Research progress on the role of histone modification in sepsis / 中华危重病急救医学

Sepsis is a life-threatening organ dysfunction caused by dysregulated body response to infection. It is also one of the major causes of death in critically ill patients. Over the past few years, despite the continuous improvement in the treatment of sepsis, there is no specific treatment, clinical morbidity and mortality are still rising. Therefore, finding effective methods to treat sepsis and reduce mortality is an urgent clinical problem. Histone modification is an epigenetic modification that produces heritable phenotypic changes without altering the DNA sequence. In recent years, many studies have shown that histone modification is closely related to sepsis. This review discusses the mechanism of histone modification in the pathogenesis of sepsis from the aspects of inflammatory factors, signaling pathways, and macrophage polarization, in aimed to provide reference for the clinical treatment of sepsis.

A Deeper Insight into the Interfacial Behavior and Structural Properties of Mixed DPPC/POPC Monolayers: Implications for Respiratory Health.

1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphorcholine (POPC) are important components in pulmonary surfactants (PSs), of which the relative content is related to lung compliance. Herein, the phase behavior and thermodynamic structure of mixed DPPC/POPC monolayers were studied to elucidate the intermolecular interaction between DPPC and POPC molecules. Surface pressure-molecular area isotherms demonstrated that POPC significantly affected the phase behavior of the lipid domain structure as a function of its concentration. The compression modulus of the mixed monolayers reduced with the increase in POPC proportion, which can be attributed to the intermolecular repulsion between DPPC and POPC. Brewster angle microscopy analysis showed that the ordered structure of the monolayers trended toward fluidization in the presence of POPC. Raman spectroscopy results revealed that the change in C-C skeleton stretching vibration was the main cause of the decrease in the monolayer packing density. These findings provide new insights into the role of different phospholipid components in the function of PS film at a molecular level, which can help us to understand the synergy effects of the proportional relationship between DPPC and POPC on the formation and progression of lung disease and provide some references for the synthesis of lung surfactants.

The physiological and molecular mechanisms of N transfer in Eucalyptus and Dalbergia odorifera intercropping systems using root proteomics.

BACKGROUND: The mixing of Eucalyptus with N2-fixing trees species (NFTs) is a frequently successful and sustainable cropping practice. In this study, we evaluated nitrogen (N) transfer and conducted a proteomic analysis of the seedlings of Eucalyptus urophylla × E. grandis (Eucalyptus) and an NFT, Dalbergia (D.) odorifera, from intercropping and monocropping systems to elucidate the physiological effects and molecular mechanisms of N transfer in mixed Eucalyptus and D. odorifera systems. RESULTS: N transfer occurred from D. odorifera to Eucalyptus at a rate of 14.61% in the intercropping system, which increased N uptake and growth in Eucalyptus but inhibited growth in D. odorifera. There were 285 and 288 differentially expressed proteins by greater than 1.5-fold in Eucalyptus and D. odorifera roots with intercropping vs monoculture, respectively. Introduction of D. odorifera increased the stress resistance ability of Eucalyptus, while D. odorifera stress resistance was increased by increasing levels of jasmonic acid (JA). Additionally, the differentially expressed proteins of N metabolism, such as glutamine synthetase nodule isozyme (GS), were upregulated to enhance N competition in Eucalyptus. Importantly, more proteins were involved in synthetic pathways than in metabolic pathways in Eucalyptus because of the benefit of N transfer, and the two groups of N compound transporters were found in Eucalyptus; however, more functional proteins were involved in metabolic degradation in D. odorifera; specifically, the molecular mechanism of the transfer of N from D. odorifera to Eucalyptus was explained by proteomics. CONCLUSIONS: Our study suggests that N transfer occurred from D. odorifera to Eucalyptus and was affected by the variations in the differentially expressed proteins. We anticipate that these results can be verified in field experiments for the sustainable development of Eucalyptus plantations.

Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses.

Macrophages can polarize into different phenotypes in response to different microenvironmental stimuli. Macrophage polarization has been assigned to two extreme states, namely proinflammatory M1 and anti-inflammatory M2. Accumulating evidences have demonstrated that M1 polarized macrophages contribute to various toxicants-induced deleterious effects. Switching macrophages from proinflammatory M1 phenotype toward anti-inflammatory M2 phenotype could be a promising approach for treating various inflammatory diseases. Studies in the past few decades have revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) can modulate the polarization of macrophages. Specifically, activation of Nrf2 could block M1 stimuli-induced production of proinflammatory cytokines and chemokines, and shift the polarization of macrophages toward M2 by cross-talking with nuclear factor kappa-B (NF-κB), mitogen-activated protein kinases (MAPKs), peroxisome proliferator-activated receptor γ (PPARγ), and autophagy. Importantly, a great number of studies have confirmed the beneficial effects of natural and synthesized Nrf2 agonists on various inflammatory diseases; however, most of these compounds are far away from clinical application due to lack of characterization and defects of study designs. Interestingly, some endogenous Nrf2 inducers and compounds with dual activities (such as the Nrf2 inducing and CO releasing effects) exhibit potent anti-inflammatory effects, which points out an important direction for future researches.

Transformed ALDH2-/- hepatocytes by ethanol could serve as a useful tool for studying alcoholic hepatocarcinogenesis.

Alcohol is a well-recognized hepatic carcinogen. Alcohol is metabolized into genotoxic acetaldehyde in hepatocytes, which is catalyzed by aldehyde dehydrogenase 2 (ALDH2). The detailed underlying mechanisms of alcohol-related hepatocellular carcinoma (HCC) remains unclear, at least partially, due to the absence of appropriate experimental models. Current studies suggest that rodents are not good models of the most common liver diseases that trigger HCC including alcoholic liver injury. We hypothesize that ethanol could induce transformation of immortalized normal liver cells, which may serve as a versatile tool for studying alcoholic HCC. Besides, we believe that knockout of ALDH2 will help to shorten the time course of transformation, as ALDH2 deficiency will significantly increase the accumulation of acetaldehyde in hepatocytes. Using this model, the dynamic changes of carcinogenesis-related molecular events could be easily examined. Furthermore, the transformed cells isolated from soft agar could be inoculated to mice for studying invasion, metastasis, and also for screening prophylactics.

Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer's disease.

BACKGROUND: Neuroinflammation is a principal element in Alzheimer's disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells. METHODS: APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aß), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B. RESULTS: In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aß and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity. CONCLUSIONS: FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease.

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.

Down-regulation of p16 and MGMT promotes the anti-proliferative and pro-apoptotic effects of 5-Aza-dC and radiation on cervical cancer cells.

Cervical cancer is one of the most common malignancies of the female reproductive system. Therefore, it is critical to investigate the molecular mechanisms involved in the development and progression of cervical cancer. In this study, we stimulated cervical cancer cells with 5-aza-2'-deoxycytidine (5-Aza-dC) and found that this treatment inhibited cell proliferation and induced apoptosis; additionally, methylation of p16 and O-6-methylguanine-DNA methyltransferase (MGMT) was reversed, although their expression was suppressed. 5-Aza-dC inhibited E6 and E7 expression and up-regulated p53, p21, and Rb expression. Cells transfected with siRNAs targeting p16 and MGMT as well as cells stimulated with 5-Aza-dC were arrested in S phase, and the expression of p53, p21, and Rb was up-regulated more significantly. However, when cells were stimulated with 5-Aza-dC after transfection with siRNAs targeting p16 and MGMT, proliferation decreased significantly, and the percentage of cells in the sub-G1 peak and in S phase was significantly increased, suggesting a marked increase in apoptosis. But E6 and E7 overexpression could rescue the observed effects in proliferation. Furthermore, X-ray radiation caused cells to arrest in G2/M phase, but cells transfected with p16- and MGMT-targeted siRNAs followed by X-ray radiation exhibited a significant decrease in proliferation and were shifted toward the sub-G1 peak, also indicating enhanced apoptosis. In addition, the effects of 5-Aza-dC and X-ray radiation were most pronounced when MGMT expression was down-regulated. Therefore, down-regulation of p16 and MGMT expression enhances the anti-proliferative effects of 5-Aza-dC and X-ray radiation. This discovery may provide novel ideas for the treatment of cervical cancer.