokine, intestinal TJ protein, and liver lipid metabolism were analysed by quantitative real-time polymerase chain reaction. Biochemical and histological analysis were also performed. P. pentosaceus PR-1 reduced body weight and BMI, indicating its anti-obesity effect. The 16S rRNA sequencing results showed HFD induced a distinct gut microbiota structure from C group, which was restored by probiotic. P. pentosaceus PR-1 improved gut health by decreasing the abundance of Ralstonia and Aeromonas which were increased induced by HFD. Moreover, probiotic restored abundance of Fusobacteria, Cetobacterium and Plesiomonas, which were decreased in HFD-fed zebrafish. The results of quantitative real-time polymerase chain reaction showed probiotic suppressed HFD-induced inflammation by decreasing the expressions of IL-1b and IL-6. Levels of hepatic TNF-α, IL-1ß, and IL-6 were reduced by probiotic in HFD-fed zebrafish. Probiotic also ameliorated gut barrier function by increasing the expressions of occludin, Claudin-1, and ZO-1. Probiotic exerted anti-adipogenic activity through regulating the expressions of SREBP1, FAS and LEPTIN. Levels of hepatic triglyceride, total cholesterol, low density lipoprotein were also reduced by probiotic. Histological analysis showed probiotic alleviated liver steatosis and injury induced by HFD. P. pentosaceus PR-1 might be useful as a dietary health supplement, especially for reducing obesity.

Effects of Aqueous Saffron Extract on Glucoregulation as Well as Hepatic Agt and TNF-α Gene Expression in Rats Subjected to Sub-Chronic Stress.

Stress and saffron seem to affect glucoregulation mechanisms and insulin resistance in different ways. Impacts of the aqueous saffron extract were investigated on serum glucose levels, serum insulin levels, the homeostatic model assessment of β-cell function (HOMA-B), the homeostatic model assessment of insulin resistance (HOMA-IR), adrenal weight, and hepatic gene expression of angiotensinogen (Agt) and tumor necrosis factor-α (TNF-α) in rats under sub-chronic stress. Forty-two male rats were divided into six groups: control, restraint stress (6h/day for seven days), saffron (30 and 60 mg/kg) treatments for seven days, and post-stress saffron (30 and 60 mg/kg) treatments for seven days. The serum glucose and insulin levels, hepatic gene expressions of Agt and TNF-α, HOMA-IR, HOMA-B, and adrenal gland weight were measured. One-week recovery following sub-chronic stress led to non-significant hyperglycemia, hyperinsulinemia, and insulin resistance. The hepatic Agt and TNF-α mRNA levels increased significantly in this group. Saffron administration led to enhanced hepatic Agt mRNA in the non-stressed subjects. In addition, serum glucose levels, insulin resistance, and hepatic Agt gene expression significantly increased in stress-saffron groups. The hepatic TNF-α gene expression was reduced only in the stress-saffron 60 group. Saffron treatment after sub-chronic stress not only did not improve glucose tolerance but also enhanced insulin resistance. It indicated the interaction of saffron and sub-chronic stress to promote renin-angiotensin system activity. In addition, the saffron treatment decreased TNF-α gene expression after sub-chronic stress. The synergistic stimulating effect of saffron and sub-chronic stress on gene expression of hepatic Agt led to insulin resistance and hyperglycemia.

Dietary camellia seed oil attenuates liver injury in mice chronically exposed to alcohol.

Dietary fat composition is closely associated with the pathological development of alcoholic liver disease (ALD). Fat enriched with saturated fatty acids protects whereas with polyunsaturated fatty acids aggravates alcohol-induced liver injury. However, limited study has addressed how monounsaturated fatty acids (MUFAs) determines the pathological process of ALD. Our study was conducted to evaluate the effect of MUFAs-enriched-camellia seed oil (CSO) on alcohol-induced liver injury. The ALD model was established by feeding C57BL/6 mice with Lieber-DeCarli diet, and with either CSO or polyunsaturated fatty acids (PUFAs)-enriched-corn oil (CO) as fat source. After 4-week-intervention, CSO-feed rescued alcohol-induced liver injury compared to CO-feed, evidenced by measurements of plasma ALT activity, H&E stain, and hepatic cleaved-Caspase-3 expression. Besides, CSO-feed alleviated alcohol-induced oxidative stress, associated with NRF2 and Hif-1α expressions improvement. The reduction of F4/80 immunostaining and the decreased expressions of hepatic TNF-α and IL-6 suggested CSO-feed improved alcohol-induced inflammation. The mechanistic analysis showed that the inhibition of ASK1 and MAPKs might contribute to CSO-protected liver injury. Notably, we observed CSO-feed relieved the gut microbiota disturbance with the decreased Firmicutes and Turicibater, and the increased Bacteroidota, Alloprevotella, and Bacteroides, and reduced circulatory endotoxin level and lipolysis of adipose tissue, which are the known pathogenic factors in alcohol-induced liver injury. Unexpectedly, CSO induced more hepatic steatosis than CO-feed. In conclusion, CSO attenuated chronic alcohol consumption-induced liver injury but enhanced hepatic steatosis. CSO could be a potential dietary choice for alcoholic individuals with liver injury.

Evaluation of Hepatoprotective and Gastroprotective Activities of Paspalidium flavidum Leaves Extract in Experimental Animal Models.

Paspalidium flavidum (watercrown grass), a medicinal plant, is traditionally used in liver ailments and stomach problems. The hepatoprotective and gastroprotective activities of the aqueous methanol extract of Paspalidium flavidum (AMEPF) were studied in experimental animal models. Paracetamol and aspirin were used to induce hepatotoxicity and gastric ulcer in rats, respectively. Biochemical hepatic parameters, gastric pH, total acidity, ulcer index, percentage protection, nitric oxide and TNF-α were measured in AMEPF-treated groups. Moreover, GC-MS analysis of AMEPF was performed. Pretreatment with AMEPF improved the blood lipid profile and restored liver function tests in paracetamol-induced hepatotoxicity. While in aspirin-induced gastric ulcer, oral administration of AMEPF significantly reduced (P<0.05) the gastric lesions, total acidity and ulcer scoring index, TNF-α with upregulation of nitric oxide when compared with the Diseased group. AMEPF exhibited anti-lipid peroxidation activity. Histopathological studies were in good agreement with the biochemical findings. GC-MS analysis revealed the presence of anti-oxidant phyto-constituents, including oleic acid and 1,2-benzenedicarboxylic acid, mono(2-ethylhexyl) in AMEPF. This study suggested that aqueous methanol extract from the leaves of P. flavidum has beneficial hepatoprotective and gastroprotective activities related to its anti-oxidant phytochemicals.

Methanolic Moringa oleifera leaf extract protects against epithelial barrier damage and enteric bacterial translocation in intestinal I/R: Possible role of caspase 3.

Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI. Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS. Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3. Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid.

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.Graphical abstract

Intestinal Microbiomics and Metabolomics Insights into the Hepatoprotective Effects of Lactobacillus paracasei CCFM1222 Against the Acute Liver Injury in Mice.

In recent years, acute liver injury (ALI) has received wide-range attention in the world due to its relatively high morbidity and mortality. This study aimed to explore the hepatoprotective effect of Lactobacillus paracasei CCFM1222 against lipopolysaccharide (LPS)-induced ALI mice and further elaborate its mechanism of action from the perspective of intestinal microbiomics and metabolomics. The results displayed that L. paracasei CCFM1222 pretreatment significantly decreased the serum ALT, and AST levels, inhibited the releases of hepatic TNF-α, IL-1β, and IL-6 levels, and activated the SOD, CAT, and GSH-Px activities in LPS-treated mice. The cecal short-chain fatty acid (SCFAs) levels were increased in LPS-treated mice with L. paracasei CCFM1222 pretreatment. In addition, L. paracasei CCFM1222 pretreatment remarkably shifted the intestinal microbiota composition, including the higher abundance of Faecalibaculum, Bifidobacterium, and lower abundance of the Prevotellaceae NK3B31 group, which is positively associated with the cecal propionic, butyric, valeric, isobutyric, and isovaleric acids. The metabolomics based on UPLC-QTOF/MS revealed that L. paracasei CCFM1222 pretreatment significantly regulated the composition of feces metabolites in LPS-treated mice, especially the potential biomarker-related butanoate metabolism, vitamin B6 metabolism, D-glutamine and D-glutamate metabolism, tryptophan metabolism, caffeine metabolism, arginine biosynthesis, arginine, and proline metabolism. Moreover, L. paracasei CCFM1222 pretreatment remarkably regulated the expression of gene-associated ALI (including Tlr4, Myd88, Nf-kβ, iNOS, Cox2, Iκ-Bα, Nrf2, and Sirt-1). In conclusion, these results suggest the possibility that L. paracasei CCFM1222 supplementation has beneficial effects on preventing the occurrence and development of ALI by inhibiting the inflammatory responses and altering intestinal microbiota composition and their metabolites.

Rhizoma curcumae Longae ameliorates high dietary carbohydrate-induced hepatic oxidative stress, inflammation in golden pompano Trachinotus ovatus

In general, starch, as a complex carbohydrate, is the most economical energy source in aquaculture for its relatively low cost. However, excessive dietary levels of carbohydrate result in pathological conditions. An 8-week feeding trial with CT (control diet, containing 21% carbohydrate), HC (a high-carbohydrate diet, containing 50% carbohydrate) and HCR (a HC diet supplemented with 0.015% Rhizoma curcumae Longae) was performed to investigate the protective effect of curcumin on high-carbohydrate-induced hepatic oxidative stress and intestine lesion in juvenile Trachinotus ovatus. In the current study, HC group significantly decreased WGR, SGR, plasma CAT activity, intestinal C4 levels, hepatic Nrf2, Keap1, Bach1, HO1, CAT, and GPX mRNA expression as well as ZO-1, Occludin, and Claudin-3, TGF-β mRNA transcription levels, while the opposite was true for plasma AST activity, hepatic MDA contents, intestinal Claudin-15, NF-κB, IL-1β, IL-6, and TNF-α mRNA expression. In contrast with the HC group, the HCR group significantly increased the activities of hepatic CAT, SOD, intestinal C3, C4, IgG and LZM levels, hepatic Nrf2, Bach1, CAT, and GPX mRNA expression as well as intestinal ZO-1, Occludin, Claudin-3, TGF-β and IL-10 mRNA expression levels, but the opposite trend was found in plasma triglyceride content, hepatic lipid deposition, hepatic Keap1 mRNA level as well as intestinal NF-κB, IL-6. In conclusion, high-carbohydrate diet can cause detrimental effect on physiological health status in Trachinotus ovatus, while adding Rhizoma curcumae Longae can improve hepatic and intestinal health status via attenuating the oxidative stress, inflammation, and reducing lipid deposition.

The biological clock enhancer nobiletin ameliorates steatosis in genetically obese mice by restoring aberrant hepatic circadian rhythm.

Nonalcoholic fatty liver disease (NAFLD) is associated with disruption of homeostatic lipid metabolism, but underlying processes are poorly understood. One possible mechanism is impairment in hepatic circadian rhythm, which regulates key lipogenic mediators in the liver and whose circadian oscillation is diminished in obesity. Nobiletin enhances biological rhythms by activating RAR-related orphan receptor nuclear receptor, protecting against metabolic syndrome in a clock-dependent manner. The effect of nobiletin in NAFLD is unclear. In this study, we investigate the clock-enhancing effects of nobiletin in genetically obese (db/db) PER2::LUCIFERASE reporter mice with fatty liver. We report microarray expression data suggesting hepatic circadian signaling is impaired in db/db mice with profound hepatic steatosis. Circadian PER2 activity, as assessed by mRNA and luciferase assay, was significantly diminished in liver of db/db PER2::LUCIFERASE reporter mice. Continuous animal monitoring systems and constant dark studies suggest the primary circadian defect in db/db mice lies within peripheral hepatic oscillators and not behavioral rhythms or the master clock. In vitro, nobiletin restored PER2 amplitude in lipid-laden PER2::LUCIFERASE reporter macrophages. In vivo, nobiletin dramatically upregulated core clock gene expression, hepatic PER2 activity, and ameliorated steatosis in db/db PER2::LUCIFERASE reporter mice. Mechanistically, nobiletin reduced serum insulin levels, decreased hepatic Srebp1c, Acaca1, Tnfα, and Fgf21 expression, but did not improve Plin2, Plin5, or Cpt1, suggesting nobiletin attenuates steatosis in db/db mice via downregulation of hepatic lipid accumulation. These data suggest restoring endogenous rhythm with nobiletin resolves steatosis in obesity, proposing that hypothesis that targeting the biological clock may be an attractive therapeutic strategy for NAFLD.NEW & NOTEWORTHY NAFLD is the most common chronic liver disease, but underlying mechanisms are unclear. We show here that genetically obese (db/db) mice with fatty liver have impaired hepatic circadian rhythm. Hepatic Per2 expression and PER2 reporter activity are diminished in db/db PER2::LUCIFERASE mice. The biological clock-enhancer nobiletin restores hepatic PER2 in db/db PER2::LUCIFERASE mice, resolving steatosis via downregulation of Srebp1c. These studies suggest targeting the circadian clock may be beneficial strategy in NAFLD.

The effect of different weight loss strategies to treat non-alcoholic fatty liver disease focusing on fibroblast growth factor 21.

ObjectiveObesity, often associated with non-alcoholic fatty liver disease (NAFLD), is characterized by an imbalance between energy expenditure and food intake, which is also reflected by desensitization of fibroblast growth factor 21 (FGF21). FGF21 is strongly influenced, among others, by TNFα, which is known to be upregulated in obesity-induced inflammation. Successful long-term treatments of NAFLD might be dietary modification, exercise, or fasting.Materials and methodsWhether succeeded NAFLD recovery is linked with improved FGF21 sensitivity and finally reverted FGF21 resistance was the focus of the present study. For this purpose, mice received a high-fat diet (HFD) for 6 months to establish obesity. Afterward, the mice were subjected to three different weight loss interventions, namely, dietary change to low-fat diet (LFD), treadmill training, and/or time-restricted feeding for additional 6 months, whereas one group remained on HFD.ResultsIn addition to the expected decrease in NAFLD activity with dietary change, this was also observed in the HFD group with additional time-restricted feeding. There was also an associated decrease in hepatic TNFα and FGF21 expression and an increase in ß-klotho expression, demonstrated mainly by using principal component analysis. Pearson correlation analysis shows that independent of any intervention, TNFα expression decreased with improved NAFLD recovery. This was accompanied with higher FGF21 sensitivity, as expressed by an increase in β-klotho and FGFR1c expression and concomitantly decreased FGF21 levels.ConclusionIn summary, we conclude that successful NAFLD therapy is associated with a reversion of the TNFα-triggered FGF21-resistant state or desensitization.

Restoration of Hepatic and Intestinal Integrity by Phyllanthus amarus Is Dependent on Bax/Caspase 3 Modulation in Intestinal Ischemia-/Reperfusion-Induced Injury.

Ethnopharmacological relevance: Oxidative stress is a key player in intestinal ischemia/reperfusion (I/R) injury (IIRI) with a tendency to trigger systemic inflammatory response, resulting in progressive distal organ injury. To date, the role of Bax/caspase 3 signaling in IIRI has not been reported. Furthermore, the discovery of a safe and effective drug remains pertinent in improving the outcome of IIRI. Therefore, this study investigated the role of Bax/caspase 3 signaling in intestinal I/R-induced intestinal and hepatic injury. In addition, the protective effect and possible associated mechanism of action of methanolic Phyllanthus amarus leaf extract (PA) against intestinal I/R-induced intestinal and hepatic injury were evaluated. Materials and methods: Fifty male Wistar rats were randomized into five groups (n = 10). The sham-operated group was received 0.5 mL of distilled water for seven days prior to the sham surgery, while the IIRI, febuxostat (FEB) + IIRI, low-dose PA (LDPA) + IIRI, and high-dose PA (HDPA) + IIRI groups underwent the I/R procedure. In addition to the procedure, IIRI, FEB + IIRI, LDPA + IIRI, and HDPA + IIRI received 0.5 mL of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of PA, and 400 mg/kg of PA, respectively, for seven days prior to the I/R procedure. Results: Administration of methanolic Phyllanthus amarus leaf extracts attenuated the intestinal I/R-induced rise in intestinal and hepatic injury markers, malondialdehyde, nitric oxide, TNF-α, IL-6, and myeloperoxidase activities. In addition, Phyllanthus amarus ameliorated I/R-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase, and glutathione peroxidase activities in intestinal and hepatic tissues. These were coupled with the suppression of I/R-induced bacterial translocation, downregulation of I/R-induced activation of Bax/caspase 3 signaling, and improvement of I/R-induced distortion of intestinal and hepatic histoarchitecture by Phyllanthus amarus. Conclusion: Methanolic Phyllanthus amarus leaf extract protects against intestinal and hepatic injuries associated with intestinal I/R by suppressing oxidative-stress-mediated activation of Bax/caspase 3 signaling. The beneficial effects of Phyllanthus amarus may be ascribed to its constituent bioactive molecules, especially tannins, anthocyanin, alkaloids, and phenolics.

Nitric Oxide Modulation as a Potential Molecular Mechanism Underlying the Protective Role of NaHS in Liver Ischemia Reperfusion Injury.

Liver IR is a frequent clinical complication with high morbidity and mortality. The present study evaluated the possible protective effect of sodium hydrosulfide (NaHS), a H2S donor, in IR-induced hepatic injury and explored the mechanisms of actions of the investigated drug. Male albino rats (200-230 g) were divided into the following groups: group 1:Sham-operated non treated rats, group 2: IR non treated rats, group 3: L-NNA + IR rats, group 4: NaHS + IR rats, group 5: L-NNA + NaHS + IR rats. Blood samples were collected for ALT determination. Liver tissue samples were used for the assessment of GPx, catalase, SOD, MDA, total nitrites and TNF- α. Parts from the liver were fixed in 10% formalin solution for histopathological examination and immunohistochemical examination of iNOS, eNOS and caspase-3. NaHS protected the liver against IR. This hepatoprotection was associated with normalization of antioxidant enzyme activity and decrease in hepatic MDA, TNF-α and expression of caspase- 3 and iNOS. NaHS is hepatoprotective in IR injury. The hepatoprotective effects of NaHS are associated with antioxidant, anti-inflammatory and antiapoptotic effects. These effects are probably mediated via NO modulation.

Galectin-3 inhibition retained expression of hepatocyte nuclear factors 4α and 1α in acetaminophen induced acute liver injury

Introduction: Hepatocyte nuclear factors HNF4α and HNF1α, key transcription factors that regulate drug metabolism enzymes expression, were linked to inflammation. Galectin-3 (Gal-3) is a multi-role animal lectin which is involved in inflammation. This study aims to evaluate the impact of galectin-3 inhibition, by using modified citrus pectin (MCP), on HNF4α and HNF1α gene expression levels after acetaminophen (APAP) induced acute liver injury in Wistar rats. Materials and Methods: Sixty-four male Wistar rats were divided into four groups as follows; control, MCP, APAP and MCP plus APAP administered groups. The groups received APAP were divided into three subgroups each; in which rats were sacrificed after 24, 48 and 72 hours (h) from APAP administration. Expression levels of HNF4α and HNF1α, beside levels of Gal-3, tumor necrosis factor- α (TNF-α), Cytochrome P450 2E1 (CYP2E1), reduced glutathione (GSH), glutathione reductase (GR) and peroxidase (GPx) activities, liver function parameters were evaluated, along with histopathological study of the liver. Results: APAP high dose induced inhibition of liver HNF4α and HNF1α gene expression, CYP2E1 and GSH levels, GR and GPx activities, and increased hepatic Gal-3, TNF-α and serum liver function parameters levels, besides inducing hepatic necrosis. The toxic effects were stronger after 24 h then declined gradually after 48 h and 72 h. Inhibiting Gal-3 functionality after APAP high dose administration reduced TNF-α level and retrieved liver levels of HNF4α and HNF1α expression, CYP2E1, GSH, GR and GPx closer to normal control levels. Conclusion: Inhibiting Gal-3 functionality affects HNF4α and HNF1α gene expression levels and reduced inflammation after APAP high dose administration.