Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression.

OBJECTS: The incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis. DESIGN: Two HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models. RESULTS: A global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis. CONCLUSIONS: The liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

The route to a 200 MHz, all-PM femtosecond Yb-doped fiber laser with a high output coupling ratio.

Based on the time-independent rate equations and nonlinear Schrödinger equation, we simulate a 200 MHz all-polarization-maintaining (PM) mode-locked Yb-doped fiber laser. The cavity round trip evolution toward stable mode locking is present. Additionally, the gain coefficients along the gain fiber as well as the pulses, chirp, and spectra at different locations in the cavity are examined. The effects of chirped fiber Bragg grating parameters on the pulse shape and spectrum profile are also investigated. According to the calculations, we experimentally realize a 200 MHz femtosecond fiber laser with 115 mW output power. The timing jitter and integrated relative intensity noise are measured as 158 fs (1 kHz to 10 MHz) and 0.0513% (1 Hz to 300 kHz), respectively. Eventually, an amplified average power of 610 mW and 79 fs compressed pulses with a peak power of approximately 28 kW are obtained. The exhibited all-PM femtosecond fiber laser system can be adopted as the foundation for an optical frequency comb.

Leukocyte cell-derived chemotaxin 2 promotes the development of nonalcoholic fatty liver disease through STAT-1 pathway in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), whose pathogenesis remains unelucidated, has become an increasingly prevalent disease globally requiring novel treatment strategies. This study aims to explore the role of leukocyte cell-derived chemotaxin 2 (LECT2), one of the known hepatokines, in the development of NAFLD. METHODS: The serum LECT2 level was evaluated in patients with NAFLD and male C57BL/6 mice fed a high-fat diet (HFD) for 8 weeks. Tail intravenous injection of adeno-associated virus that contained Lect2 short hairpin RNA or Lect2 overexpression plasmid was administered to mice to inhibit or increase hepatic Lect2 expression. Hepatic steatosis was evaluated by histological staining with haematoxylin and eosin and Oil Red O, and also by quantitative hepatic triglyceride measurements. RNA-seq was performed to discover the specific targets of LECT2 on NAFLD. RESULTS: Serum and hepatic LECT2 levels were elevated in NAFLD patients and HFD-fed mice. Inhibition of hepatic Lect2 expression alleviated HFD-induced hepatic steatosis and inflammation, whereas hepatic overexpression of Lect2 aggravated HFD-induced hepatic steatosis and inflammation. RNA-seq and bioinformatical analysis suggested that the signal transducers and activators of transcription-1 (STAT-1) pathway might play an indispensable role in the interaction between LECT2 and NAFLD. A STAT-1 inhibitor could reverse the accumulation of hepatic lipids caused by Lect2 overexpression. CONCLUSION: LECT2 expression is significantly elevated in NAFLD. LECT2 induces the occurrence and development of NAFLD through the STAT-1 pathway. LECT2 may be a potential therapeutic target for NAFLD.

Uptake Mechanism and Direct Translocation of a New CPP for siRNA Delivery.

Since their development, cell-penetrating peptides (CPPs) have been used as delivery vehicles for various genetic or therapeutic agents; however, the uptake mechanisms of CPPs and the delivery details are still unclear. Understanding the mechanisms of cellular internalization of CPPs facilitate their development of CPPs as gene delivery vectors. In the present study, we evaluated the internalization process of a previously designed CPP, STR-KV, complexed with small interference RNA (siRNA) targeting at the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Using heparin treatment and chemical endocytic inhibitors, we elucidated that the electrostatic interaction of STR-KV/siRNA complex with heparin sulfate proteoglycans at the cell membrane surface triggered the energy-independent uptake of the majority of the complexes, which most likely through a direct translocation pathway. The intracellular trafficking and internalization kinetics observed by confocal microscopy also confirmed that the complex was uptaken through a nonendocytic pathway.

Design and evaluation of endosomolytic biocompatible peptides as carriers for siRNA delivery.

Gene therapy using RNA interference (RNAi) technology has been explored to treat cancers, by regulating the expression of oncogene. However, even though small interfering RNA (siRNA), which triggers RNAi, may have great therapeutic potential, efforts at using them in vivo have been hampered by the difficulty of effective and safe delivery into cells of interest. In this study, to develop a safe and efficient carrier for in vitro and in vivo siRNA delivery, we designed a peptide library. These peptides are improved variants of a known peptide based siRNA carrier C6. All the modifications improved the transfection efficiency of C6 to some degree. After completing prescreening for activity, several promising candidates were used for further evaluation. Selected peptides C6M3 and C6M6 could form stable complexes with siRNA. These complexes could be greatly uptaken by cells and showed a punctate perinuclear distribution. Moreover, peptide/siRNA complexes achieved high transfection efficiency in vitro without inducing substantial cytotoxicity. We have validated the therapeutic potential of this strategy for cancer treatment by targeting Bcl-2 gene in mouse tumor models, and demonstrated that tumor growth was inhibited. In order to address possible immune side effects of these peptide carriers, biocompatibility study in terms of complement activation and cytokine activation assay were carried out, whereas none of the peptides induced such effects. In conclusion, these results support the potential of these peptides as therapeutic siRNA carrier.

Design and characterization of a new peptide vector for short interfering RNA delivery.

RNA interference holds tremendous potential as one of the most powerful therapeutic strategies. However, the properties of short interfering RNA (siRNA), such as hydrophilicity, negative charge, and instability in serum have limited its applications; therefore, significant efforts have been undertaken to improve its cellular uptake. Cell penetrating peptides have been utilized to deliver various biologically active molecules, such as proteins, liposomes, nanoparticles, peptide nucleic acids, and recently small interfering RNAs. Here, we introduce a new cell penetrating peptide GL1(Ac-GLWRAWLWKAFLASNWRRLLRLLR-NH2) to improve the intracellular uptake of siRNA. This peptide consists of four tryptophan residues that facilitated its binding with the cell membrane, five arginine residues and one lysine residue which are positively charged at physiological pH, which induced the formation of peptide-siRNA complexes and enhanced the affinity of the peptide and cell membrane. Moreover, GL1 adopted helical secondary structure due to the altered distribution of polar and nonpolar residues in the sequence. In this study, we investigated the effect of peptide/siRNA molar ratio on the particle size, surface charge, secondary structure, and uptake efficiency. The results showed that GL1 formed stable complexes with siRNA mainly through electrostatic interaction and hydrophobic interaction, and the complexes displayed a spherical shape with the size of ~100 nm and positive surface charge. Utilizing the techniques of fluorescence microscopy and flow cytometry, the intracellular localization of Cy3-labeled GAPDH siRNA was visualized and the cellular uptake was quantified. It is worth noting that in the serum free environment, compared to Lipofectamine 2000, GL1 achieved higher cellular uptake of siRNA (~95%); in the presence of serum, GL1 retained the same level of siRNA cellular uptake (~84%) as Lipofectamine 2000. In addition, the viability of cells treated by GL1 in all studied molar ratios was >85%, which was significantly higher than that treated by Lipofectamine 2000 (~70%). Taken together, the peptide GL1 demonstrated promise as a siRNA delivery system.

DEGylation Enhanced the Stability of Peptide-siRNA Complexes in Serum.

Small interfering RNA (siRNA) shows great therapeutic potential due to its ability to regulate gene expression in a highly selective manner, but this application has been limited by effective delivery, partly because of the low nuclease resistance of siRNA in the presence of serum, and inefficient cellular uptake. We previously reported a library of cell-penetrating and amino acid-pairing peptides that facilitate effective siRNA delivery to mammalian cells without causing cytotoxicity, but they are unstable within serum-containing medium. Here, we investigated the possibility of conjugating the peptide with diethylene glycol to improve its serum stability without compromising its gene-regulation capability. One of the most promising peptides, C6M1, was conjugated with diethylene glycol, and its incorporated siRNA complexes had excellent serum stability and highly efficient cellular uptake with negligible cytotoxicity. The gene-silencing ability of diethylene glycol conjugated-peptide/siRNA complexes was comparable to that of non-conjugated peptide/siRNA at both mRNA and protein levels. Our data demonstrate that conjugating peptides with diethylene glycol is a promising method for improving siRNA delivery by improving its serum stability.

Rational modification of oligoarginine for highly efficient siRNA delivery: structure-activity relationship and mechanism of intracellular trafficking of siRNA.

Recently, cell-penetrating peptides (CPPs) have received much attention for cellular delivery of therapeutic molecules. However, in the case of CPPs as carriers for siRNA delivery, their utility is often restricted by low cellular uptake and/or entrapment in endosomes. Here, in order to deliver siRNAs with high efficiency, oligoarginine, a prominent member in CPPs, is rationally modified with oligohistidine and stearyl moieties (STR-) by fully taking into account the formation of nanoparticles, uptake and intracellular trafficking. We show that when the ratio of histidine/arginine in a peptide sequence is >1.5, pronounced gene silencing is induced. Following this rule, STR-HnR8 (n=16 and 20) are developed, which show a high knockdown efficiency rarely reported before. Finally, we find that endosomal escape of siRNA induced by stearylated and oligohistidylated oligoarginine is only from "proton-sponge" effect. Taken together, our results suggest a new strategy for the improvement of CPP-based siRNA delivery systems. FROM THE CLINICAL EDITOR: This study present a novel cell penetrating peptide-based siRNA delivery system utilizing modified oligo-arginine demonstrating a successful siRNA delivery approach.

Analysis of diffraction imaging in non-conjugate configurations.

Diffraction imaging of scattered light allows extraction of information on scatterer's morphology. We present a method for accurate simulation of diffraction imaging of single particles by combining rigorous light scattering model with ray-tracing software. The new method has been validated by comparison to measured images of single microspheres. Dependence of fringe patterns on translation of an objective based imager to off-focus positions has been analyzed to clearly understand diffraction imaging with multiple optical elements. The calculated and measured results establish unambiguously that diffraction imaging should be pursued in non-conjugate configurations to ensure accurate sampling of coherent light distribution from the scatterer.

Binary Pd-polyoxometalates and isolation of a ternary Pd-V-polyoxomolybdate active species for selective aerobic oxidation of alcohols.

Binary Pd-polyoxometalates [Pd(dpa)2]3 [PW12 O40]2 ⋅12 DMSO (2), [Pd(dpa)2]3 [PMo12 O40]2 ⋅12 DMSO⋅2 H2 O (3), and [Pd(dpa)(DMSO)2]2 [HPMo10 V2 O40 ]⋅4 DMSO (4) were synthesized by reaction of [Pd(dpa)(OAc)2]⋅2 H2 O (1; dpa=2,2'-dipyridylamine) with three Keggin-type polyoxometalates and fully characterized by single-crystal and powder XRD analyses, IR spectroscopy, and elemental analyses. The synthesis is facile and straightforward, and the complicated ligand-modification procedure often used in the traditional charge-transfer method can be omitted. In 2-4, Pd complexes and polyoxometalate anions are coupled through electrostatic interaction. Compound 4 is more active than the other three compounds in the selective aerobic oxidation of alcohols at ambient pressure. Interestingly, during catalytic recycling of compound 4, unprecedented ternary Pd-V-polyoxometalate [Pd(dpa)2 {VO(DMSO)5}2][PMo12 O40]2 ⋅4 DMSO (5), which was captured and characterized by single-crystal XRD, proved to be the true active species and showed high catalytic activity for the selective aerobic oxidation of aromatic alcohols (98.1-99.8 % conversion, 91.5-99.1 % selectivity). Moreover, on the basis of control experiments and EPR and UV/Vis spectra, a plausible reaction mechanism for the oxidation of alcohols catalyzed by 5 was proposed.

Study of low speed flow cytometry for diffraction imaging with different chamber and nozzle designs.

Achieving effective hydrodynamic focusing and flow stability at low speed presents a challenging design task in flow cytometry for studying phenomena such as cell adhesion and diffraction imaging of cells with low-cost cameras. We have developed different designs of flow chamber and sheath nozzle to accomplish the above goal. A 3D computational model of the chambers has been established to simulate the fluid dynamics in different chamber designs and measurements have been performed to determine the velocity and size distributions of the core fluid from the nozzle. Comparison of the simulation data with experimental results shows good agreement. With the computational model significant insights were gained for optimization of the chamber design and improvement of the cell positioning accuracy for study of slow moving cells. The benefit of low flow speed has been demonstrated also by reduced blurring in the diffraction images of single cells. Based on these results, we concluded that the new designs of chamber and sheath nozzle produce stable hydrodynamic focusing of the core fluid at low speed and allow detailed study of cellular morphology under various rheological conditions using the diffraction imaging method.

The Influence of Cryogenic Treatment on the Microstructure and Mechanical Characteristics of Aluminum Silicon Carbide Matrix Composites.

Aluminum matrix composites have been widely used in aerospace and automotive fields due to their excellent physical properties. Cryogenic treatment was successfully adopted to improve the performance of aluminum alloy components, while its effect and mechanism on the aluminum matrix composite remained unclear. In this work, the effects of cryogenic treatment on the microstructure evolution and mechanical properties of 15%SiCp/2009 aluminum matrix composites were systematically investigated by means of Thermoelectric Power (TEP), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The results showed that TEP measurement can be an effective method for evaluating the precipitation characteristics of 15%SiCp/2009 aluminum matrix composites during aging. The addition of cryogenic treatment after solution and before aging treatment promoted the precipitation from the beginning stage of aging. Furthermore, the aging time for the maximum precipitation of the θ″ phase was about 4 h advanced, as the conduction of cryogenic treatment accelerates the aging kinetics. This was attributed to the great difference in the linear expansion coefficient between the aluminum alloy matrix and SiC-reinforced particles, which could induce high internal stress in their boundaries for precipitation. Moreover, the lattice contraction of the aluminum alloy matrix during cryogenic treatment led to the increase in dislocation density and micro defects near the boundaries, thus providing more nucleation sites for precipitation during the aging treatment. After undergoing artificial aging treatment for 20 h, the increase in dispersive, distributed precipitates after cryogenic treatment improved the hardness and yield strength by 4% and 16 MPa, respectively.

Si Doping Enables Activity and Stability Enhancement on Atomically Dispersed Fe-Nx /C Electrocatalysts for Oxygen Reduction in Acid.

Fe-N-C represents the most promising non-precious metal catalysts (NPMCs) for the oxygen reduction reaction (ORR) in fuel cells, but often suffers from poor stability in acid due to the dissolution of metal sites and the poor oxidation resistance of carbon substrates. In this work, silicon-doped iron-nitrogen-carbon (Si/Fe-N-C) catalysts were developed by in situ silicon doping and metal-polymer coordination. It was found that Si doping could not only promote the density of Fe-Nx /C active sites but also elevated the content of graphitic carbon through catalytic graphitization. The best-performing Si/Fe-N-C exhibited a half-wave potential of 0.817 V vs. reversible hydrogen electrode in 0.5 m H2 SO4 , outperforming that of undoped Fe-N-C and most of the reported Fe-N-C catalysts. It also exhibited significantly enhanced stability at elevated temperature (≥60 °C). This work provides a new way to develop non-precious metal ORR catalysts with improved activity and stability in acidic media.

Apolipoprotein E (ApoE) orchestrates adipose tissue inflammation and metabolic disorders through NLRP3 inflammasome.

Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood. Here, we describe a novel role of apolipoprotein E (ApoE), which associated with lipid particles, in maintaining fat deposition and system metabolic inflammation. Using human samples and mouse models, we show that ApoE is robustly downregulated in obese individuals, db/db mice, and mice of high-fat diet (HFD) feeding and increased in obese subjects with diabetes. Furthermore, we found that ApoE deficiency mice globally prevented obesity by restraining adipose tissue expansion and improved systemic glucose tolerance and insulin sensitivity. However, macrophage contributed to metabolic inflammation due to increased IL-1ß production in adipose tissue from ApoE-/- mice induced by HFD. Our results suggest that the role of ApoE in regulating obesity and obesity-associated glucose dysregulation is inconsistent. Mechanistically, ApoE modulates of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome priming and activation step. Thus, our studies might provide new sights into ApoE, which is required for obesity-induced hyperglycemia, hyperinsulinism, and adaptive inflammation responses but diminishes the tolerance towards a subsequent metabolic inflammatory challenge. Our study shed new light on the integral role of apolipoprotein APOE in immunometabolism and adipose tissue homeostasis.

Comparative efficacy of secukinumab against adalimumab and infliximab in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Psoriasis is a common, chronic, immune-mediated inflammatory skin disease with increased epidermal proliferation. The objective of this review was to systematically identify the evidence and perform a network meta-analysis (NMA) to estimate the relative efficacy of secukinumab (SEC) against adalimumab (ADA) and infliximab (INF) for the treatment of moderate-to-severe plaque psoriasis. METHODS: A systematic literature review (SLR) was conducted according to a pre-specified protocol to identify relevant studies. Initially, the databases were searched from database inception till June 2013, and the SLR was updated in April 2020. The eligibility criteria included adult patients (≥18 years old) with moderate-to-severe plaque psoriasis, and the SLR included randomized controlled trials (RCTs). The comparators of interest were SEC, ADA, INF, and placebo (PLA), while outcomes of interest were Psoriasis Area and Severity Index (PASI) (50, 75, and 90) at weeks 12, 16, and 24. A Bayesian NMA for PASI was utilized with a framework that evaluated the probability of PASI responses in different categories of PASI thresholds within a single model. RESULTS: A total of 23 RCTs that assessed the efficacy of SEC, ADA, and INF in patients with moderate-to-severe plaque psoriasis were identified. At 12 weeks, SEC was associated with a significantly better response compared with PLA and ADA for PASI 75 and 90, while response results were comparable against INF. At 12 weeks, risk ratio (95% confidence interval) derived from NMA for SEC vs. ADA and INF for PASI 75 was 1.35 (1.19, 1.57) and 1.01 (0.90, 1.18), respectively. At the 16-week and 24-week time interval, SEC was significantly better than PLA, ADA, and INF for PASI 75 and 90. CONCLUSION: Efficacy of SEC in the treatment of patient populations with moderate-to-severe plaque psoriasis is well demonstrated through NMA.

BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation.

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation, and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions in type 2 diabetic mice. Myeloid-specific BAF60a knockout (BaMKO) promotes ATM proinflammatory activation, exacerbating diet-induced obesity, insulin resistance, and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage proinflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of proinflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the proinflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the proinflammatory activation of macrophage. This work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation, and metabolic diseases.

Dietary intervention preserves ß cell function in mice through CTCF-mediated transcriptional reprogramming.

Pancreatic ß cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of ß cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of ß cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues ß cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention-induced preservation of ß cell function. CTCF expression is markedly decreased in ß cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate ß cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for ß cell glucose metabolism and stress response.

The values of AHCY and CBS promoter methylation on the diagnosis of cerebral infarction in Chinese Han population.

BACKGROUND: The goal of our study is to investigate whether the methylation levels of AHCY and CBS promoters are related to the risk of cerebral infarction by detecting the methylation level of AHCY and CBS genes. METHODS: We extracted peripheral venous blood from 152 patients with cerebral infarction and 152 gender- and age-matched healthy controls, and determined methylation levels of AHCY and CBS promoters using quantitative methylation-specific polymerase chain reaction. We used the percentage of methylation reference (PMR) to indicate gene methylation level. RESULTS: We compared the promoter methylation levels of two genes (AHCY and CBS) in peripheral blood DNA between the cerebral infarction case group and the control group. Our study showed no significant difference in AHCY promoter methylation between case and control. Subgroup analysis by gender showed that the methylation level of AHCY in males in the case group was lower than that in the control group, but the difference was not statistically significant in females. In a subgroup analysis by age, there was no significant difference in the AHCY methylation level between the case and control in the young group (≤44 years old). However, the level of AHCY gene methylation in the middle-aged group (45-59 years old) was significantly higher and the aged group (≥60 years old) was significantly lower than that in the control groups. However, CBS promoter methylation levels were significantly lower in the case group than in the control group (median PMR: 70.20% vs 104.10%, P = 3.71E-10). In addition, the CBS methylation levels of males and females in the case group were significantly lower than those in the control group (male: 64.33% vs 105%, P = 2.667E-08; female: 78.05% vs 102.8%, P = 0.003). We also found that the CBS levels in the young (23-44), middle-aged (45-59), and older (60-90) groups were significantly lower than those in the control group (young group: 69.97% vs 114.71%; P = 0.015; middle-aged group: 56.04% vs 91.71%; P = 6.744E-06; older group: 81.6% vs 119.35%; P = 2.644E-04). Our ROC curve analysis of CBS hypomethylation showed an area under the curve of 0.713, a sensitivity of 67.4%, and a specificity of 74.0%. CONCLUSION: Our study suggests that hypomethylation of the CBS promoter may be closely related to the risk of cerebral infarction and may be used as a non-invasive diagnostic biomarker for cerebral infarction.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control.

Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and oxidative injury of hepatocytes. Rutin is a natural flavonoid with significant roles in combating cellular oxidative stress and regulating lipid metabolism. The current study aims to investigate the molecular mechanisms underlying rutin's hypolipidemic and hepatoprotective effects in nonalcoholic fatty liver disease. Rutin treatment was applied to male C57BL/6 mice maintained on a high-fat diet and HepG2 cells challenged with oleic acid. Hepatic lipid accumulation was evaluated by triglyceride assay and Oil Red O staining. Oxidative hepatic injury was assessed by malondialdehyde assay, superoxide dismutase assay and reactive oxygen species assay. The expression levels of various lipogenic and lipolytic genes were determined by quantitative real-time polymerase chain reactions. In addition, liver autophagy was investigated by enzyme-linked immunosorbent assay. In both fat-challenged murine liver tissues and HepG2 cells, rutin treatment was shown to significantly lower triglyceride content and the abundance of lipid droplets. Rutin was also found to reduce cellular malondialdehyde level and restore superoxide dismutase activity in hepatocytes. Among the various lipid-related genes, rutin treatment was able to restore the expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its downstream targets, carnitine palmitoyltransferase 1 and 2 (CPT-1 and CPT-2), while suppressing those of sterol regulatory element-binding protein 1c (SREBP-1c), diglyceride acyltransfase 1 and 2 (DGAT-1 and 2), as well as acyl-CoA carboxylase (ACC). In addition, rutin was shown to repress the autophagic function of liver tissues by down-regulating key autophagy biomarkers, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß). The experimental data demonstrated that rutin could reduce triglyceride content and mitigate oxidative injuries in fat-enriched hepatocytes. The hypolipidemic properties of rutin could be attributed to its ability to simultaneously facilitate fatty acid metabolism and inhibit lipogenesis.