The acetylation of MDH1 and IDH1 is associated with energy metabolism in acute liver failure.

The liver is the main organ associated with metabolism. In our previous studies, we identified that the metabolic enzymes malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) were differentially expressed in ALF. The aim of this study was to explore the changes in the acetylation of MDH1 and IDH1 and the therapeutic effect of histone deacetylase (HDAC) inhibitor in acute liver failure (ALF). Decreased levels of many metabolites were observed in ALF patients. MDH1 and IDH1 were decreased in the livers of ALF patients. The HDAC inhibitor ACY1215 improved the expression of MDH1 and IDH1 after treatment with MDH1-siRNA and IDH1-siRNA. Transfection with mutant plasmids and adeno-associated viruses, identified MDH1 K118 acetylation and IDH1 K93 acetylation as two important sites that regulate metabolism in vitro and in vivo.

Effect of lipopolysaccharide on TAK1-mediated hepatocyte PANoptosis through Toll-like receptor 4 during acute liver failure.

BACKGROUND: Intestinal endotoxemia (IETM) is an important pathogenic mechanism of acute liver failure (ALF), and TAK1-mediated PANoptosis is a novel cell death mode. This study investigated whether IETM can induce hepatocyte PANoptosis during ALF. METHOD: PANoptosis cell and mouse models were generated, and lentiviruses (LVs), adeno-associated viral vectors (AVVs), and small interfering RNAs (siRNAs) were subsequently used to overexpress or knock down TLR and TAK1. Then, the levels of hepatocyte injury, TLR4, TAK1 and PANoptosis were detected via an enzyme-labeling instrument, tissue staining, RT-PCR, western blotting, immunofluorescence, and flow cytometry. RESULTS: The BioGRID database search revealed that TAK1 might interact with TLR4. According to the in vivo experiments, compared with those in ALF mice, liver tissue damage, hepatocyte mortality and PANoptosis in mice in the AAV-TAK1 group were significantly lower, and liver function was significantly improved. According to the in vitro experiments, after promoting the expression of TLR4 in the model group, the degree of cell damage, TLR4 expression and PANoptosis further increased, while the level of TAK1 further decreased. The opposite result was obtained when TLR4 expression was inhibited. The increase in TAK1 expression in the model group reduced the degree of cell damage and PANoptosis, but the level of TLR4 was not significantly changed. In the model group of cells that exhibited TAK1 expression, further promotion of TLR4 expression inhibited the protective effect of TAK1 on cells. In the model group of cells after TAK1 expression was promoted, if the expression of TLR4 was further promoted, the protective effect of TAK1 on cells was inhibited. CONCLUSION: IETM inhibited the expression of TAK1 by binding to TLR4 molecules and promoting hepatocyte PANoptosis during ALF. Promoting TAK1 expression effectively relieved lipopolysaccharide-induced hepatocyte PANoptosis.

Impaired Sensitivity to Thyroid Hormones is Associated with the Risk of Diabetic Nephropathy in Euthyroid Patients with Type 1 Diabetes Mellitus.

Purpose: This study aims to investigate the relationship between thyroid and type 1 diabetic nephropathy (T1DN) in euthyroid populations, focusing on thyroid hormone sensitivity. Methods: A cross-sectional study was conducted between January 2016 and December 2021, including 357 euthyroid patients with type 1 diabetes mellitus (T1DM). Parameters representing thyroid hormone sensitivity were assessed, including the thyroid feedback quantile-based index (TFQI), parameter thyroid feedback quantile index (PTFQI), thyroid stimulating hormone index (TSHI), thyrotropin thyroxine resistance index (TT4RI), and free triiodothyronine/free thyroxine (FT3/FT4). Logistic regression and restricted cubic spline regression were performed to detect the association between thyroid hormone sensitivity and the risk of T1DN. Results: The study found a negative correlation between the risk of T1DN and FT3/FT4 in euthyroid T1DM patients (OR 0.71, 95% CI 0.51-0.97, P <0.01). PTFQI (P<0.05), TSHI (P<0.05), and TT4RI (P<0.01) showed an M-shaped nonlinear relationship with the risk of T1DN. Elevated risk of T1DN was associated with PTFQI, TSHI, and TT4RI values outside the range of zero, 2.3-3.88, and 27.56-32.19, respectively. Conclusion: This study confirms the relationship between impaired thyroid hormone sensitivity and the risk of T1DN in euthyroid patients. It emphasizes the importance of evaluating thyroid hormone sensitivity in T1DM patients, even when their thyroid function appears normal, to promptly prevent the occurrence of T1DN.

IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis.

BACKGROUND: Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which NETosis regulates the development of ALF is unclear. In this article, we explore the role and mechanism of NETosis in the pathogenesis of ALF. METHODS: Clinically, we evaluated NETs-related markers in the liver and peripheral neutrophils of patients with ALF. In in vitro experiments, HL-60 cells were first induced to differentiate into neutrophil-like cells (dHL-60 cells) with dimethyl sulfoxide (DMSO). NETs were formed by inducing dHL-60 cells with PMA. In in vivo experiments, the ALF model in mice was established with LPS/D-gal, and the release of NETs was detected by immunofluorescence staining and western blotting. Finally, the acetylation levels of IDH1 and MDH1 were detected in dHL-60 cells and liver samples by immunoprecipitation. RESULTS: Clinically, increased release of NETs in liver tissue was observed in patients with ALF, and NETs formation was detected in neutrophils from patients with liver failure. In dHL-60 cells, mutations at IDH1-K93 and MDH1-K118 deacetylate IDH1 and MDH1, which promotes the formation of NETs. In a mouse model of ALF, deacetylation of IDH1 and MDH1 resulted in NETosis and promoted the progression of acute liver failure. CONCLUSIONS: Deacetylation of IDH1 and MDH1 reduces their activity and promotes the formation of NETs. This change aggravates the progression of acute liver failure.

AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway.

BACKGROUND: Acute liver failure (ALF) is an unpredictable and life-threatening critical illness. The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure. METHODS: Animals were divided into 3 groups, normal, thioacetamide (TAA, ALF model) and TAA + AGK2. Cultured L02 cells were divided into 5 groups, normal, TAA, TAA + mitofusin 2 (MFN2)-siRNA, TAA + AGK2, and TAA + AGK2 + MFN2-siRNA groups. The liver histology was evaluated with hematoxylin and eosin staining, inositol-requiring enzyme 1 (IRE1), activating transcription factor 6ß (ATF6ß), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylated-PERK (p-PERK). C/EBP homologous protein (CHOP), reactive oxygen species (ROS), MFN2 and glutathione peroxidase 4 (GPX4) were measured with Western blotting, and cell viability and liver chemistry were also measured. Mitochondria-associated endoplasmic reticulum membranes (MAMs) were measured by immunofluorescence. RESULTS: The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis, which were reduced by AGK2 pre-treatment. In comparison to the normal group, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ in the TAA-induced ALF model group were significantly increased, which were decreased by AGK2 pre-treatment. The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group, which were enhanced by AGK2 pre-treatment. Compared with the TAA-induced L02 cell, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group. AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell. Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells. CONCLUSIONS: The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.

Distinct Types of Cell Death and Implications in Liver Diseases: An Overview of Mechanisms and Application.

Cell death is associated with a variety of liver diseases, and hepatocyte death is a core factor in the occurrence and progression of liver diseases. In recent years, new cell death modes have been identified, and certain biomarkers have been detected in the circulation during various cell death modes that mediate liver injury. In this review, cell death modes associated with liver diseases are summarized, including some cell death modes that have emerged in recent years. We described the mechanisms associated with liver diseases and summarized recent applications of targeting cell death in liver diseases. It provides new ideas for the diagnosis and treatment of liver diseases. In addition, multiple cell death modes can contribute to the same liver disease. Different cell death modes are not isolated, and they interact with each other in liver diseases. Future studies may focus on exploring the regulation between various cell death response pathways in liver diseases.

Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity.

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe2+, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe2+, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION: SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.

Inhibition of GSK3ß activity alleviates acute liver failure via suppressing multiple programmed cell death.

BACKGROUND: Acute liver failure (ALF) is one of the most common life-threatening diseases in adults without previous liver disease. Glycogen synthase kinase 3ß (GSK3ß) is a serine/threonine protein kinase that is widely distributed in the cells. Inhibition of its activity can inhibit cell death and promote autophagy through various pathways, thus providing a protective effect. In this study, we aimed to investigate the effect on ALF after inhibition of GSK3ß and its potential mechanisms. METHODS: D- galactosamine(D-Gal) in combination with lipopolysaccharide(LPS) was used to induce ALF in vitro and in vivo. And then GSK3ß inhibitor TDZD-8 was used to explore the protective effect against ALF. After TDZD-8 treatment TUNEL staining and flow techniques were used to detect the proportion of apoptosis in liver tissues and cells respectively, while western blotting and immunofluorescence assays were performed to detect the expression levels of apoptosis, pyroptosis and necroptosis-related proteins in tissues and cells. In addition, western blotting was performed to explore the specific mechanism of hepatoprotective effect after GSK3ß inhibition to detect the expression levels of TAK1, TRAF6 and HDAC3 after TRAF6 and HDAC3 inhibition alone. The co-localization of TRAF6 and HDAC3 in vitro was detected by immunofluorescence, while the interaction between TRAF6 and HDAC3 was detected by immunoprecipitation assay. RESULTS: Both in vivo and in vitro experiments, GSK3ß inhibitor TDZD-8 can significantly alleviate the progression of ALF. Inhibition of GSK3ß activity could significantly reduce the level of hepatocyte apoptosis, pyroptosis, necroptosis and improve liver dysfunction and tissue damage. Furthermore, we found that hepatocyte TAK1 and TRAF6 levels decreased and HDAC3 levels increased in ALF, whereas inhibition of GSK3ß upregulated TAK1 and TRAF6 levels and decreased HDAC3 expression. CONCLUSION: GSK3ß inhibitor TDZD-8 can prevent the progression of ALF, and its action may involve the TRAF6/HDAC3/TAK1 pathway.

Anesthesia management for pericardiectomy- a case series study.

BACKGROUND: Constrictive pericarditis (CP) is an uncommon disease that limits both cardiac relaxation and contraction. Patients often present with right-sided heart failure as the pericardium thickens and impedes cardiac filling. Pericardiectomy is the treatment of choice for improving hemodynamics in CP patients; however, the procedure carries a high morbidity and mortality, and the anesthetic management can be challenging. Acute heart failure, bleeding and arrhythmias are all concerns postoperatively. METHODS: After IRB approval, we performed the retrospective analysis of 66 consecutive patients with CP who underwent pericardiectomy from July 2018 to May 2022. RESULTS: Most patients had significant preoperative comorbidities, including congestive hepatopathy (75.76%), New York Heart Association Type III/IV heart failure (59.09%) and atrial fibrillation (51.52%). Despite this, 75.76% of patients were extubated within the first 24 h and all but 2 of the patients survived to discharge (96.97%). CONCLUSIONS: Anesthetic management, including a thorough understanding of the pathophysiology of CP, the use of advanced monitoring and transesophageal echocardiography (TEE) guidance, all played an important role in patient outcomes.

PANoptosis: A Cell Death Characterized by Pyroptosis, Apoptosis, and Necroptosis.

PANoptosis is a new cell death proposed by Malireddi et al in 2019, which is characterized by pyroptosis, apoptosis and necroptosis, but cannot be explained by any of them alone. The interaction between pyroptosis, apoptosis and necroptosis is involved in PANoptosis. In this review, from the perspective of PANoptosis, we focus on the relationship between pyroptosis, apoptosis and necroptosis, the key molecules in the process of PANoptosis and the formation of PANoptosome, as well as the role of PANoptosis in diseases. We aim to understand the mechanism of PANoptosis and provide a basis for targeted intervention of PANoptosis-related molecules to treat human diseases.

Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective.

Over the past two decades, non-alcoholic fatty liver disease (NAFLD) has become a leading burden of hepatocellular carcinoma and liver transplantation. Although the exact pathogenesis of NAFLD has not been fully elucidated, recent hypotheses placed more emphasis on the crucial role of the gut microbiome and its derivatives. Reportedly, microbial metabolites such as short-chain fatty acids, amino acid metabolites (indole and its derivatives), bile acids (BAs), trimethylamine N-oxide (TMAO), and endogenous ethanol exhibit sophisticated bioactive properties. These molecules regulate host lipid, glucose, and BAs metabolic homeostasis via modulating nutrient absorption, energy expenditure, inflammation, and the neuroendocrine axis. Consequently, a broad range of research has studied the therapeutic effects of microbiota-derived metabolites. In this review, we explore the interaction of microbial products and NAFLD. We also discuss the regulatory role of existing NAFLD therapies on metabolite levels and investigate the potential of targeting those metabolites to relieve NAFLD.

NOD2-mediated HDAC6/NF-κb signalling pathway regulates ferroptosis induced by extracellular histone H3 in acute liver failure.

Acute liver failure (ALF) is life-threatening and often associated with high mortality rates. The aim of the present study was to investigate whether extracellular histone H3 could induce ferroptosis in hepatic macrophages in ALF and explore its potential mechanism. RAW264.7 macrophages and C57BL/6 mice were used in this study. LPS, D-galactosamine (D-Gal), histone H3, histone H3 antibody, NOD2 agonist Muramyl Dipeptide (MDP) and HDAC6-siRNA were administered in this study. The key molecules of ferroptosis, NOD2, HDAC6 and the NF-κb pathway, were detected. In vitro, histone H3 was released into the extracellular environment from cell nucleus after LPS exposure. In addition, histone H3 could induce ferroptosis in RAW264.7 macrophages with increased level of Fe2+ and ROS and decreased levels of GPX4 and GSH. MDP further aggravated ferroptosis in RAW264.7 macrophages stimulated by histone H3, which was accompanied by elevated NOD2, HDAC6, p-P65 and IκBα. HDAC6-siRNA ameliorated ferroptosis in RAW264.7 macrophages induced by histone H3, which was accompanied by decreased levels of HDAC6, p-P65 and IκBα. However, HDAC6-siRNA did not alter NOD2 levels in RAW264.7 macrophages administered histone H3. In vivo, the levels of NOD2, HDAC6 the NF-κb pathway and ferroptosis were increased in ALF mice, which were downregulated by histone H3 antibody and upregulated by histone H3. Extracellular histone H3 could induce ferroptosis in hepatic macrophages in ALF by regulating theNOD2-mediated HDAC6/NF-κb signalling pathway.

Bladder perforation injury after percutaneous peritoneal dialysis catheterization: A case report.

BACKGROUND: Insertion of a catheter into the bladder is a rare complication of peritoneal dialysis (PD), and is mainly related to surgical injury. This paper reports a case of bladder perforation that was caused by percutaneous PD catheterization. CASE SUMMARY: A 64-year-old man underwent percutaneous PD catheterization for end-stage renal disease. On the second day after the operation, urgent urination and gross hematuria occurred. Urinalysis showed the presence of red and white blood cells. Empirical anti-infective treatment was given. On the third day after the operation, urgent urination occurred during PD perfusion. Ultrasound showed that the PD catheter was located in the bladder, and subsequent computed tomography (CT) showed that the PD catheter moved through the anterior wall into the bladder. The PD catheter was withdrawn from the bladder and catheterization was retained. Repeat CT on the fourth day after the operation showed that the PD catheter was removed from the bladder, but there was poor catheter function. The PD catheter was removed and the patient was changed to hemodialysis. CT cystography showed that the bladder healed well and the patient was discharged 14 d after the operation. CONCLUSION: Bladder perforation injury should be considered and treated timeously in case of bladder irritation during and after percutaneous PD catheterization. The use of Doppler ultrasound and other related technologies may reduce the incidence of such complications.

Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy: A Systematic Review and Meta-analysis of RCTs.

BACKGROUND: Previous research demonstrated that short-term treatment of dilated cardiomyopathy with thyroid hormones exerted beneficial hemodynamic effects when added to standard anti-heart failure therapy, but it remains debatable whether thyroid hormones can be used to treat dilated cardiomyopathy. Therefore, we conducted a meta-analysis to evaluate the effectiveness and safety of thyroid hormone treatment in patients with dilated cardiomyopathy. METHODS: The Cochrane Clinical Trials Registry database, PubMed, Embase, Chinese Biomedical Literature Database, China Academic Journals full-text database, Wanfang Database, China Science and Technology Journal Database, and Clinical Trials.gov were screened through 15 October, 2021. Randomized controlled clinical trials were selected based on study inclusion criteria. Two independent reviewers extracted the data and assessed study bias using the Cochrane risk of bias tool. For the data synthesis, the weighted mean difference was calculated using baseline and post-thyroid hormone treatment data. Random-effects models were used for the meta-analysis. The primary outcomes were left ventricular ejection fraction after a minimum follow-up of 1 week and adverse events. RESULTS: Ten of the 1149 published reports met the inclusion criteria (N = 608 randomized individuals). After reasonable use of thyroid hormone therapy, left ventricular ejection fraction increased (weighted mean difference, 3.94; 95% confidence interval 3.06-4.81; I2 = 0.00%), cardiac output increased, and left ventricular end-diastolic diameter decreased, but left ventricular mass index and thyroid function were unaffected. Adverse events were reported in the intervention group of two studies. The ten studies demonstrated a low risk of bias. CONCLUSIONS: Adding thyroid hormones to conventional anti-heart failure treatment in patients with DCM appears to be an effective and well tolerated therapeutic option. CLINICAL TRIAL REGISTRATION: The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021286043).

SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice.

The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1ß) were measured by ELISA and Western blotting. The cell type expression of IL-1ß in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.

The Effectiveness of Thyroid Hormone Replacement Therapy on Heart Failure and Low-Triiodothyronine Syndrome: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to conduct a systematic review and meta-analysis evaluating the role of thyroid hormone therapy in patients with heart failure and low-triiodothyronine syndrome. METHODS: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine disc were systematically searched to identify eligible studies published before November 27, 2021. The mean difference was pooled for randomized controlled trials using a random-effects model. RESULTS: The meta-analysis showed that thyroid hormone treatment improved the left ventricular ejection fraction (weighted mean difference [WMD] 5.61, 95% confidence interval [CI]: 4.38 to 6.85, I2 = 63.12%, P < 0.01). The cardiac output improved with thyroid hormone therapy (WMD 0.65, 95% CI: 0.42 to 0.89, I2 = 84.28%, P < 0.01). The early-to-late diastolic transmitral flow velocity in the thyroid hormone group was also improved compared to the control group (WMD 0.29, 95% CI: 0.15 to 0.42, I2 = 95.08%, P < 0.01). The left ventricular diastolic dysfunction was decreased with thyroid hormone treatment (WMD -5.17, 95% CI: -7.47 to -2.88, I2 = 90.18%, P < 0.01). The brain natriuretic peptide decreased with thyroid hormone treatment (standardized mean difference -1.49, 95% CI: -2.15 to -0.84, I2 = 90.18%, P < 0.01). Noradrenaline decreased with thyroid hormone therapy (WMD -349.86, 95% CI: -401.05 to -298.67, I2 = 0%, P < 0.01). Free triiodothyronine increased with thyroid hormone treatment (standardized mean difference 2.18, 95% CI: 0.75 to 2.60, I2 = 98.20%, P < 0.01). CONCLUSION: This meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome.

Fusobacterium nucleatum promotes the development of acute liver failure by inhibiting the NAD+ salvage metabolic pathway.

BACKGROUND: Acute liver failure (ALF) patients are often accompanied by severe energy metabolism abnormalities and intestinal microecological imbalance. The intestinal mucosal barrier is severely damaged. Intestinal endotoxin can induce intestinal endotoxemia through the "Gut-Liver axis". More and more evidence shows that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are related to inflammatory bowel disease, but whether F. nucleatum is involved in the development of ALF and whether it affects the liver energy metabolism is unclear. METHODS: This study first detected the abundance of F. nucleatum and its effect on ALF disease, and explored whether F. nucleatum aggravated liver inflammation in vitro and in vivo. RESULTS: Our data showed that liver tissues of ALF patients contained different abundances of F. nucleatum, which were related to the degree of liver inflammation. In addition, we found that F. nucleatum infection affected the energy metabolism of the liver during the development of ALF, inhibited the synthesis pathway of nicotinamide adenine dinucleotide (NAD+)'s salvage metabolism, and promoted inflammatory damage in the liver. In terms of mechanism, F. nucleatum inhibited NAD+ and the NAD+-dependent SIRT1/AMPK signaling pathway, and promoted liver damage of ALF. CONCLUSIONS: Fusobacterium nucleatum coordinates a molecular network including NAD+ and SIRT1 to control the progress of ALF. Detection and targeting of F. nucleatum and its related pathways may provide valuable insights for the treatment of ALF.

Sirtuin1 attenuates acute liver failure by reducing reactive oxygen species via hypoxia inducible factor 1α.

BACKGROUND: The occurrence and development of acute liver failure (ALF) is closely related to a series of inflammatory reactions, such as the production of reactive oxygen species (ROS). Hypoxia inducible factor 1α (HIF-1α) is a key factor that regulates oxygen homeostasis and redox, and the stability of HIF-1α is related to the ROS level regulated by Sirtuin (Sirt) family. The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease. However, little is known about the relationship between HIF-1α and Sirt1 in the process of ALF and the molecular mechanism. AIM: To investigate whether HIF-1α may be a target of Sirt1 deacetylation and what the effects on ALF are. METHODS: Mice were administrated lipopolysaccharide (LPS)/D-gal and exposed to hypoxic conditions as animal model, and resveratrol was used as an activator of Sirt1. The cellular model was established with L02 cells stimulated by LPS. N-acetyl-L-cysteine was used to remove ROS, and the expression of Sirt1 was inhibited by nicotinamide. Western blotting was used to detect Sirt1 and HIF-1α activity and related protein expression. The possible signaling pathways involved were analyzed by immunofluorescent staining, co-immunoprecipitation, dihydroethidium staining, and Western blotting. RESULTS: Compared with mice stimulated with LPS alone, the expression of Sirt1 decreased, the level of HIF-1α acetylation increased in hypoxic mice, and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly, which was regulated by HIF-1α, indicating an increase of HIF-1α activity. Under hypoxia, the down-regulation of Sirt1 activated and acetylated HIF-1α in L02 cells. The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS. The regulation of ROS was partly through peroxisome proliferator-activated receptor alpha or AMP-activated protein kinase. Resveratrol, a Sirt1 activator, effectively relieved ALF aggravated by hypoxia, the production of ROS, and cell apoptosis. It also induced the deacetylation of HIF-1α and inhibited the activity of HIF-1α. CONCLUSION: Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.

Low Serum Albumin Is Associated with Poor Prognosis in Patients Receiving Peritoneal Dialysis Treatment.

Background: The number of patients receiving dialysis treatment is sustainably increasing, especially peritoneal dialysis. Objectives: It is necessary to find out potential factors that may indicate the prognosis of patients receiving peritoneal dialysis treatment. Methods: This study retrospectively involved 325 patients who received peritoneal dialysis treatment. Results: Low serum albumin (HR = 2.254; 95% CI: 1.534-3.311; P < 0.001) and high FBG (Fasting blood glucose) (HR = 1.474; 95% CI: 1.025-2.120; P=0.037) were risk factors for death in patients receiving peritoneal dialysis treatment. Serum albumin (AUC = 0.683; P < 0.001) and creatinine (AUC = 0.625; P < 0.001) exhibited value of prognosis prediction. Both high FBG (P=0.005) and low albumin (P < 0.001) were associated with poor prognosis, and low albumin predicted poorer survival. Conclusions: Low serum albumin and high fasting blood glucose were risk factors and associated with poor prognosis. Low albumin has a potential in predicting the prognosis of patients receiving peritoneal dialysis treatment.

Effect of lipid-lowering medications in patients with coronary artery bypass grafting surgery outcomes.

BACKGROUND: Increased life expectancy and improved medical technology allow increasing numbers of elderly patients to undergo cardiac surgery. Elderly patients may be at greater risk of postoperative morbidity and mortality. Complications can lead to worsened quality of life, shortened life expectancy and higher healthcare costs. Reducing perioperative complications, especially severe adverse events, is key to improving outcomes in patients undergoing cardiac surgery. The objective of this study is to determine whether perioperative lipid-lowering medication use is associated with a reduced risk of complications and mortality after coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). METHODS: After IRB approval, we reviewed charts of 9,518 patients who underwent cardiac surgery with CPB at three medical centers between July 2001 and June 2015. The relationship between perioperative lipid-lowering treatment and postoperative outcome was investigated. 3,988 patients who underwent CABG met inclusion criteria and were analyzed. Patients were divided into lipid-lowering or non-lipid-lowering treatment groups. RESULTS: A total of 3,988 patients were included in the final analysis. Compared to the patients without lipid-lowering medications, the patients with lipid-lowering medications had lower postoperative neurologic complications and overall mortality (P < 0.05). Propensity weighted risk-adjustment showed that lipid-lowering medication reduced in-hospital total complications (odds ratio (OR) = 0.856; 95% CI 0.781-0.938; P < 0.001); all neurologic complications (OR = 0.572; 95% CI 0.441-0.739; P < 0.001) including stroke (OR = 0.481; 95% CI 0.349-0.654; P < 0.001); in-hospital mortality (OR = 0.616; 95% CI 0.432-0.869; P = 0.006; P < 0.001); and overall mortality (OR = 0.723; 95% CI 0.634-0.824; P < 0.001). In addition, the results indicated postoperative lipid-lowering medication use was associated with improved long-term survival in this patient population. CONCLUSIONS: Perioperative lipid-lowering medication use was associated with significantly reduced postoperative adverse events and improved overall outcome in elderly patients undergoing CABG surgery with CPB.