BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

T Cell Receptor-Regulated TGF-ß Type I Receptor Expression Determines T Cell Quiescence and Activation.

It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ß (TGF-ß) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-ß signaling during T cell activation by downregulating TGF-ß type 1 receptor (TßRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-ß prevented TCR-mediated TßRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TßRI downregulation through overexpression of TßRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TßRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TßRI-TGF-ß signaling acts as a crucial criterion to determine T cell quiescence and activation.

Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS: TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. CONCLUSIONS: This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.

Surface Defect and Wettability Engineering of Porous SnOx for Reliable Bioassays with High Selectivity and Wide Linear Dynamic Range.

Bioassay systems that can selectively detect biomarkers at both high and low levels are of great importance for clinical diagnosis. In this work, we report an enzyme electrode with an oxygen reduction reaction (ORR)-tolerant H2O2 reduction property and an air-liquid-solid triphase interface microenvironment by regulating the surface defects and wettability of nanoporous tin oxide (SnOx). The enzyme electrode allows the oxygen that is required for the oxidase catalytic reaction to be transported from the air phase to the reaction zone, which greatly enhances the enzymatic kinetics and increases the linear detection upper limit. Meanwhile, the ORR-tolerant H2O2 reduction property of SnOx catalysts achieved via oxygen vacancy engineering greatly reduces the interferent signals caused by oxygen and various easily oxidizable endogenous/exogenous species, which enables the selective detection of biomarkers at trace levels. The synergistic effect between these two novel qualities features a bioassay system with a wide dynamic linear range and high selectivity for the accurate detection of a wide range of biomarkers, such as glucose, lactic acid, uric acid, and galactose, offering the potential for reliable clinical diagnosis applications.

Stable Inorganic Colloidal Tin and Tin-Lead Perovskite Nanocrystals with Ultralong Carrier Lifetime via Sn(IV) Control.

Inorganic tin (Sn) perovskite nanocrystals offer a promising solution to the potential toxicity concerns associated with their established lead (Pb)-based counterparts. Yet, achieving their superior stability and optoelectronic properties remains an ongoing challenge. Here, we report a synthesis of high-symmetry α-phase CsSnI3 nanocrystals with an ultralong 278 ns carrier lifetime, exceeding previous benchmarks by 2 orders of magnitude through meticulous Sn(IV) control. The nanocrystals demonstrate excellent colloidal stability, uniform monodispersity, and a distinct exciton peak. Central to these outcomes is our designed solid-liquid antioxidation suspension of tri-n-octylphosphine (TOP) and zerovalent tin (Sn(0)) that fully addresses the unique coexisting oxygen-driven and solvent-driven Sn oxidation mechanisms in Sn perovskite nanocrystal synthesis. We uncover the largely undervalued function of TOP in mitigating oxygen-driven Sn oxidation and introduce Sn(0) powder to generate a synergistic antioxidation function with TOP, significantly reducing Sn(IV)-induced defects and distortions and contributing to enhanced optoelectronic properties. Strikingly, this approach also profoundly impacts inorganic Sn-Pb perovskite nanocrystals, boosting lifetimes by 2 orders of magnitude and increasing photoluminescence quantum yield over 100-fold to 35%. Our findings illuminate the potential of Sn-based nanocrystals for optoelectronic applications.

Circular RNA HSDL2 promotes breast cancer progression via miR-7978 ZNF704 axis and regulating hippo signaling pathway.

Circular RNAs (circRNAs) are a new group of endogenous RNAs recently found to be involved in the development of various diseases, including their confirmed involvement in the progression of several types of cancers. Unluckily, the abnormal expression and functions of circRNAs in breast cancer shall be further investigated. This work aims to elucidate the action and molecular mechanism of circHSDL2 in the malignant progression of breast cancer. Differential expression profiles of circRNAs in breast cancer tissues relative to normal breast tissues and in the exosomes of breast cancer patients compared to healthy women were analyzed from databases to identify potentially functional circRNAs. CircHSDL2 was selected for further investigation. Cell proliferation, migration and invasion assays were done to assess the effect of circHSDL2 overexpression on breast cancer cells. Bioinformatics test and dual-luciferase reporter experiments were done to explore the interaction between circHSDL2 and miRNA. Downstream target genes were further investigated through proteomics analysis and Western blotting. The influence of circHSDL2 on breast cancer in vivo was evaluated through xenograft experiments in nude mice. Functional analysis demonstrated circHSDL2 overexpression promoted the division, movement, and invasion of breast cancer cells both in vivo and in vitro. Mechanistically, circHSDL2 acted as a sponge for miR-7978 to affect ZNF704 expression and thereby regulate the Hippo pathway in breast cancer cells. In conclusion, circHSDL2 regulates the Hippo pathway through the miR-7978/ZNF704 axis to facilitate the malignancy of breast cancer. This may be a potential biomarker and treatment target.

The Property of a Key Amino Acid Determines the Function of Farnesyl Pyrophosphate Synthase in Sporobolomyces pararoseus NGR.

Farnesyl pyrophosphate synthase (FPPS) catalyzes the synthesis of C15 farnesyl diphosphate (FPP) from C5 dimethylallyl diphosphate (DMAPP) and two or three C5 isopentenyl diphosphates (IPPs). FPP is an important precursor for the synthesis of isoprenoids and is involved in multiple metabolic pathways. Here, farnesyl pyrophosphate synthase from Sporobolomyces pararoseus NGR (SpFPPS) was isolated and expressed by the prokaryotic expression system. The SpFPPS full-length genomic DNA and cDNA are 1566 bp and 1053 bp, respectively. This gene encodes a 350-amino acid protein with a predicted molecular mass of 40.33 kDa and a molecular weight of 58.03 kDa (40.33 kDa + 17.7 kDa), as detected by SDS-PAGE. The function of SpFPPS was identified by induction, purification, protein concentration and in vitro enzymatic activity experiments. Structural analysis showed that Y90 was essential for chain termination and changing the substrate scope. Site-directed mutation of Y90 to the smaller side-chain amino acids alanine (A) and lysine (K) showed in vitro that wt-SpFPPS catalyzed the condensation of the substrate DMAPP or geranyl diphosphate (GPP) with IPP at apparent saturation to synthesize FPP as the sole product and that the mutant protein SpFPPS-Y90A synthesized FPP and C20 geranylgeranyl diphosphate (GGPP), while SpFPPS-Y90K hydrolyzed the substrate GGPP. Our results showed that FPPS in S. pararoseus encodes the SpFPPS protein and that the amino acid substitution at Y90 changed the distribution of SpFPPS-catalyzed products. This provides a baseline for potentially regulating SpFPPS downstream products and improving the carotenoid biosynthesis pathway.

Comparison of Tumor Non-specific and PD-L1 Specific Imaging by Near-Infrared Fluorescence/Cerenkov Luminescence Dual-Modality In-situ Imaging.

Background: Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of specific antibodies in-vivo may be inferior to non-specific IgG in some cases. Objectives: To explore factors affecting labeled antibody visualization by PD-L1 specific and non-specific imaging of nude mouse tumors. Methods: TTU was observed in RKO model on Cerenkov luminescence (CL) and near-infrared fluorescence (NIRF) imaging of radionuclide 131I or NIRF dyes labeled Atezolizumab and IgG. A mixture of NIRF dyes labeled Atezolizumab and 131I-labeled IgG was injected, and TTU was observed in the RKO and HCT8 model by NIRF/CL dual-modality in-situ imaging. TTU were observed by 131I-labeled Atezolizumab and IgG in-vitro distribution. Results: Labeled IgG concentrated more in tumors than Atezolizumab. NIRF/CL imaging in 24 to 168 h showed that TTU gradually decreased over time, which decreased more slowly on CL imaging compared to NIRF imaging. The distribution data in-vitro showed that TTU of 131I-labeled IgG was higher than that of 131I-labeled Atezolizumab at any time point. Conclusion: Non-specific IgG may not be suitable as a control for Atezolizumab in comparing tumor PD-L1 expression in nude mice via labeled antibody optical imaging under certain circumstances.

Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction.

GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.

Light-Initiated Imprinted Membrane-Based Biomimetic SERS Sensor toward Selective Detection of Trace MC-LR.

Microcystin-LR (MC-LR) is a severe threat to human and animal health; thus, monitoring it in the environment is essential, especially in water quality protections. Herein, in this work, we synthesize PVDF/CNT/Ag molecular imprinted membranes (PCA-MIMs) via an innovative combination of surface-enhanced Raman spectroscopy (SERS) detection, membrane separation, and molecular-imprinted technique toward the analysis of MC-LR in water. In particular, a light-initiated imprint is employed to protect the chemical structure of the MC-LR molecules. Furthermore, in order to ensure the detection sensitivity, the SERS substrates are combined with the membrane via the assistance of magnetism. The effect of synthesis conditions on the SERS sensitivity was investigated in detail. It is demonstrated from the characteristic results that the PCA-MIMs present high sensitivity to the MC-LR molecules with excellent selectivity against the interfere molecules. Results clearly show that the as-prepared PCA-MIMs hold great potential applications to detect trace MC-LR for the protection of water quality.

Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy.

BACKGROUND AIMS: Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. METHODS: We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. RESULTS: The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. CONCLUSIONS: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

Role of cell rearrangement and related signaling pathways in the dynamic process of tip cell selection.

Angiogenesis is a complex, highly-coordinated and multi-step process of new blood vessel formation from pre-existing blood vessels. When initiated, the sprouting process is spearheaded by the specialized endothelial cells (ECs) known as tip cells, which guide the organization of accompanying stalk cells and determine the function and morphology of the finally-formed blood vessels. Recent studies indicate that the orchestration and coordination of angiogenesis involve dynamic tip cell selection, which is the competitive selection of cells to lead the angiogenic sprouts. Therefore, this review attempt to summarize the underlying mechanisms involved in tip cell specification in a dynamic manner to enable readers to gain a systemic and overall understanding of tip cell formation, involving cooperative interaction of cell rearrangement with Notch and YAP/TAZ signaling. Various mechanical and chemical signaling cues are integrated to ensure the right number of cells at the right place during angiogenesis, thereby precisely orchestrating morphogenic functions that ensure correct patterning of blood vessels. Video Abstract.

Segregation of endosymbionts in complex symbiotic system of cicadas providing novel insights into microbial symbioses and evolutionary dynamics of symbiotic organs in sap-feeding insects.

The most extraordinary systems of symbiosis in insects are found in the suborder Auchenorrhyncha of Hemiptera, which provide unique perspectives for uncovering complicated insect-microbe symbiosis. We investigated symbionts associated with bacteriomes and fat bodies in six cicada species, and compared transmitted cell number ratio of related symbionts in ovaries among species. We reveal that Sulcia and Hodgkinia or a yeast-like fungal symbiont (YLS) are segregated from other host tissues by the bacteriomes in the nymphal stage, then some of them may migrate to other organs (i.e., fat bodies and ovaries) during host development. Particularly, YLS resides together with Sulcia in the "symbiont ball" of each egg and the bacteriomes of young-instar nymphs, but finally migrates to the fat bodies of adults in the majority of Hodgkinia-free cicadas, whereas it resides in both bacteriome sheath and fat bodies of adults in a few other species. The transmitted Sulcia/YLS or Sulcia/Hodgkinia cell number ratio in ovaries varies significantly among species, which could be related to the distribution and/or lineage splitting of symbiont(s). Rickettsia localizes to the nuclei of bacteriomes and fat bodies in some species, but it was not observed to be transmitted to the ovaries, indicating that this symbiont may be acquired from environments or from father to offspring. The considerable difference in the transovarial transmission process of symbionts suggests that cellular mechanisms underlying the symbiont transmission are complex. Our results may provide novel insights into insect-microbe symbiosis.

Oxygen Vacancy Engineering of FeOx toward Oxygen-Tolerant Hydrogen Peroxide Reduction for Reliable Bioassays.

The accurate determination of hydrogen peroxide (H2O2), an important clinical disease relevant biomarker, is of great importance for the diagnosis and management of illnesses. By using the cathodic monitoring approach, H2O2 can be accurately detected because interfering signals from easily oxidizable endogenous and exogenous species in biofluids can be avoided. However, the simultaneous occurrence of the oxygen reduction reaction (ORR) restricts the practical use of this cathodic method. In this study, via oxygen vacancy modulation, we synthesized FeOx catalysts that can selectively reduce H2O2 over O2. The H2O2 detection system based on this catalyst exhibits an outstanding ORR inhibition ability. Furthermore, by integrating this catalyst with glucose oxidase, a model enzyme, a reliable bioassay system was developed that can selectively detect glucose over a wide variety of interferents in artificially simulated tissue fluids. The bioassay system employing this catalyst in conjunction with oxidases is generally applicable to accurate detect a wide range of biomarkers.

Boosting the Capacitor Performance of the Metal Organic Frameworks Derived V2O5 Nanoflower by Cu Doping.

Due to its ultrahigh theoretical capacitance, vanadium pentoxide (V2O5) is considered to be a valid candidate for advanced supercapacitors. However, because of the low electron/electrolyte transfer rate, the capacitive performance still remains to be improved. In this report, Cu doping is adopted to improve the capacitive performance by a two-steps strategy consisting of microwave-assisted solvothermal and postannealing treatments. The electrochemical results indicate that the Cu doping was beneficial for improving the specific capacitance, extending the potential window, and improving the rate ability and long-term stability of V2O5. Furthermore, the mechanism for the performance improvement is explained in detail by combining theoretical calculation and experiments. The results indicated that, compared with that of undoped V2O5, the larger interplanar spacing, better electrical conductivity, a larger proportion of V3+/V4+, and more abundant oxygen vacancies result in an improved capacitive performance. Our proposed Cu-doped V2O5 (Cu-V2O5) can be used as both a positive electrode and a negative electrode for the assembly of the symmetric supercapacitor, which can be used as an energy storage device for light emitting diode lamps.

Biodeterioration of polyethylene by Bacillus cereus and Rhodococcus equi isolated from soil.

Polyethylene (PE), a non-biodegradable plastic, is widely used in agriculture as a mulch material, which causes serious plastic pollution when it is discarded. Recent studies have described the biodeterioration of PE by bacteria, but it is difficult for a single bacterial species to effectively degrade PE plastic. We isolated two strains with PE-degrading ability, Bacillus cereus (E1) and Rhodococcus equi (E3), from the soil attached to plastic waste on the south side of Mount Tai, China, using a medium with PE plastic as the only carbon source. By clear zone area analysis, we found that E1 mixed with E3 could improve the degradation of PE plastics. The mixture of E1 and E3 was incubated for 110 days in a medium containing PE and mulch film as the only carbon source, respectively. After 110 days, a decrease in pH and mass was observed. Obvious slits and depressions were observed on the surface of the PE film and the mulch films using scanning electron microscopy. The surface hydrophobicity of both films decreased, and FTIR revealed the formation of new oxidation groups on their surfaces during the degradation process and the destruction of the original CH2 long chains of PE. Besides, we found that surface of the mulch films contained more viable bacteria than the liquid medium. In conclusion, we identified two PE-degrading strains whose mixture can effectively degrade mulch film than pure PE film. Our results provide a reference for understanding PE plastic degradation pathways and their associated degradation processes.

Simultaneous quantification of six proteins related to liver injury using nano liquid chromatography-tandem mass spectrometry.

RATIONALE: In clinical diagnosis of liver injury, which is an important health concern, serum aminotransferase assays have been the go-to method used worldwide. However, the measurement of serum enzyme activity has limitations, including inadequate disease specificity and enzyme specificity. METHODS: With the high selectivity and specificity provided by nano liquid chromatography-tandem mass spectrometry (LC/MS/MS), this work describes a method for the simultaneous determination of six proteins in liver that can be potentially used as biomarkers for liver injury: glutamic-pyruvic transaminase 1 (GPT1), glutamic oxaloacetic transaminase 1 (GOT1), methionine adenosyl transferase 1A (MAT1A), glutathione peroxidase 1 (GPX1), cytokeratin 18 (KRT18) and apolipoprotein E (APOE). RESULTS: In validation, the method was shown to have good selectivity and sensitivity (limits of detection at pg/mL level). The analytical method revealed that, compared with normal mice, in carbon tetrachloride-induced acute liver injury mice, liver MAT1A and GPX1 were significantly lower (p < 0.01 and p < 0.05, respectively), KRT18 was significantly higher (p < 0.05) and APOE and GPT1 were marginally significantly lower (p between 0.05 and 0.1). This is the first work reporting the absolute contents of GPT1, GOT1, MAT1A, GPX1 and KRT18 proteins based on LC/MS. CONCLUSIONS: The proposed method provides a basis for establishing more specific diagnostic indicators of liver injury.

In vitro suppression of porcine epidemic diarrhea virus by Panax notoginseng saponins: assessing antiviral potential.

Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high mortality in neonatal suckling piglets, leading to significant economic losses to the swine industry. Panax notoginseng saponins (PNS) are bioactive extracts derived from the P. notoginseng plant. In this study, we investigated the anti-PEDV effect of PNS by employing various methodologies to assess their impact on PEDV in Vero cells. Using a CCK-8 (Cell Counting Kit-8) assay, we found that PNS had no significant cytotoxicity below the concentration of 128 µg/mL in Vero cells. Using immunofluorescence assays (IFAs), an enzyme-linked immunosorbent assay (ELISA), and plaque formation assays, we observed a dose-dependent inhibition of PEDV infection by PNS within 24-48 hours postinfection. PNS exerts its anti-PEDV activity specifically at the genome replication stage, and mRNA-seq analysis demonstrated that treatment with PNS resulted in increased expression of various genes, including IFIT1 (interferon-induced protein with tetratricopeptide repeats 1), IFIT3 (interferon-induced protein with tetratricopeptide repeats 3), CFH (complement factor H), IGSF10 (immunoglobulin superfamily member 10), ID2 (inhibitor of DNA binding 2), SPP1 (secreted phosphoprotein 1), PLCB4 (phospholipase C beta 4), and FABP4 (fatty acid binding protein 4), but it resulted in decreased expression of IL1A (interleukin 1 alpha), TNFRSF19 (TNF receptor superfamily member 19), CDH8 (cadherin 8), DDIT3 (DNA damage inducible transcript 3), GADD45A (growth arrest and DNA damage inducible alpha), PTPRG (protein tyrosine phosphatase receptor type G), PCK2 (phosphoenolpyruvate carboxykinase 2), and ADGRA2 (adhesion G protein-coupled receptor A2). This study provides insights into the potential mechanisms underlying the antiviral effects of PNS. Taken together, the results suggest that the PNS might effectively regulate the defense response to the virus and have potential to be used in antiviral therapies.

Design, selective synthesis and biological activities evaluation of novel thiazol-2-ylbenzamide and thiazole-2-ylbenzimidoyl chloride derivatives.

To promote the development and exploitation of novel antifungal agents, a series of thiazol-2-ylbenzamide derivatives (3A-3V) and thiazole-2-ylbenzimidoyl chloride derivatives (4A-4V) were designed and selective synthesis. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activities against five plant pathogenic fungi (Valsa mali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani and Trichoderma viride). The antifungal effects of compounds 3B (EC50 = 0.72 mg/L) and 4B (EC50 = 0.65 mg/L) against S. scleotiorum were comparable to succinate dehydrogenase inhibitors (SDHIs) thifluzamide (EC50 = 1.08 mg/L) and boscalid (EC50 = 0.78 mg/L). Especially, compounds 3B (EC50 = 0.87 mg/L) and 4B (EC50 = 1.08 mg/L) showed higher activity against R. solani than boscalid (EC50 = 2.25 mg/L). In vivo experiments in rice leaves revealed that compounds 3B (86.8 %) and 4B (85.3 %) exhibited excellent protective activities against R. solani comparable to thifluzamide (88.5 %). Scanning electron microscopy (SEM) results exhibited that compounds 3B and 4B dramatically disrupted the typical structure and morphology of R. solani mycelium. Molecular docking demonstrated that compounds 3B and 4B had significant interactions with succinate dehydrogenase (SDH). Meanwhile, SDH inhibition assay results further proved their potential as SDHIs. In addition, acute oral toxicity tests on A. mellifera L. showed only low toxicity for compounds 3B and 4B to A. mellifera L. populations. These results suggested that these two series of compounds had merit for further investigation as potential low-risk agricultural SDHI fungicides.

Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.