Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease.

Backgrounds: Non-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD. Methods: Gene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples. Results: Through the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity. Conclusion: This comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease's development.

Study on Chemical Constituents of Panax notoginseng Leaves.

Panax notoginseng (Burk.) F. H. is a genuine medicinal material in Yunnan Province. As accessories, P. notoginseng leaves mainly contain protopanaxadiol saponins. The preliminary findings have indicated that P. notoginseng leaves contribute to its significant pharmacological effects and have been administrated to tranquilize and treat cancer and nerve injury. Saponins from P. notoginseng leaves were isolated and purified by different chromatographic methods, and the structures of 1-22 were elucidated mainly through comprehensive analyses of spectroscopic data. Moreover, the SH-SY5Y cells protection bioactivities of all isolated compounds were tested by establishing L-glutamate models for nerve cell injury. As a result, twenty-two saponins, including eight dammarane saponins, namely notoginsenosides SL1-SL8 (1-8), were identified as new compounds, together with fourteen known compounds, namely notoginsenoside NL-A3 (9), ginsenoside Rc (10), gypenoside IX (11), gypenoside XVII (12), notoginsenoside Fc (13), quinquenoside L3 (14), notoginsenoside NL-B1 (15), notoginsenoside NL-C2 (16), notoginsenoside NL-H2 (17), notoginsenoside NL-H1 (18), vina-ginsenoside R13 (19), ginsenoside II (20), majoroside F4 (21), and notoginsenoside LK4 (22). Among them, notoginsenoside SL1 (1), notoginsenoside SL3 (3), notoginsenoside NL-A3 (9), and ginsenoside Rc (10) showed slight protective effects against L-glutamate-induced nerve cell injury (30 µM).

Exploration for the Optical Properties and Fluorescent Prediction of Nitrotriazole and Nitrofurazan: First-Principles and TD-DFT Calculations.

High-energy materials containing azole and furazan have revealed numerous properties; however, the underlying optical properties need to be solved. Meanwhile, the uncertainty for the choice of fluorescent matrix materials and the flexible situational conditions prompted us to estimate the optical and fluorescent properties of 5,5'-dinitro-2H,2H'-3,3'-bi-1,2,4-triazole (DNBT), 4,4'-dinitroazolefurazan (DNAF), and 4,4'-dinitro-3,3'-4,3'-ter-1,2,5-oxadiazole (DNTO). The first-principles calculation with improved dispersion correction terms and time-dependent density functional theory were utilized to calculate the absorbance and excitation energy of DNBT, DNAF, and DNTO, as well as characterization for their crystal structure, electronic structure, molecular orbitals, and so forth, synchronously. In this work, the absorbance anisotropy of DNBT and DNTO is stronger than that of DNAF. The absorbance for each of the (0,0,1) crystal planes in the three compounds is greater than that of the other two crystal planes. Moreover, DNBT has the maximum absorbance on the (0,0,1) crystal plane. The N-N-H from DNBT and N-O-N from DNTO and DNAF are responsible for these results, while N=N in DNAF weakens the performance of N-O-N. UV-vis spectra show that the maximum absorption wavelengths λmax for DNBT, DNAF, and DNTO are 225, 228, and 201 nm, respectively. The number of five-membered rings and the coplanarity of groups in the intermolecular non-conjugation interaction potentially improve this ability due to the results from the crystal diffraction analysis. In addition, the polarization rate DNBT > DNTO > DNAF based on the molecular orbital analysis and the electrostatic potential calculation implies that the excitation energy of DNBT is less than DNTO, and the excitation energy of DNTO is less than DNAF. This work is beneficial to the expansion of energetic materials into the optical field and the accelerated application process of the related industry.

Using Wool Keratin Derived Metallo-Nanozymes as a Robust Antioxidant Catalyst to Scavenge Reactive Oxygen Species Generated by Smoking.

Self-assembled nanostructures based on biomolecules (e.g., proteins and amino acids) and metal ions have promising applications in mimicking the nanostructure, properties, and functions of natural enzymes. Herein, a metal ion-mediated self-assembly method for constructing catalytically active Cu-wool-keratin (CuWK) two-dimensional nanozymes is presented. Specifically, by introducing copper ions as abiological cofactors, WK can serve as a protein scaffold to design and create Cu catalytic sites. The optimized hybrids with Cu-WK coordination framework exhibit significant superoxide dismutases-like activity, catalase-like activity, and hydroxyl radical scavenging ability. These combined antioxidant activities make CuWK a robust nanozyme to effectively remove various reactive oxygen species (ROS). In this work, the as-prepared CuWK as a new additive can be integrated into a cigarette filter system to effectively remove the produced ROS from the burning of tobacco. More importantly, the CuWK nanozymes as a critical element can be further utilized to construct a recycling cigarette holder. Therefore, the present work shows that nanozymes with advanced catalytic capabilities can be constructed by self-assembly of metal ions and proteins, thus facilitating the rational design and discovery of this kind of artificial metalloenzymes.

A Mild Method for Encapsulation of Citral in Monodispersed Alginate Microcapsules.

Citral is a typical UV-irritation and acid-sensitive active and here we develop a mild method for the encapsulation of citral in calcium alginate microcapsules, in which UV irritation or acetic acid is avoided. Monodispersed oil-in-water-in-oil (O/W/O) emulsions are generated in a capillary microfluidic device as precursors. The middle aqueous phase of O/W/O emulsions contains sodium alginate, calcium-ethylenediaminetetraacetic acid (EDTA-Ca) complex as the calcium source, and D-(+)-Gluconic acid δ-lactone (GDL) as the acidifier. Hydrolysis of GDL will decrease the pH value of the middle aqueous solution, which will trigger the calcium ions released from the EDTA-Ca complex to cross-link with alginate molecules. After the gelling process, the O/W/O emulsions will convert to alginate microcapsules with a uniform structure and monodispersed size. The preparation conditions for alginate microcapsules are optimized, including the constituent concentration in the middle aqueous phase of O/W/O emulsions and the mixing manner of GDL with the alginate-contained aqueous solution. Citral-containing alginate microcapsules are successfully prepared by this mild method and the sustained-release characteristic of citral from alginate microcapsules is analyzed. Furthermore, a typical application of citral-containing alginate microcapsules to delay the oxidation of oil is also demonstrated. The mild gelling method provides us a chance to encapsulate sensitive hydrophobic actives with alginate, which takes many potential applications in pharmaceutical, food, and cosmetic areas.

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

Synergistic Flame Retardant Effect of Barium Phytate and Intumescent Flame Retardant for Epoxy Resin.

Recently, widespread concern has been aroused on environmentally friendly materials. In this article, barium phytate (Pa-Ba) was prepared by the reaction of phytic acid with barium carbonate in deionized water, which was used to blend with intumescent flame retardant (IFR) as a flame retardant and was added to epoxy resin (EP). Afterward, the chemical structure and thermal stability of Pa-Ba were characterized by Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA), respectively. On this basis, the flammability and flame retardancy of EP composites were researched. It is shown that EP/14IFR/2Ba composite has the highest limiting oxygen index (LOI) value of 30.7%. Moreover, the peak heat release rate (PHRR) of EP/14IFR/2Ba decreases by 69.13% compared with pure EP. SEM and Raman spectra reveal the carbonization quality of EP/14IFR/2Ba is better than that of other composites. The results prove that Pa-Ba can cooperate with IFR to improve the flame retardancy of EP, reducing the addition amount of IFR in EP, thus expanding the application range of EP. In conclusion, adding Pa-Ba to IFR is a more environmentally friendly and efficient method compared with others.

Flame Retardant Properties of a Guanidine Phosphate-Zinc Borate Composite Flame Retardant on Wood.

This work combines guanidine dihydrogen phosphate (GDP) and zinc borate (ZB) to modify wood via microwave-ultrasonic impregnation for realizing favorable flame retardancy and thermal stability, which were investigated by the limiting oxygen index (LOI), thermogravimetric analysis (TGA), and cone calorimetry tests (CONE). The treated samples show better performance in fire retardancy with the LOI value increasing to 47.8%, and the results of TGA indicate the outstanding thermal stability of wood. In addition, the decline of heat release rate, total heat release, smoke production rate, and total smoke production examined by CONE further demonstrates the achievement of excellent flame retardancy and smoke suppression properties of the GDP/ZB-modified wood.

Anatomies for the thermal decomposition behavior and product rule of 5,5'-dinitro-2H,2H'-3,3'-bi-1,2,4-triazole.

High-performance energetic materials are mainly used in the military, aerospace industry and chemical fields. The ordinary technology of producing energetic materials cannot avoid the domination of its unique needs. At present, revealing the underlying mechanism of the formation of high-energy materials is of great significance for improving their quality characteristics. We pay special attention to the decomposition and reactive molecular dynamics (RMD) simulation of 5,5'-dinitro-2H,2H'-3,3'-bi-1,2,4-triazole (DNBT). Various forms were captured in the simulation, and the form is determined by the temperature of the initial reactant. By observing the heating pattern and morphological changes under the initial thermal equilibrium, interesting temperature jumps were found in 325 K and 350 K. Observation of continuous heating (simulated temperatures are 2600 K, 2900 K, 3200 K and 3500 K) shows that DNBT has the maximum heating rate at 3500 K. In addition, N2 occupies this dominant position in the product, moreover, N2 and NO2 respectively dominate the gas phase products during the initial heating process. According to the transition state analysis results of the intermediates, we found 4 interesting intermediate products, which were determined by high frequency reaction under the 4 simulated temperatures and performed with transition state calculations. It shows that the selection of reactant temperature and its activity is the key to orderly decomposition of DNBT. It is expected that these findings will be widely used in comprehensive decomposition devices and to improve the concept of learning military and industrial technology.

Controllable preparation of monodisperse alginate microcapsules with oil cores.

Here we report a novel strategy for controllable preparation monodisperse alginate microcapsules with oil cores, where the thickness of the alginate shells, as well as the number and diversity of the oil cores can be tailored precisely. Monodisperse oil-in-water-in-oil (O/W/O) emulsions are generated in a microfluidic device as templates, which contain alginate molecules and a water-soluble calcium complex in the middle aqueous phase. Alginate microcapsules are produced by gelling O/W/O emulsions in oil solution with acetic acid, where the pH decreasing will trigger the calcium ions being released from calcium complex and cross-linking with alginate molecules. Increasing the alginate molecule concentration in emulsion templates affects little on the thickness of the microcapsules but improves their stability in DI water. The strength of alginate microcapsules can be reinforced by post cross-linking in calcium chloride, polyetherimide, or chitosan solution. Typical payloads, such as thyme essential oil, lavender essential oil and W/O emulsions are encapsulated in alginate microcapsules successfully. Furthermore, tailoring the thickness of the alginate shells, as well as the number and the diversity of the oil cores precisely by manipulation the emulsion templates with microfluidics is also demonstrated. The proposed method shows excellent controllability in designing alginate microcapsules with oil cores.

Suberoylanilide Hydroxamic Acid Triggers Autophagy by Influencing the mTOR Pathway in the Spinal Dorsal Horn in a Rat Neuropathic Pain Model.

Histone acetylation levels can be upregulated by treating cells with histone deacetylase inhibitors (HDACIs), which can induce autophagy. Autophagy flux in the spinal cord of rats following the left fifth lumber spinal nerve ligation (SNL) is involved in the progression of neuropathic pain. Suberoylanilide hydroxamic acid (SAHA), one of the HDACIs can interfere with the epigenetic process of histone acetylation, which has been shown to ease neuropathic pain. Recent research suggest that SAHA can stimulate autophagy via the mammalian target of rapamycin (mTOR) pathway in some types of cancer cells. However, little is known about the role of SAHA and autophagy in neuropathic pain after nerve injury. In the present study, we aim to investigate autophagy flux and the role of the mTOR pathway on spinal cells autophagy activation in neuropathic pain induced by SNL in rats that received SAHA treatment. Autophagy-related proteins and mTOR or its active form were assessed by using western blot, immunohistochemistry, double immunofluorescence staining and transmission electron microscopy (TEM). We found that SAHA decreased the paw mechanical withdrawal threshold (PMWT) of the lower compared with SNL. Autophagy flux was mainly disrupted in the astrocytes and neuronal cells of the spinal cord dorsal horn on postsurgical day 28 and was reversed by daily intrathecal injection of SAHA (n = 100 nmol/day or n = 200 nmol/day). SAHA also decreased mTOR and phosphorylated mTOR (p-mTOR) expression, especially p-mTOR expression in astrocytes and neuronal cells of the spinal dorsal horn. These results suggest that SAHA attenuates neuropathic pain and contributes to autophagy flux in astrocytes and neuronal cells of the spinal dorsal horn via the mTOR signaling pathway.

Discovery of Novel, Orally Bioavailable ß-Amino Acid Azaindole Inhibitors of Influenza PB2.

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Biosorption of malachite green from aqueous solutions by Pleurotus ostreatus using Taguchi method.

Dyes released into the environment have been posing a serious threat to natural ecosystems and aquatic life due to presence of heat, light, chemical and other exposures stable. In this study, the Pleurotus ostreatus (a macro-fungus) was used as a new biosorbent to study the biosorption of hazardous malachite green (MG) from aqueous solutions. The effective disposal of P. ostreatus is a meaningful work for environmental protection and maximum utilization of agricultural residues.The operational parameters such as biosorbent dose, pH, and ionic strength were investigated in a series of batch studies at 25°C. Freundlich isotherm model was described well for the biosorption equilibrium data. The biosorption process followed the pseudo-second-order kinetic model. Taguchi method was used to simplify the experimental number for determining the significance of factors and the optimum levels of experimental factors for MG biosorption. Biosorbent dose and initial MG concentration had significant influences on the percent removal and biosorption capacity. The highest percent removal reached 89.58% and the largest biosorption capacity reached 32.33 mg/g. The Fourier transform infrared spectroscopy (FTIR) showed that the functional groups such as, carboxyl, hydroxyl, amino and phosphonate groups on the biosorbent surface could be the potential adsorption sites for MG biosorption. P. ostreatus can be considered as an alternative biosorbent for the removal of dyes from aqueous solutions.

[Evaluation of the cellulase cost during the cassava cellulose ethanol fermentation process].

Cellulose takes nearly 10% (W/W) dry weight of cassava tubers. In this study, the cellulase cost of different ethanol fermentation from cassava cellulose was evaluated. The processes include the direct saccharification and fermentation of original cassava cellulose residues, the direct saccharification and fermentation of pretreated cassava cellulose residues, and the simultaneous co-saccharification and fermentation of cassava starch and cassava cellulose. The results show that the cassava cellulose utilization in the first two processes were low with the enzyme cost of 13 602 and 11 659 RMB Yuan per tone of ethanol, respectively. In the third process, the final ethanol concentration increased from 101.5 g/L to 107.0 g/L when cassava cellulose and cassava starch were saccharified simultaneously. Comparing to the first two processes, the third one demonstrated the lowest enzyme cost at 3 589 RMB Yuan per ton of ethanol, which was less than the ethanol price and no additional equipment and operation cost input were added. The conclusion provided a practical way of cassava cellulose utilization in cassava ethanol industry.

Cost analysis of cassava cellulose utilization scenarios for ethanol production on flowsheet simulation platform.

Cassava cellulose accounts for one quarter of cassava residues and its utilization is important for improving the efficiency and profit in commercial scale cassava ethanol industry. In this study, three scenarios of cassava cellulose utilization for ethanol production were experimentally tested under same conditions and equipment. Based on the experimental results, a rigorous flowsheet simulation model was established on Aspen plus platform and the cost of cellulase enzyme and steam energy in the three cases was calculated. The results show that the simultaneous co-saccharification of cassava starch/cellulose and ethanol fermentation process (Co-SSF) provided a cost effective option of cassava cellulose utilization for ethanol production, while the utilization of cassava cellulose from cassava ethanol fermentation residues was not economically sound. Comparing to the current fuel ethanol selling price, the Co-SSF process may provide an important choice for enhancing cassava ethanol production efficiency and profit in commercial scale.

A simplified filter paper assay method of cellulase enzymes based on HPLC analysis.

A simplified filter paper assay (FPA) method of cellulase enzymes was proposed based on high-performance liquid chromatography (HPLC) measurement. The method was according to the sum of glucose and cellobiose concentrations measured by HPLC that was able to be correlated with filter paper units (FPU) of the cellulase enzymes assayed by the traditional FPA method, regardless of the differences in the sources, activities, and components of the cellulases. This simple and quick assay method for the cellulase enzymes provided another parameter of the ratio of glucose to cellobiose (G/C ratio) representing the capacity of cellulase enzymes degrading cellulose into fermentable monomeric sugars.

Ankle brachial index is a valuable index of the severity of atherosclerotic renal artery stenosis.

OBJECTIVE: The objective of this study was to investigate the relationship between the ankle brachial index (ABI) and the severity of atherosclerotic renal artery stenosis (ARAS). MATERIAL AND METHODS: In total, 138 patients with a complete clinical record were enrolled in this study. The severity of ARAS was judged by renal artery angiography and the ABI was measured according to the method recommended by the American Heart Association. RESULTS: Hypertension, coronary artery disease, chronic renal dysfunction and hyperlipidaemia were significantly increased in the ARAS group (p < 0.05 or 0.01), and the ARAS patients were significantly older than the non-ARAS patients (p < 0.05). There were 31 cases of mild renal artery stenosis, 26 of midrange stenosis, 14 of severe stenosis and 16 of bilateral stenosis. In total, 104 cases had a normal ABI, while 34 cases had an abnormal ABI (≤0.9). Abnormal ABI values were not significantly correlated with mild ARAS, but the abnormal ABI value in patients with midrange and severe ARAS was approximately four times the normal ABI in these patients. CONCLUSION: ABI is a valuable predictive index of midrange to severe ARAS.

Enhanced models for expertise retrieval using community-aware strategies.

Expertise retrieval, whose task is to suggest people with relevant expertise on the topic of interest, has received increasing interest in recent years. One of the issues is that previous algorithms mainly consider the documents associated with the experts while ignoring the community information that is affiliated with the documents and the experts. Motivated by the observation that communities could provide valuable insight and distinctive information, we investigate and develop two community-aware strategies to enhance expertise retrieval. We first propose a new smoothing method using the community context for statistical language modeling, which is employed to identify the most relevant documents so as to boost the performance of expertise retrieval in the document-based model. Furthermore, we propose a query-sensitive AuthorRank to model the authors' authorities based on the community coauthorship networks and develop an adaptive ranking refinement method to enhance expertise retrieval. Experimental results demonstrate the effectiveness and robustness of both community-aware strategies. Moreover, the improvements made in the enhanced models are significant and consistent.

[Process strategy for ethanol production from lignocellulose feedstock under extremely low water usage and high solids loading conditions].

The massive water and steam are consumed in the production of cellulose ethanol, which correspondingly results in the significant increase of energy cost, waster water discharge and production cost as well. In this study, the process strategy under extremely low water usage and high solids loading of corn stover was investigated experimentally and computationally. The novel pretreatment technology with zero waste water discharge was developed; in which a unique biodetoxification method using a kerosene fungus strain Amorphotheca resinae ZN1 to degrade the lignocellulose derived inhibitors was applied. With high solids loading of pretreated corn stover, high ethanol titer was achieved in the simultaneous saccharification and fermentation process, and the scale-up principles were studied. Furthermore, the flowsheet simulation of the whole process was carried out with the Aspen plus based physical database, and the integrated process developed was tested in the biorefinery mini-plant. Finally, the core technologies were applied in the cellulose ethanol demonstration plant, which paved a way for the establishment of an energy saving and environment friendly technology of lignocellulose biotransformation with industry application potential.