Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents.

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.

Silage Fermentation: A Potential Biological Approach for the Long-Term Preservation and Recycling of Polyphenols and Terpenes in Globe Artichoke (Cynara scolymus L.) By-Products.

An economic and effective method for storage is necessary to make full use of the nature of active components in artichoke by-products and ease environmental pressure. In this paper, the potential of silage fermentation for the preservation and recycling of polyphenols and terpenes in artichoke by-products is evaluated. The silage of artichoke by-products is characterized by lactic acid bacteria fermentation. Silage distinctly increases the abundance of lactic acid bacteria in artichoke by-products, such as Lactobacillus, Lactococcus, Serratia, and Weissella, and greatly increases the abundance of Firmicutes. The improvement of the microorgan structure and composition is of great significance for the quality of artichoke by-products. Polyphenols in the stems and leaves of artichokes are preserved well in silage. Among the 18 polyphenol compounds detected by high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-QqQ-MS/MS), the contents of 11 phenolic acids and four flavonoids increased significantly. For terpenes detected by gas chromatography-mass spectrometry (GC-MS), the contents of four pentacyclic triterpenoids increased significantly, while two sterols were kept stable in the silage process. Silage is a potential biotechnology for the long-term preservation of bioactive components, such as polyphenols and terpenes in artichoke by-products, and the results provide a scientific basis for the efficient utilization of by-products.

The pelvic radius technique in the assessment of spinopelvic sagittal alignment of degenerative spondylolisthesis and lumbar spinal stenosis.

BACKGROUND: Degenerative spondylolisthesis (DS) and lumbar spinal stenosis (LSS) are the most common degenerative spinal diseases. The evaluating of spinopelvic sagittal alignment of the two diseases using pelvic radius (PR) technique have not been reported. The purpose of this study was to use PR measurement technique to compare the differences in spinopelvic sagittal alignment between DS and LSS. METHODS: A total of 145 patients with DS or LSS were retrospectively reviewed. Seventy patients with DS (DS group) and 75 age-matched patients with LSS (LSS group) were enrolled. Spinopelvic parameters including pelvic angle (PA), regional lumbopelvic lordosis (PR-L1, PR-L2, PR-L3, PR-L4 and PR-L5), total lumbopelvic lordosis (PR-T12), pelvic morphology (PR-S1), sagittal vertical axis from the C7 plumb line (SVA), lumbar lordosis (LL), thoracic kyphosis (TK), L4 slope and L5 slope were assessed in the two groups. Several parameters of DS and LSS group were compared with the normal population (NP). RESULTS: The PR-L4, PR-L5 and PR-S1 in the DS group were significantly smaller than those in the LSS group. There was no difference in PR-T12 between the DS group and NP (p > 0.05), while PR-T12 of the LSS group were significantly lower (p < 0.01). Degree of correlations among spinopelvic parameters differed between the two groups. PR-T12 of the DS group was more strongly correlated with PA (r = -0.829, p < 0.001) than with LL (r = 0.664, p < 0.001), TK (r = 0.582, p < 0.001). PR-T12 of the LSS group was more strongly correlated with LL (r = 0.854, p < 0.001), TK (r = 0.616, p < 0.001) than with PA (r = -0.582, p < 0.001). CONCLUSIONS: PR-L4 and PR-L5 may be the predisposing factors for DS development. Spinopelvic morphology differed in patients with DS and LSS compared to NP. The compensatory mechanisms to maintain spinopelvic sagittal alignment in DS and LSS patients may be different.

Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader.

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.

The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.

Superhydrophobic PVDF membrane formed by crystallization process for direct contact membrane distillation.

With growing demand for freshwater resources, membrane distillation (MD) attracts intensive attention owing to the possibility of reclaiming almost 100% freshwater with superhydrophobic membranes as the pivotal separation units. Current superhydrophobic membrane still suffers relatively complex preparation process and limited membrane flux. Herein, we developed a promising route to fabricate a high-flux superhydrophobic poly(vinylidene fluoride) (PVDF) membrane by a simple solute and solvent co-crystallization (SSCC) method, which endowed the membrane ultra-high porosity and flux. We also found that the pore size of superhydrophobic membrane can be adjusted by controlling the crystallization process of DMSO, which gave rise to membrane higher flexibility. The membrane exhibited the outperforming desalination performance even in multiple harsh environments including different temperature, salty concentration, and pH, with/without humic acid. The membrane also displayed distinguished anti-fouling performance and long-term stability, which is quite significant for practical application.

Flavor Profile Evaluation of Soaked Greengage Wine with Different Base Liquor Treatments Using Principal Component Analysis and Heatmap Analysis.

The selection of base liquor plays a crucial role in the flavor of soaked greengage wine. This study aimed to investigate the effects of different base liquor treatments on the physicochemical characteristics and aroma composition of greengage wine. We carried out a comprehensive analysis using HPLC for the determination of organic acids and GC-MS for the determination of volatile aroma compounds, combined with sensory evaluation. The results showed that the red and yellow colors were the darkest in the high-alcohol group, while the citric acid content was the highest in the sake group (21.95 ± 2.19 g/L). In addition, the greengage wine steeped in 50% edible alcohol had more terpenes, a significantly higher concentration of acid-lipid compounds, and a more intense aroma compared to that of the low-alcohol group, whose typical aroma compounds were greatly reduced. The sensory results showed that the greengage wine treated with baijiu had a distinct alcoholic flavor, while almond flavors were more intense in the greengage wine treated with 15% edible alcohol. In this study, base liquor was used as the main influencing factor to provide new research ideas for the flavor optimization of soaked greengage wine.

Family characteristics in adolescents with overweight or obesity: a network analysis.

Background: Rates of overweight and obesity continue to grow in adolescents. Overweight and obesity in adolescence are associated with numerous immediate and long-term adverse health conditions. Throughout adolescence, parents and the family have an important and central influence on adolescents' health and lifestyle. The home environment may be a major factor in shaping children's weight. However, our current understanding of the interplay between family-related variables in adolescents with overweight or obesity is limited and fragmented. This study aimed to assess the relationship between family-related variables in adolescents who are overweight or obese using network analysis and inform future health promotion for family-based intervention. Methods: Participants (n = 488) were recruited from middle schools in Nanjing from October 2022 to March 2023. Participants, together with their parents, completed a questionnaire at school about the family food environment, family size, family APGAR index, family physical activity facilities, parental mental health, rearing behavior, parental weight status, drinking history, marital satisfaction, and sociodemographic characteristics. Results: The network split into three distinct communities of items. Network analysis showed that parental mental health and paternal rearing styles-rejection were the most central nodes in the network. In contrast, maternal weight status was the most peripheral and least connected nodes. Conclusion: Family-related variables constituted a connected network in adolescents with overweight or obesity. The pattern of network node connections supports that interventions could prioritize targeting changing parental mental health and paternal rearing styles in adolescents with overweight or obesity.

The plasmid-encoded lactose operon plays a vital role in the acid production rate of Lacticaseibacillus casei during milk beverage fermentation.

Lacticaseibacillus casei is used extensively in the fermented milk-beverage industry as a starter culture. Acid production capacity during fermentation is the main criterion for evaluating starters although it is strain-dependent. In this study, the acid production rates of 114 L. casei strains were determined and then classified into high acid (HC), medium acid (MC), and low acid (LC) groups. Comparative genomics analysis found that the lac operon genes encoding the phosphoenolpyruvate-lactose phosphotransferase system (PTSLac) were located on plasmids in the HC strains; however, it is notable that the corresponding operons were located on the chromosome in LC strains. Real-time PCR analysis showed that the copy numbers of lac operon genes in HC strains were between 3.1 and 9.3. To investigate the relationship between copy number and acid production rate, the lac operon cluster of the HC group was constitutively expressed in LC strains. The resulting copy numbers of lac operon genes were between 15.8 and 18.1; phospho-ß-galactosidase activity increased by 1.68-1.99-fold; and the acid production rates increased by 1.24-1.40-fold, which enhanced the utilization rate of lactose from 17.5 to 42.6% in the recombinant strains. The markedly increased expression of lac operon genes increased lactose catabolism and thereby increased the acid production rate of L. casei.

Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells.

EGFR inhibitor therapies have brought significant benefit to NSCLC patients. However, all patients gradually progress to acquired resistance via diverse mechanisms. Akt3 overexpression but not Akt1/2 is one of the found molecular events that mediate osimertinib (1) resistance in NSCLC patients. Here, we report 12l as the first bona fide isoform-selective Akt3 degrader which potently induced proteasomal degradation of the target both in vitro and in vivo, whereas its effects on Akt1/2 were minimal. Using 12l as a tool, non-canonical function of Akt3 was validated to contribute greatly to survival of 1-resistant H1975OR NSCLC cells. Degrader 12l potently suppressed the growth of H1975OR as well as several NSCLC cell lines with low nanomolar IC50 values and demonstrated promising in vivo antitumor efficacy in nude mice bearing H1975OR or PC9 NSCLC xenograft models. Selective degradation of Akt3 may be considered as a novel strategy for human cancer therapy.

Minimizing greenhouse gas emission from wastewater treatment process by integrating activated sludge and microalgae processes.

A novel integrated microalgae and activated sludge (MA/AS) system was constructed to minimize greenhouse gas emission from traditional wastewater treatment plants. Its removal properties for aqueous pollutants were assessed as well. The ratio of microalgae-to-activated sludge volatile suspended solids of 1.3 and an incident light intensity of 12 W/m2 provided the best performance: COD, NH4+, and total phosphorus (TP) removals were up to 100%, 99.6% and 100%, respectively. Even without illumination, COD, NH4+, and TP removal efficiencies were as high as 95.1%, 96.5% and 100%, respectively. In both cases, nutrient uptake by MA was proved to play an important role in nutrients removal. And no CH4 or N2O emissions were detected during the whole experimental period of the MA/AS system (mass ratio of 1.3:1). Only negligible CO2 was detected up to 45 µmol with illumination and 130 µmol without illumination in the headspace of the serum bottles, which merely accounted for 2.0% and 5.8% of the initial total carbon equivalent (glucose serving as organic carbon source). Since photosynthesis by microalgae could provide oxygen to heterotrophs or nitrifying bacteria, extra energy demand (mainly from aeration units) could be greatly cut down, which would heavily reduce the total energy demands and further indirect CO2 emission from wastewater treatment plants. Our integrated system is demonstrated to be a sustainable approach for contaminants removal from aqueous phase, restraining greenhouse gas emission and saving energy consumption contemporaneously.

Enhanced Acid Tolerance in Bifidobacterium longum by Adaptive Evolution: Comparison of the Genes between the Acid-Resistant Variant and Wild-Type Strain.

Acid stress can affect the viability of probiotics, especially Bifidobacterium. This study aimed to improve the acid tolerance of Bifidobacterium longum BBMN68 using adaptive evolution. The stress response, and genomic differences of the parental strain and the variant strain were compared by acid stress. The highest acid-resistant mutant strain (BBMN68m) was isolated from more than 100 asexual lines, which were adaptive to the acid stress for 10(th), 20(th), 30(th), 40(th), and 50(th) repeats, respectively. The variant strain showed a significant increase in acid tolerance under conditions of pH 2.5 for 2 h (from 7.92 to 4.44 log CFU/ml) compared with the wildtype strain (WT, from 7.87 to 0 log CFU/ml). The surface of the variant strain was also smoother. Comparative whole-genome analysis showed that the galactosyl transferase D gene (cpsD, bbmn68_1012), a key gene involved in exopolysaccharide (EPS) synthesis, was altered by two nucleotides in the mutant, causing alteration in amino acids, pI (from 8.94 to 9.19), and predicted protein structure. Meanwhile, cpsD expression and EPS production were also reduced in the variant strain (p < 0.05) compared with WT, and the exogenous WT-EPS in the variant strain reduced its acid-resistant ability. These results suggested EPS was related to acid responses of BBMN68.

Complete genome sequence of Lactobacillus paracasei L9, a new probiotic strain with high lactic acid-producing capacity.

Lactobaillus paracasei L9 (CGMCC No. 9800) is a new strain with probiotic properties originating from healthy human intestine. Previous studies evidenced that the strain regulates immune modulation and contributes to the production of high amounts of lactic acid. The genome of L. paracasei L9 contains a circular 3076,437-bp chromosome, encoding 3044 CDSs, 15 rRNA genes and 59 tRNA genes.