2D to 3D Reconstruction of Boron-Linked Covalent-Organic Frameworks.

The transformation of two-dimensional (2D) covalent-organic frameworks (COFs) into three-dimensions (3D) is synthetically challenging, and it is typically addressed through interlayer cross-linking of alkene or alkyne bonds. Here, we report the first example of the chemical reconstruction of a 2D COF to a 3D COF with a complete lattice rearrangement facilitated by base-triggered boron hybridization. This chemical reconstruction involves the conversion of trigonal boronate ester linkages to tetrahedral anionic spiroborate linkages. This transformation reticulates the coplanar, closely stacked square cobalt(II) phthalocyanine (PcCo) units into a 3D perpendicular arrangement. As a result, the pore size of COFs expands from 2.45 nm for the initial 2D square lattice (sql) to 3.02 nm in the 3D noninterpenetrated network (nbo). Mechanistic studies reveal a base-catalyzed boronate ester protodeboronation pathway for the formation of the spiroborate structure.

Weak-Interaction Environment in a Composite Electrolyte Enabling Ultralong-Cycling High-Voltage Solid-State Lithium Batteries.

Poly(vinylidene fluoride) (PVDF)-based solid electrolytes with a Li salt-polymer-little residual solvent configuration are promising candidates for solid-state batteries. Herein, we clarify the microstructure of PVDF-based composite electrolyte at the atomic level and demonstrate that the Li+-interaction environment determines both interfacial stability and ion-transport capability. The polymer works as a "solid diluent" and the filler realizes a uniform solvent distribution. We propose a universal strategy of constructing a weak-interaction environment by replacing the conventional N,N-dimethylformamide (DMF) solvent with the designed 2,2,2-trifluoroacetamide (TFA). The lower Li+ binding energy of TFA forms abundant aggregates to generate inorganic-rich interphases for interfacial compatibility. The weaker interactions of TFA with PVDF and filler achieve high ionic conductivity (7.0 × 10-4 S cm-1) of the electrolyte. The solid-state Li||LiNi0.8Co0.1Mn0.1O2 cells stably cycle 4900 and 3000 times with cutoff voltages of 4.3 and 4.5 V, respectively, as well as deliver superior stability at -20 to 45 °C and a high energy density of 300 Wh kg-1 in pouch cells.

Benefits and challenges experienced by participants on long-term methadone maintenance treatment in China: a qualitative study.

BACKGROUND: Methadone maintenance treatment (MMT) has been implemented in China for nearly two decades, with a significant decrease in the number of participants in recent years. However, there is a lack of comprehensive research focusing on the long-term effectiveness in the context of this decline, especially from the perspectives of MMT participants themselves. This study aims to address this gap by examining the benefits and challenges experienced by long-term MMT participants in China, to uncover potential causes of the decrease in participant numbers and to improve the effectiveness of the program. METHODS: We conducted semi-structured interviews with 21 long-term MMT participants (treatment duration ≥ 5 years) recruited through purposive sampling from 6 MMT clinics in the Guangdong Province, China, between December 2021 and August 2022. Thematic analysis was employed to analyze the transcribed interviews. Two analysts independently coded the data, and a third researcher double-coded 20% of transcripts to ensure intercoder reliability. RESULTS: Overall, participants corroborated the notable decline in MMT participants during their long-term MMT, citing death, arrest, and self-perceived abstinence from heroin, as their perceived driving factors. They reported positive changes in their health, family relationships, and social functioning. However, they identified economic hardship as their greatest challenge associated with MMT, further exacerbated by other barriers including the conflict of clinic opening hours and working schedules, discrimination from employers, and COVID-19-related restrictions. Additionally, participants identified issues with dose adjustment and emergency treatment continuation. CONCLUSIONS: This study outlines the overall improvement in the quality of life of long-term MMT participants. However, it highlights the need for official guidelines for dose adjustment and emergency treatment continuation as well as the provision of health education, job referrals, and flexibility of clinic opening times to facilitate the return to society receiving participants. Establishing a follow-up mechanism for those receiving MMT is also recommended to prevent relapses to heroin and other illicit substances.

Amidation-Reaction Strategy Constructs Versatile Mixed Matrix Composite Membranes towards Efficient Volatile Organic Compounds Adsorption and CO2 Separation.

Mixed matrix composite membranes (MMCMs) have shown advantages in reducing VOCs and CO2 emissions. Suitable composite layer, substrate, and good compatibility between the filler and the matrix in the composite layer are critical issues in designing MMCMs. This work develops a high-performance UiO-66-NA@PDMS/MCE for VOCs adsorption and CO2 permea-selectivity, based on a simple and facile fabrication of composite layer using amidation-reaction approach on the substrate. The composite layer shows a continuous morphological appearance without interface voids. This outstanding compatibility interaction between UiO-66-NH2 and PDMS is confirmed by molecular simulations. The Si─O functional group and UiO-66-NH2 in the layer leads to improved VOCs adsorption via active sites, skeleton interaction, electrostatic interaction, and van der Waals force. The layer and ─CONH─ also facilitate CO2 transport. The MMCMs show strong four VOCs adsorption and high CO2 permeance of 276.5 GPU with a selectivity of 36.2. The existence of VOCs in UiO-66-NA@PDMS/MCE increases the polarity and fine-tunes the pore size of UiO-66-NH2 , improving the affinity towards CO2 and thus promoting the permea-selectivity for CO2 , which is further verified by GCMC and EMD methods. This work is expected to offer a facile composite layer manufacturing method for MMCMs with high VOC adsorption and CO2 permea-selectivity.

A Sunlight-Driven Self-Cleaning CuCo-MOF Composite Membrane for Highly Efficient Emulsion Separation and Water Purification.

The fouling phenomenon of membranes has hindered the rapid development of separation technology in wastewater treatment. The integration of materials into membranes with both excellent separation performance and self-cleaning properties still pose challenges. Here, a self-assembled composite membrane with solar-driven self-cleaning performance is reported for the treatment of complex oil-water emulsions. The mechanical robustness of the composite membrane is enhanced by the electrostatic attraction between chitosan and metal-organic frameworks (MOF) CuCo-HHTP as well as the crosslinking effect of glutaraldehyde. Molecular dynamics (MD) simulations also revealed the hydrogen bonding interaction between chitosan and CuCo-HHTP. The composite membrane of CuCo-HHTP-5@CS/MPVDF exhibits a high flux ranging from 700.6 to 2350.6 L∙m-2∙h-1∙bar-1 and excellent separation efficiency (>99.0%) for various oil-water emulsions, including crude oil, kerosene, and other light oils. The addition of CuCo-HHTP shows remarkable photothermal effects, thus demonstrating excellent solar-driven self-cleaning capability and antibacterial performance (with an efficiency of ≈100%). Furthermore, CuCo-HHTP-5@CS/MPVDF can activate peroxomonosulfate (PMS) under sunlight, quickly removing oil-fouling and dyes. Density functional theory (DFT) calculations indicate that the bimetallic sites of Cu and Co in CuCo-HHTP effectively promoted the activation of PMS. This study provides distinctive insights into the multifaceted applications of MOFs-derived photothermal anti-fouling composite membranes.

Hybrid integrated optical chaos circuits with optoelectronic feedback.

A chip-scale chaotic laser system with optoelectronic delayed feedback is proposed and analyzed by numerical simulation. This chip eliminates the need for bulky delay components such as long optical fibers, free propagation and external cavities, relying solely on internal devices and waveguides to achieve feedback delay. This approach simplifies integration, maintaining a compact chip size. According to the results, the chip-scale system exhibits rich dynamics, including periodicity, quasi-periodicity, and chaotic states. Chaos resembling Gaussian white noise is achieved with picosecond-level delay time, highlighting the complexity of chip-scale signals. Furthermore, time delay signature (TDS) concealment is enhanced with a short delay comparable to the inverse bandwidth τ, albeit at a cost of sacrificing chaotic signal complexity. Applying the photonic integrated circuits to practical applications, 1 Gbps back-to-back communication transmission is feasible. Results demonstrate low bit error rates (BERs) for authorizers (<10-6) and high BERs for eavesdroppers (>10-2), ensuring communication confidentiality and chaotic synchronization. Lastly, preliminary experiments validate the feasibility. Our theoretical work has demonstrated the feasibility of hybrid integrated optical chaos circuits with optoelectronic feedback based on photonic wire bonding, which can provide a stable and flexible integrated chaos source.

Effects of glycerol monolaurate on estradiol and follicle-stimulating hormones, offspring quality, and mRNA expression of reproductive-related genes of zebrafish (Danio rerio) females.

This study aims to explore whether glycerol monolaurate (GML) can improve reproductive performance of female zebrafish (Danio rerio) and the survival percentage of their offspring. Three kinds of isonitrogenous and isolipid diets, including basal diet (control) and basal diet containing 0.75 g/kg GML (L_GML) and 1.5 g/kg GML (H_GML), were prepared for 4 weeks feeding trial. The results show that GML increased the GSI of female zebrafish. GML also enhanced reproductive performance of female zebrafish. Specifically, GML increased spawning number and hatching rate of female zebrafish. Moreover, GML significantly increased the levels of triglycerides (TG), lauric acid, and estradiol (E2) in the ovary (P < 0.05). Follicle-stimulating hormone (FSH) levels in the ovary and brain also significantly increased in the L_GML group (P < 0.05). Besides, dietary GML regulated the hypothalamus-pituitary-gonad (HPG) axis evidenced by the changed expression levels of HPG axis-related genes in the brain and ovary of the L_GML and H_GML groups compared with the control group. Furthermore, compared with the control group, the expression levels of HPG axis-related genes (kiss2, kiss1r, kiss2r, gnrh3, gnrhr1, gnrhr3, lhß, and esr2b) in the brain of the L_GML group were significantly increased (P < 0.05), and the expression levels of HPG axis-related genes (kiss1, kiss2, kiss2r, gnrh2, gnrh3, gnrhr4, fshß, lhß, esr1, esr2a, and esr2b) in the brain of the H_GML group were significantly increased (P < 0.05). These results suggest that GML may stimulate the expression of gnrh2 and gnrh3 by increasing the expression level of kiss1 and kiss2 genes in the hypothalamus, thus promoting the synthesis of FSH and E2. The expression levels of genes associated with gonadotropin receptors (fshr and lhr) and gonadal steroid hormone synthesis (cyp11a1, cyp17, and cyp19a) in the ovary were also significantly upregulated by dietary GML (P < 0.05). The increasing expression level of cyp19a also may promote the FSH synthesis. Particularly, GML enhanced the richness and diversity and regulated the species composition of intestinal microbiota in female zebrafish. Changes in certain intestinal microorganisms may be related to the expression of certain genes involved in the HPG axis. In addition, L_GML and H_GML both significantly decreased larvae mortality at 96 h post fertilization and their mortality during the first-feeding period (P < 0.05), revealing the enhanced the starvation tolerance of zebrafish larvae. In summary, dietary GML regulated genes related to HPG axis to promote the synthesis of E2 and FSH and altered gut microbiota in female zebrafish, and improved the survival percentage of their offspring.

Genome-wide identification and characterization of tomato 14-3-3 (SlTFT) genes and functional analysis of SlTFT6 under heat stress.

The plant 14-3-3 proteins are essential for many biological processes and responses to abiotic stress. We performed genome-wide identification and analysis of the 14-3-3 family genes in tomato. To explore the properties of the thirteen Sl14-3-3 found in the tomato genome, their chromosomal location, phylogenetic, and syntenic relationships were analyzed. The Sl14-3-3 promoters were found to have a number of growth-, hormone-, and stress-responsive cis-regulatory elements. Moreover, the qRT-PCR assay revealed that Sl14-3-3 genes are responsive to heat and osmotic stress. Subcellular localization experiments evidenced that the SlTFT3/6/10 proteins occur in the nucleus and cytoplasm Additional analysis on Sl14-3-3 putative interactor proteins revealed a number of prospective clients that potentially participate in stress reactions and developmental processes. Furthermore, overexpression of an Sl14-3-3 family gene, SlTFT6, improved tomato plants thermotolerance. Taken together, the study provides basic information on tomato 14-3-3 family genes in plant growth and abiotic stress response (high temperature stress), which can be helpful to further study the underlying molecular mechanisms.

Transcriptional characteristics and functional validation of three monocyte subsets during aging.

BACKGROUND: Age-associated changes in immunity are inextricably linked to chronic inflammation and age-related diseases, the impact of aging on monocyte subsets is poorly understood. METHODS: Flow cytometry was applied to distinguish three monocyte subsets between 120 young and 103 aged individuals. We then analyzed the expression profiles of three monocyte subsets from 9 young and 9 older donors and CD14+ monocytes from 1202 individuals between 44 and 83 years old. Flow cytometry was used to measure ß-galactosidase activities, ROS levels, mitochondrial contents, mitochondrial membrane potentials (MMPs) and intracellular IL-6 levels in three monocyte subsets of young and elderly individuals, and plasma IL-6 levels were detected by electrochemiluminescence immunoassay. Mitochondrial stress and glycolytic rate of CD14+ monocytes from young and aged individuals were measured by Seahorse XFe24 Analyzer. RESULTS: Compared with young individuals, the percentage of classical subset in aged persons significantly decreased, while the proportion of nonclassical subset increased. Age-related differential genes were obviously enriched in cellular senescence, ROS, oxidative phosphorylation, mitochondrial respiratory chain, IL-6 and ribosome-related pathways. Compared with young individuals, the ß-galactosidase activities, ROS contents, intracellular IL-6 levels of three monocyte subsets, and plasma IL-6 levels in aged individuals were significantly elevated, while the MMPs apparently declined with age and the mitochondrial contents were only increased in intermediate and nonclassical subsets. CD14+ monocytes from elderly adults had conspicuously lower basal and spare respiratory capacity and higher basal glycolysis than those from young individuals. CONCLUSIONS: During aging, monocytes exhibited senescence-associated secretory phenotype, mitochondrial dysfunction, decreased oxidative phosphorylation and increased glycolysis and the nonclassical subset displayed the clearest features of aging. Our study comprehensively investigated age-related transcriptional alterations of three monocyte subsets and identified the pivotal pathways of monocyte senescence, which may have significant implications for tactics to alleviate age-related conditions.

Identification of Potential Biomarkers for Group I Pulmonary Hypertension Based on Machine Learning and Bioinformatics Analysis.

A number of processes and pathways have been reported in the development of Group I pulmonary hypertension (Group I PAH); however, novel biomarkers need to be identified for a better diagnosis and management. We employed a robust rank aggregation (RRA) algorithm to shortlist the key differentially expressed genes (DEGs) between Group I PAH patients and controls. An optimal diagnostic model was obtained by comparing seven machine learning algorithms and was verified in an independent dataset. The functional roles of key DEGs and biomarkers were analyzed using various in silico methods. Finally, the biomarkers and a set of key candidates were experimentally validated using patient samples and a cell line model. A total of 48 key DEGs with preferable diagnostic value were identified. A gradient boosting decision tree algorithm was utilized to build a diagnostic model with three biomarkers, PBRM1, CA1, and TXLNG. An immune-cell infiltration analysis revealed significant differences in the relative abundances of seven immune cells between controls and PAH patients and a correlation with the biomarkers. Experimental validation confirmed the upregulation of the three biomarkers in Group I PAH patients. In conclusion, machine learning and a bioinformatics analysis along with experimental techniques identified PBRM1, CA1, and TXLNG as potential biomarkers for Group I PAH.

Analogy Powered by Prediction and Structural Invariants: Computationally Led Discovery of a Mesoporous Hydrogen-Bonded Organic Cage Crystal.

Mesoporous molecular crystals have potential applications in separation and catalysis, but they are rare and hard to design because many weak interactions compete during crystallization, and most molecules have an energetic preference for close packing. Here, we combine crystal structure prediction (CSP) with structural invariants to continuously qualify the similarity between predicted crystal structures for related molecules. This allows isomorphous substitution strategies, which can be unreliable for molecular crystals, to be augmented by a priori prediction, thus leveraging the power of both approaches. We used this combined approach to discover a rare example of a low-density (0.54 g cm-3) mesoporous hydrogen-bonded framework (HOF), 3D-CageHOF-1. This structure comprises an organic cage (Cage-3-NH2) that was predicted to form kinetically trapped, low-density polymorphs via CSP. Pointwise distance distribution structural invariants revealed five predicted forms of Cage-3-NH2 that are analogous to experimentally realized porous crystals of a chemically different but geometrically similar molecule, T2. More broadly, this approach overcomes the difficulties in comparing predicted molecular crystals with varying lattice parameters, thus allowing for the systematic comparison of energy-structure landscapes for chemically dissimilar molecules.

Accelerated Synthesis and Discovery of Covalent Organic Framework Photocatalysts for Hydrogen Peroxide Production.

A high-throughput sonochemical synthesis and testing strategy was developed to discover covalent organic frameworks (COFs) for photocatalysis. In total, 76 conjugated polymers were synthesized, including 60 crystalline COFs of which 18 were previously unreported. These COFs were then screened for photocatalytic hydrogen peroxide (H2O2) production using water and oxygen. One of these COFs, sonoCOF-F2, was found to be an excellent photocatalyst for photocatalytic H2O2 production even in the absence of sacrificial donors. However, after long-term photocatalytic tests (96 h), the imine sonoCOF-F2 transformed into an amide-linked COF with reduced crystallinity and loss of electronic conjugation, decreasing the photocatalytic activity. When benzyl alcohol was introduced to form a two-phase catalytic system, the photostability of sonoCOF-F2 was greatly enhanced, leading to stable H2O2 production for at least 1 week.

Associations between polybrominated diphenyl ethers (PBDEs) levels in adipose tissues and blood lipids in women of Shantou, China.

Animal studies have indicated that exposure to polybrominated diphenyl ethers (PBDEs) during development can permanently affect blood/liver lipid balance. However, no epidemiological study has assessed the relationship between PBDEs in adipose tissues and blood lipid metabolism. In this study, we explored the associations between PBDEs levels in female adipose tissues and lipid profiles. We recruited 150 female patients undergoing plastic surgery from hospital in Shantou, China, collected their characteristics, clinical information, and adipose tissue samples. Fourteen PBDE congeners in adipose tissues were analyzed by gas chromatography-mass spectrometry (GC-MS). Multiple linear and logistic regression models were used to explore the relationships between PBDEs and lipid profiles, while restricted cubic spline (RCS) regression and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Median levels of ΣPBDEs and dominant congeners BDE-153, -209, and -183 in adipose tissues were 73.91, 26.12, 14.10 and 9.01 ng/g lipid, respectively. In the multiple linear model, BDE-153 and BDE-209 were negatively associated with triglycerides (TG), similarly for BDE-190 and total cholesterol (TC). While in the adjusted logistic models, BDE-138 was negatively associated with TC (OR = 0.76, 95%CI: 0.58, 0.99) and total lipids (TL) (OR = 0.76, 95%CI: 0.58, 0.99). Diastolic blood pressure was positively correlated with BDE-28 and BDE-71 (P < 0.05). Furthermore, a non-linear relationship was observed in BDE-138 and blood lipid levels using a RCS model (Pnonlinearity<0.05). BKMR analysis indicated that with the cumulative levels across PBDEs increased, the health risks of hypertriglyceridemia gradually rebounded, and the health risks of hypercholesterolemia and high total lipid gradually rebounded and then declined, but without statistical significance. PBDEs pollution was still prevalent in Shantou city, and several PBDE congeners were significant risk factors for dyslipidemia and blood pressure alteration. There exist deleterious effects of PBDEs and blood lipids.

Multicomponent Copper-Zinc Alloy Layer Enabling Ultra-Stable Zinc Metal Anode of Aqueous Zn-ion Battery.

Constructing stable surface modification layer is an effective strategy to suppress dendrite growth and side reactions of Zinc (Zn) metal anode in aqueous Zn-ion battery. Herein, a multicomponent Cu-Zn alloy interlayer with superior Zn affinity, high toughness and effective inhibition effect on lattice distortion is constructed on Zn foil (Cu-Zn@Zn) to fabricate ultra-stable Zn metal anode. Owning to the advantages of high binding energy of Cu-Zn alloy layer with Zn atoms and less contact area between metallic Zn and electrolyte, the as-prepared Cu-Zn@Zn electrode not only restricts the aggregation of Zn atoms, but also suppresses the pernicious hydrogen evolution and corrosion, leading to homogeneous Zn deposition and outstanding electrochemical performances. Accordingly, the symmetric battery with Cu-Zn@Zn electrode exhibits an ultra-long cycle life of 5496 h at 1 mA cm-2 for 1 mAh cm-2 , and the Cu-Zn@Zn//V2 O5 pouch cell demonstrates excellent cycling stability with a capacity retention of 88 % after 600 cycles.

Effects of progesterone on the lipolysis of lipid droplets and prostaglandin E2 synthesis in murine cervical epithelial cells.

Previous studies demonstrated that progesterone (P4) can promote prostaglandin (PG) E2 production; however, how P4 mediates the synthesis of PGE2 remains unclear. In this study, cervical epithelial cells from mice during the follicular phase were cultured invitro and treated with different concentrations of P4 (5, 10, and 20nM). The results of the present study suggest that treatment of murine cervical epithelial cells with 10nM P4 for 24h contributed to: (1) significantly increased expression of protein kinase A (PKA), cytosolic phospholipase A2 (cPLA2) and PGE synthase (PGES)-1; (2) higher phosphorylated (p-) to total extracellular signal-regulated kinase (ERK) 1/2 and hormone-sensitive lipase (HSL) ratios; (3) a significant decrease in the number of lipid droplets (LDs) and fatty acid content within LDs in epithelial cells; and (4) enhanced arachidonic acid and PGE2 levels in cells compared with the control (0nM P4) group (P<0.01 for all findings). In contrast, the PKA inhibitor H89 contributed to significantly decreased cPLA2, PGES-1 and HSL expression, ERK1/2 phosphorylation and arachidonic acid and PGE2 levels, even in the presence of P4. These data show that P4 can act via the PKA/ERK1/2 pathway to stimulate lipolysis of triacylglycerol in the LD core and degradation of phospholipid in the LD membrane to promote PGE2 synthesis in murine cervical epithelial cells.

Mink Aleutian disease seroprevalence in China during 1981-2017: A systematic review and meta-analysis.

Mink Aleutian disease (AMD) is the first of the three major diseases of fur animals. It is a common immunosuppressive disease in mink farms worldwide, which seriously endangers the development of the mink farming industry. Strengthening the understanding of the positive serum rate and spatial distribution of AMD is of great significance for the prevention and control of disease caused by the Aleutian virus. Therefore, we conducted a systematic review and meta-analysis to assess the seroprevalence of AMD in China. We extracted 45 studies related to the seroprevalence of Chinese AMD, with samples taken between 1981 and 2017. Our systematic review and meta-analysis results show that, during the selected period, the overall positive rate of AMD in China was 55.3% (95% CI 48.5-62.0). The results from subgroups analysis of the potential risk factors showed that the seroprevalence rate of AMD in China in the past 36 years rose from 48% (95% CI 37.0-60.5) in 1981-2009 to 61.4% (95% CI 43.6-79.3) in 2010-2017. The date of the spatial difference in AMD seroprevalence indicated that AMD seroprevalence was unevenly distributed in different regions: the number of mink in eastern China and northeastern China was relatively high, and the seroprevalence rates were 57.9%, (95% CI 46.2-69.7) and 61.3% (95% CI 53.1-69.5), respectively. Central China had the highest seroprevalence rate of AMD at 69.8% (95% CI 64.4-75.2). At the provincial level, the AMD seroprevalence rate in Jiangsu was as high as 96% (95% CI 94.1-97.8), and the AMD seroprevalence rate in Shaanxi was the lowest at 22.1% (95% CI 20.3-23.9). This suggested that the AMD seroprevalence rate in China was unevenly distributed. In other subgroups, the positive rate of AMD in adult mink was higher than in juvenile mink. This implied that the high prevalence of AMD in China was caused by multiple factors. The meta-regression results indicated that the detection method subgroup (P = 0.008) may be the source of heterogeneity. Our data system evaluated the prevalence of Aleutian disease in China in the last 37 years and a preliminary discussion on the risk factors of AMD. It may help prevent and control AMD in China. It is recommended to conduct further epidemiological testing and develop a comprehensive testing plan to determine the risk factors associated with Aleutian disease and improve the Aleutian disease control strategy.

The asymmetric construction of CF3-containing spiro-thiazolone-pyrrolidine compounds via [3 + 2] cycloaddition.

The first organocatalytic method for the asymmetric construction of CF3-containing spiro-thiazolone-pyrrolidine compounds has been developed. This is one of the very few methods to reach spiro-thiazolones, and afforded the products in excellent yields and stereoselectivities catalysed by only 1 mol% cinchona alkaloid-derived catalyst.

S-allyl-l-cysteine attenuates bleomycin-induced pulmonary fibrosis and inflammation via AKT/NF-κB signaling pathway in mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by inflammation, multifocal fibrotic lesions and excessive collagen deposition with limited therapies. As a major bioactive compound in garlic, S-allyl-l-cysteine (SAC) is a neuroprotective drug candidate to prevent cognitive decline, however, its anti-pulmonary fibrotic activity remains unknown. Here, we investigated whether SAC could attenuate bleomycin (BLM)-induced pulmonary fibrosis and inflammation in mice. Our results showed that SAC dose-dependently reduced the infiltration of inflammatory cells, pulmonary lesions and collagen deposition in BLM treated mice with downregulated mRNA expression levels of fibrotic genes including alpha smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III as well as the protein level of α-SMA. In addition, SAC could also reduce the mRNA expression of inflammatory mediators such as TNF-α and iNOS. Furthermore, higher phosphorylation of AKT and NF-κB p65 in IPF patient samples and murine samples was verified by immunohistochemistry while SAC could decrease the phosphorylation level of AKT and NF-κB p65 in mice stimulated with BLM. These findings, for the first time, indicate that SAC might mediate AKT/NF-κB signaling pathway to inhibit BLM-induced pulmonary fibrosis and support the potential role of SAC as an anti-pulmonary fibrosis agent.

Lanatoside C protects mice against bleomycin-induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation.

It has been established that lanatoside C, a FDA-approved cardiac glycoside, reduces proliferation of cancer cell lines. The proliferation of fibroblasts is critical to the pathogenesis of pulmonary fibrosis (PF), a progressive and fatal fibrotic lung disease lacking effective treatment. In this study we have investigated the impact of lanatoside C on a bleomycin (BLM)-induced mouse model of PF and through the evaluation of fibroblast proliferation and activation in vitro. We evaluated explanted lung tissue by histological staining, western blot analysis, qRT-PCR and survival analysis, demonstrating that lanatoside C was able to protect mice against BLM-induced pulmonary fibrosis. The proliferation of cultured pulmonary fibroblasts isolated from BLM-induced PF mice was suppressed by lanatoside C, as hypothesized, through the induction of cell apoptosis and cell cycle arrest at the G2/M phase. The Akt signalling pathway was involved in this process. Interestingly, the production of α-SMA, fibronectin, and collagen I and III in response to TGF-ß1 in healthy mouse fibroblasts was suppressed following lanatoside C administration by inhibition of TGF-ß1/Smad signalling. In addition, TGF-ß1-induced migration in lung fibroblasts was also impeded after lanatoside C treatment. Together, our data revealed that lanatoside C alleviated BLM-induced pulmonary fibrosis in mice via attenuation of growth and differentiation of fibroblasts, suggesting that it has potential as a candidate therapy for PF patients.

Dehydrocostus Lactone Suppresses LPS-induced Acute Lung Injury and Macrophage Activation through NF-κB Signaling Pathway Mediated by p38 MAPK and Akt.

Acute lung injury (ALI) is a severe clinical disease marked by dysregulated inflammation response and has a high rate of morbidity and mortality. Macrophages, which play diverse roles in the inflammatory response, are becoming therapeutic targets in ALI. In this study we investigated the effects of dehydrocostus lactone (DHL), a natural sesquiterpene, on macrophage activation and LPS-induced ALI. The macrophage cell line RAW264.7 and primary lung macrophages were incubated with DHL (0, 3, 5, 10 and 30 µmol/L) for 0.5 h and then challenged with LPS (100 ng/mL) for up to 8 hours. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI) and then treated with a range of DHL doses intraperitoneally (5 to 20 mg/kg). The results showed that DHL inhibited LPS-induced production of proinflammatory mediators such as iNOS, NO, and cytokines including TNF-α, IL-6, IL-1ß, and IL-12 p35 by suppressing the activity of NF-κB via p38 MAPK/MK2 and Akt signaling pathway in macrophages. The in vivo results revealed that DHL significantly attenuated LPS-induced pathological injury and reduced cytokines expression in the lung. NF-κB, p38 MAPK/MK2 and Akt signaling molecules were also involved in the anti-inflammatory effect. Collectively, our findings suggested that DHL is a promising agent for alleviating LPS-induced ALI.