Repeated amino acid sequences in proteins are widely found, and the glycine-serine-alanine repeat is an element with a general propensity to form β-sheet aggregates as found in key pathological factors, in several neurodegenerative diseases. Such properties of this repeat may guide development of disease-modifying therapies for neurodegenerative disease. However, details of its role and underlying mechanism(s) remain largely unknown.

As the most known therapeutic component of bear bile acids, ursodeoxycholic acid (UDCA) is an FDA-approved drug for the treatment of primary biliary cirrhosis (PBC), the dissolution of cholesterol gallstones. UDCA produces many beneficial effects on metabolism and immune responses via its interaction with the membrane G protein-coupled bile acid receptor (GPBAR); however, how UDCA interacts with GPBAR and its selective cellular effects remain elusive. In this study, we delineated the interaction of UDCA with GPBAR and activation mechanism of GPBAR by scattered alanine scanning and molecular docking. Our results indicated that transmembrane helix 2 (TM2), TM3, TM5 and TM6 of GPBAR contribute to the interaction of UDCA in GPBAR binding pocket. Moreover, we predicted that the engagement of the 3-OH of UDCA with phenolic oxygen of Y2406.51 in GPBAR plays a key role in GPBAR activation. Unexpectedly, in addition to the well-known roles of intracellular loop2 (ICL2) residues, we identified that ICL3 residues play an important role in G protein coupling to GPBAR in response to UDCA binding. Our study provides a preliminary molecular mechanism of how GPBAR recognizes UDCA and subsequent activation and G protein interaction, which may facilitate the development of new bile acid derivatives as therapeutics.

Stretchability is an essential property for wearable devices to match varying strains when interfacing with soft tissues or organs. While piezoelectricity has broad application potentials as tactile sensors, artificial skins, or nanogenerators, enabling tissue-comparable stretchability is a main roadblock due to the intrinsic rigidity and hardness of the crystalline phase. Here, an amino acid-based piezoelectric biocrystal thin film that offers tissue-compatible omnidirectional stretchability with unimpaired piezoelectricity is reported. The stretchability was enabled by a truss-like microstructure that was self-assembled under controlled molecule-solvent interaction and interface tension. Through the open and close of truss meshes, this large scale biocrystal microstructure was able to endure up to 40% tensile strain along different directions while retained both structural integrity and piezoelectric performance. Built on this structure, a tissue-compatible stretchable piezoelectric nanogenerator was developed, which could conform to various tissue surfaces, and exhibited stable functions under multidimensional large strains. In this work, we presented a promising solution that integrates piezoelectricity, stretchability and biocompatibility in one material system, a critical step toward tissue-compatible biomedical devices.

In cancer patients, chemotherapeutic medication induces aberrant ROS (reactive oxygen species) accumulation in skeletal muscles, resulting in myofiber degradation, muscle weakness, and even cachexia, which further leads to poor therapeutic outcomes. Acting as an antioxidant, taurine is extensively used to accelerate postexercise muscle recovery in athletes. The antioxidant effects of taurine have been shown in mature myotubes and myofibers but not yet in myoblasts, the myotube precursor. The proliferation and differentiation ability of myoblasts play a very important role in myofiber repair and regeneration, which is usually impaired during chemotherapeutics in cancer patients as well. Here, we explored the effects of taurine supplementation on C2C12 myoblasts exposed to cisplatin-induced ROS. We found that cisplatin treatment led to dramatically decreased cell viability; accumulated ROS level; down-regulated expressions of MyoD1 (myoblast determination protein 1), myogenin, and MHC (myosin heavy chain); and impaired myotube differentiation in myoblasts. Significantly, taurine supplementation protected myoblasts against cisplatin-induced cell viability decrease, promoted cellular ROS clearance, and, most importantly, preserved the expressions of MyoD1, myogenin, and MHC as well as myotube differentiation ability. We further conducted NMR-based metabolomic analysis to clarify the underlying molecular mechanisms. We identified 14 characteristic metabolites primarily responsible for the discrimination of metabolic profiles between cisplatin-treated cells and normal counterparts, including increased levels of BCAAs (branched-chain amino acids: leucine and isoleucine), alanine, glycine, threonine, glucose, ADP (adenosine diphosphate), phenylalanine, and PC (O-phosphocholine), and decreased levels of lysine, β-alanine, choline, GPC (sn-glycero-3-phosphocholine), and myo-inositol. Evidently, taurine supplementation partially reversed the changing trends of several metabolites (isoleucine, threonine, glycine, PC, β-alanine, lysine, and myo-inositol). Furthermore, taurine supplementation promoted the proliferation and myotube differentiation of myoblasts by alleviating cellular catabolism, facilitating GSH (reduced glutathione) biosynthesis, improving glucose utilization and TCA (tricarboxylic acid) cycle anaplerosis, and stabilizing cellular membranes. Our results demonstrated the protective effects of taurine on cisplatin-impaired myoblasts and elucidated the mechanistic rationale for the use of taurine to ameliorate muscle toxicity in clinical chemotherapy cancer patients.

Bone metabolism can be influenced by sex steroid hormones. However, the relationship between sex steroid hormones and bone mineral density (BMD) remains inconsistent. Our study explored existing evidence of the association between sex hormones, blood glucose and BMD.

The core pluripotency transcription factor NANOG is critical for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Although NANOG is phosphorylated at multiple residues, the role of NANOG phosphorylation in ESC self-renewal is incompletely understood, and no information exists regarding its functions during reprogramming. Here we report our findings that NANOG phosphorylation is beneficial, although nonessential, for ESC self-renewal, and that loss of phosphorylation enhances NANOG activity in reprogramming. Mutation of serine 65 in NANOG to alanine (S65A) alone has the most significant impact on increasing NANOG reprogramming capacity. Mechanistically, we find that pluripotency regulators (ESRRB, OCT4, SALL4, DAX1, and TET1) are transcriptionally primed and preferentially associated with NANOG S65A at the protein level due to presumed structural alterations in the N-terminal domain of NANOG. These results demonstrate that a single phosphorylation site serves as a critical interface for controlling context-dependent NANOG functions in pluripotency and reprogramming.

We reported previously that acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1) to its C terminus (CT), independent of its ion-conducting function. Here we show that the N-terminus (NT) of ASIC1a interacts with its CT to form an auto-inhibition that prevents RIPK1 recruitment/activation under resting conditions. The interaction involves glutamate residues at distal NT and is disrupted by acidosis. Expression of mutant ASIC1a bearing truncation or glutamate-to-alanine substitutions at distal NT causes constitutive cell death. The NT-CT interaction is further disrupted by N-ethylmaleimide-sensitive fusion ATPase (NSF), which associates with ASIC1a-NT under acidosis, facilitating RIPK1 interaction with ASIC1a-CT. Importantly, a membrane-penetrating synthetic peptide representing the distal 20 ASIC1a NT residues, NT1-20, reduced neuronal damage in both in vitro model of acidotoxicity and in vivo mouse model of ischemic stroke, demonstrating the therapeutic potential of targeting the auto-inhibition of ASIC1a for neuroprotection against acidotoxicity.

The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development.

The dipeptide alanyl-glutamine (Ala-Gln) is a well-known parenteral nutritional supplement. The Ala-Gln supplementation is a potential treatment for muscle-related diseases and injuries. However, molecular mechanisms underlying the polyphenic effects of Ala-Gln supplementation remain elusive. Here, we performed NMR-based metabolomic profiling to analyze the effects of Ala-Gln, and the free alanine (Ala) and glutamine (Gln) supplementations on the mouse myoblast cell line C2C12 injured by glucose and glutamine deprivation. All the three supplementations can promote the differentiation ability of the injured C2C12 cells, while only Ala-Gln supplementation can facilitate the proliferation of the injured cells. Ala-Gln supplementation can partially restore the metabolic profile of C2C12 myoblasts disturbed by glucose and glutamine deprivation, and exhibits more significant effects than Ala and Gln supplementations. Our results suggest that Ala-Gln supplementation can promote MyoD1 protein synthesis, upregulate the muscle ATP-storage phosphocreatine (PCr), maintain TCA cycle anaplerosis, enhance the antioxidant capacity through promoting GSH biosynthesis, and stabilize lipid membranes by suppressing glycerophospholipids metabolism. This work provides new insight into mechanistic understanding of the polyphenic effects of Ala-Gln supplementation on muscle cells injured by energy deprivation.

Viral myocarditis (VMC), which is defined as inflammation of the myocardium with consequent myocardial injury, may develop chronic disease eventually leading to dilated cardiomyopathy (DCM). Molecular mechanisms underlying the progression from acute VMC (aVMC), to chronic VMC (cVMC) and finally to DCM, are still unclear. Here, we established mouse models of VMC and DCM with Coxsackievirus B3 infection and conducted NMR-based metabolomic analysis of aqueous metabolites extracted from cardiac tissues of three histologically classified groups including aVMC, cVMC and DCM. We showed that these three pathological groups were metabolically distinct from their normal counterparts and identified three impaired metabolic pathways shared by these pathological groups relative to normal controls, including nicotinate and nicotinamide metabolism; alanine, aspartate and glutamate metabolism; and D-glutamine and D-glutamate metabolism. We also identified two extra impaired metabolic pathways in the aVMC group, including glycine, serine and threonine metabolism; and taurine and hypotaurine metabolism Furthermore, we identified potential cardiac biomarkers for metabolically distinguishing these three pathological stages from normal controls. Our results indicate that the metabolomic analysis of cardiac tissues can provide valuable insights into the molecular mechanisms underlying the progression from acute VMC to DCM.

2,4',5'-Trihydroxyl-5,2'-dibromo diphenylmethanone (LM49), an active halophenol derivative synthesized by our group, which exhibits a broad spectrum of therapeutic properties, such as antioxidant and anti-inflammatory activities. In this study, we found LM49 could obviously attenuate acute liver injury induced by lipopolysaccharide (LPS) in mice by polarizing macrophages. The protective effect was described by reducing the hepatic inflammation and improving hepatic function using aspartate transaminase (AST) and alanine transaminase (ALT) assay. Further study revealed that LM49 pretreatment induced the Kupffer cells (KCs) to M2 polarization and decreased the production of inflammatory cytokines. The action mechanism in RAW 264.7 macrophages showed that LM49 could induce the activation of JAK1/STAT6 signaling pathway and the inhibition of TLR-4/NF-kB axis. Morever, LM49 also upregulated the expression of SOCS1 and FLK-4, which can promote M2 polarization by cooperating with STAT6 and inhibit M1 formation by reducing JAK1/STAT1. Our results suggested that LM49 could protect against LPS-induced acute liver injury in mice via anti-inflammatory signaling pathways and subsequent induction of M2 Kupffer cells. The results provided the first experimental evidence of active halophenols for the anti-inflammatory therapy by targeting M2 macrophages.

During the long-term evolution of animal toxins acting on potassium channels, the acidic residues can orientate the toxin binding interfaces by adjusting the molecular polarity. Based on the evolutionary function of toxin acidic residues, de novo peptide drugs with distinct binding interfaces were designed for the immunotherapeutic target, the Kv1.3 channel. Using a natural basic toxin, BmKTX, as a template, which contains 2 acidic residues (Asp19 and Asp33), we engineered two new peptides BmKTX-19 with 1 acidic residue (Asp33), and BmKTX-196 with 2 acidic residues (Asp6 and Asp33) through only adjusting acidic residue distribution for reorientation of BmKTX binding interface. Pharmacological experiments indicated that BmKTX-19 and BmKTX-196 peptides were specific inhibitors of the Kv1.3 channel and effectively suppressed cytokine secretion. In addition to the structural similarity between the designed and native peptides, both experimental alanine-scanning mutagenesis and computational simulation further indicated that the binding interface of wild-type BmKTX was successfully reoriented in BmKTX-19 and BmKTX-196, which adopted distinct toxin surfaces as binding interfaces. Together, these findings indicate not only the promising prospect of BmKTX-19 and BmKTX-196 as drug candidates but also the desirable feasibility of the evolution-guided peptide drug design for discovering numerous peptide drugs for the Kv1.3 channel.

Epidemiological studies have shown that chronic sleep disturbances resulted in metabolic disorders. The purpose of this study was to assess the relationship between chronic sleep deprivation (CSD) and the glucose homeostasis in rats. Twenty-four rats were randomly divided into CSD group and control (CON) group. The CSD rats were intervened by a modified multiple platform method (MMPM) to establish an animal model of chronic sleep disturbances. After 3-month intervention, all rats were subjected to an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT), and the body weight, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, lipid profile group, and homeostasis model assessment-IR (HOMA-IR) were measured. Both the CSD and CON groups had an attenuation of weight gain after 3-month intervention. The plasma glucose level of CSD group was higher than that of the CON group during the IPGTT (P < 0.01). The CSD rats showed a marked increase in HOMA-IR and ITT compared with the CON group (P < 0.01). There were no significant differences of AST, ALT, creatinine, and most lipid parameters between the CSD and CON groups (P > 0.05). The CSD has a marked effect on glucose homeostasis, comprising glucose intolerance and insulin resistance.

The gut microbial metabolite trimethylamine N-oxide (TMAO) has received increased attention due to its close relationship with cardiovascular disease and type 2 diabetes. In previous studies, TMAO has shown both harmful and beneficial effects on various tissues, but the underlying molecular mechanisms remain to be clarified. Here, we explored the effects of TMAO treatment on H2O2-impaired C2C12 myoblasts, analyzed metabolic changes and identified significantly altered metabolic pathways through nuclear magnetic resonance-based (NMR-based) metabolomic profiling. The results exhibit that TMAO treatment partly alleviated the H2O2-induced oxidative stress damage of cells and protected C2C12 myoblasts by improving cell viability, increasing cellular total superoxide dismutase capacity, improving the protein expression of catalase, and reducing the level of malondialdehyde. We further showed that H2O2 treatment decreased levels of branched-chain amino acids (isoleucine, leucine and valine) and several amino acids including alanine, glycine, threonine, phenylalanine and histidine, and increased the level of phosphocholine related to cell membrane structure, while the TMAO treatment partially reversed the changing trends of these metabolite levels by improving the integrity of the cell membranes. This study indicates that the TMAO treatment may be a promising strategy to alleviate oxidative stress damage in skeletal muscle.

The Lon protease selectively degrades abnormal proteins or certain normal proteins in response to environmental and cellular conditions in many prokaryotic and eukaryotic organisms. However, the mechanism(s) behind the substrate selection of normal proteins remains largely unknown. In this study, we identified 10 new substrates of F. tularensis Lon from a total of 21 candidate substrates identified in our previous work, the largest number of novel Lon substrates from a single study. Cross-species degradation of these and other known Lon substrates revealed that human Lon is unable to degrade many bacterial Lon substrates, suggestive of a "organism-adapted" substrate selection mechanism for the natural Lon variants. However, individually replacing the N, A, and P domains of human Lon with the counterparts of bacterial Lon did not enable the human protease to degrade the same bacterial Lon substrates. This result showed that the "organism-adapted" substrate selection depends on multiple domains of the Lon proteases. Further in vitro proteolysis and mass spectrometry analysis revealed a similar substrate cleavage pattern between the bacterial and human Lon variants, which was exemplified by predominant representation of leucine, alanine, and other hydrophobic amino acids at the P(-1) site within the substrates. These observations suggest that the Lon proteases select their substrates at least in part by fine structural matching with the proteins in the same organisms.

Copper (Cu) is an essential trace element that is required for the catalysis of several cellular enzymes. Excessive Cu could induce hepatotoxicity in humans and multiple animals. The purpose of this study was to investigate the effects of autophagy machinery on Cu-induced hepatotoxicity. Chicken hepatocytes were cultured in medium in the absence and presence of Cu sulfate (CuSO4) (0, 10, 50, and 100 μM) for 0, 6, 12, and 24 h, and in the combination of CuSO4 and N-acetyl-l-cysteine (NAC) (1 mM), rapamycin (10 nM), and 3-methyladenine (3-MA) (5 mM) for 24 h. Results showed that Cu could markedly increase the number of autophagosomes and LC3 puncta, induce autophagy-related genes (Beclin1, ATG5, LC3Ⅰ, LC3Ⅱ, mTOR, and Dynein) mRNA expression and proteins (BECN1, LC3Ⅱ/LC3Ⅰ) expression. NAC could relieve Cu-induced the changes of above genes and proteins. Additionally, rapamycin attenuated Cu-induced the increased lactic dehydrogenase (LDH), aspartate amino transferase (AST), and alanine aminotransferase (ALT) activities, and SOD-1 mRNA expression as well as the decreased cell viability, reactive oxygen species (ROS), hydrogen peroxide, total superoxide dismutase (T-SOD), malonaldehyde (MDA), catalase (CAT), HO-1 mRNA expression, adenosine triphosphate (ATP) levels, mitochondrial mass, and mitochondria membrane potential (MMP). But 3-MA had the opposite effects on above factors. Collectively, these findings provide strong evidence that Cu could induce autophagy by generating excessive ROS in hepatocytes, and autophagy might attenuate Cu-induced mitochondrial dysfunction by regulating oxidative stress.

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we undertook NMR-based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among 5 histologically classified groups: control, gastritis, low-grade gastric dysplasia, high-grade gastric dysplasia (HGD), and GC. Furthermore, we carried out metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with the 4 pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Krebs cycle, and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism. Both the Krebs cycle and glycine, serine, and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine, and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for higher energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the 4 pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of GCG and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.

β‑myosin heavy chain (MHC) 7 (MYH7) is the dominant pathogenic gene that harbors mutations in 20‑30% of cases of familial hypertrophic cardiomyopathy (HCM). The aim of this study was to elucidate the distribution and type of genetic variations among Chinese HCM families. From 2013 to 2017, the clinical data of 387 HCM probands and their families were collected. Targeted exome‑sequencing technology was used in all probands, and the selected mutations were subsequently verified by Sanger sequencing in the probands, family members and 300 healthy ethnic‑matched volunteers. Three‑dimensional models were created using Swiss‑PdbViewer 4.1, and further genetic analyses were performed to determine sequence conservation and frequency of the mutations. Among the 5 probands with double MYH7 mutations, 4 carried compound heterozygous mutations, and 1 carried monoallelic double mutations (A934V and E1387K). Four family members of the proband with monoallelic double mutations had the same mutation as the proband. Echocardiography and 12‑lead electrocardiography revealed abnormalities in the proband and 3 of the 4 carriers. The probands with compound heterozygous mutation had a higher left ventricular mass as revealed by echocardiography and higher QRS, SV1 and RV5+SV1 amplitudes than those with monoallelic double mutations (P<0.05). Simulation of the 3D structure of mutated proteins showed that the replacement of alanine by valine affected the flexibility of the MHC neck domain in case of the A934V mutation, whereas reactivity of the MHC rod domain was affected in the case of the E1387K mutation. In conclusion, we identified several novel HCM‑causing MYH7 mutations. More importantly, this is the first study to report a rare HCM family with monoallelic double mutations.

It has been reported that intestinal epithelial barrier dysfunction serves an important role in the development of liver cirrhosis. However, at present there is no satisfactory treatment for intestinal mucosal lesions and ulcers associated with cirrhosis. The aim of the present study was to investigate the effect of Bletilla striata polysaccharide (BSP) on intestinal epithelial barrier disruption in rats with thioacetamide (TAA)-induced liver cirrhosis. Rats were randomly divided into 5 groups (n=10): BSP low dosage (15 mg/kg), BSP middle dosage (30 mg/kg), BSP high dosage (60 mg/kg), experiment and control groups. All groups except control group were administered with TAA (200 mg/kg/day) to induce liver cirrhosis. Following modeling, rats in the low, middle and high-dose BSP groups received BSP. ELISA kits were used to measure the endotoxin, alanine transaminase (ALT) and aspartate transaminase (AST) levels in the portal vein, while interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression in the ileal tissue was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression of zonula occludens (ZO)-1 and occludin mRNA and protein, respectively. Intestinal epithelial tissue pathology was detected using hematoxylin-eosin (HE) staining. Immunohistochemistry was performed to assess the expression of ZO-1 and occludin in intestinal epithelial tissues. Following treatment with BSP, ALT, AST and endotoxin levels in the portal vein, as well as IL-6 and TNF-α expression in ileal tissues, were significantly decreased compared with model group (P<0.05 or 0.01). Furthermore, BSP treatment upregulated the expression of ZO-1 and occludin mRNA and protein compared with the model group (P<0.05 or 0.01) and cytoplasmic staining for these proteins was increased. The degree of intestinal epithelial tissue pathological damage was significantly reduced in the BSP groups. In conclusion, BSP is able to reduce endotoxin levels, inhibit the inflammatory cytokines IL-6 and TNF-α and elevate expression of ZO-1 and occludin at tight junctions. Together, these results suggest a novel protective agent for the restoration of intestinal epithelial barrier disruption.

The purpose of this study was to investigate the modulation of histone deacetylase 2 (HDAC2) on mitochondrial apoptosis in acute liver failure (ALF). The cellular model was established with LO2 cells stimulated by tumor necrosis factor alpha (TNF-α)/D-galactosamine (D-gal). Rats were administrated by lipopolysaccharide (LPS)/D-gal as animal model. The cell and animal models were then treated by HDAC2 inhibitor CAY10683. HDAC2 was regulated up or down by lentiviral vector transfection in LO2 cells. The mRNA levels of bcl2 and bax were detected by real-time PCR. The protein levels of HDAC2, bcl2, bax, cytochrome c (cyt c) in mitochondrion and cytosol, apoptosis protease activating factor 1 (apaf1), caspase 3, cleaved-caspase 3, caspase 9, cleaved-caspase 9, acetylated histone H3 (AH3), and histone H3 (H3) were assayed by western blot. Apoptosis was detected by flow cytometry. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels were also assayed. The openness degree of the mitochondrial permeability transition pore (MPTP) was detected by ultraviolet spectrophotometry. The apoptosis of hepatocytes in liver tissues was determined by tunnel staining. The liver tissue pathology was detected by hematoxylin eosin (HE) staining. The ultrastructure of liver tissue was observed by electron microscopy. Compared with cell and rat model groups, the bax mRNA level was decreased, and bcl2 mRNA was increased in the CAY10683 treatment group. The protein levels of HDAC2, bax, cyt c in cytosol, apaf1, cleaved-caspase 3, and cleaved-caspase 9 were decreased, and the apoptosis rate was decreased (P < 0.05), whereas the protein level of bcl2 and cyt c in the mitochondrion was elevated (P < 0.05) in the CAY10683 treatment group. In the HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was inhibited or activated, respectively. After being treated with TNF-α/D-gal in HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was further suppressed or activated, respectively. The MPTP value was elevated in CAY10683-treated groups compared with the rat model group (P < 0.05). Liver tissue pathological damage and apoptotic index in the CAY10683-treated group were significantly reduced. In addition, AH3 was elevated in both cell and animal model groups (P < 0.05). Downregulated or overexpressed HDAC2 could accordingly increase or decrease the AH3 level, and TNF-α/D-gal could enhance the acetylation effect. These results suggested that modulations of histone deacetylase 2 offer a protective effect through the mitochondrial apoptosis pathway in acute liver failure.