Metal-Free Perovskite Ferroelectrics with the Most Equivalent Polarization Axes.

Ferroelectricity in metal-free perovskites (MFPs) has emerged as an academic hotspot for their lightweight, eco-friendly processability, flexibility, and degradability, with considerable progress including large spontaneous polarization, high Curie temperature, large piezoelectric response, and tailoring coercive field. However, their equivalent polarization axes as a key indicator are far from enough, although multiaxial ferroelectrics are highly preferred for performance output and application flexibility that profit from as many equivalent polarization directions as possible with easier reorientation. Here, by implementing the synergistic overlap of regulating anionic geometries (from spherical I- to octahedral [PF6]- and to tetrahedral [ClO4]- or [BF4]-) and cationic asymmetric modification, we successfully designed multiaxial MFP ferroelectrics CMDABCO-NH4-X3 (CMDABCO = N-chloromethyl-N'-diazabicyclo[2.2.2]octonium; X = [ClO4]- or [BF4]-) with the lowest P1 symmetry. More impressively, systemic characterizations indicate that they possess 24 equivalent polarization axes (Aizu notations of 432F1 and m3̅mF1, respectively)─the maximum number achievable for ferroelectrics. Benefiting from the multiaxial feature, CMDABCO-NH4-[ClO4]3 has been demonstrated to have excellent piezoelectric sensing performance in its polycrystalline sample and prepared composite device. Our study provides a feasible strategy for designing multiaxial MFP ferroelectrics and highlights their great promise for use in microelectromechanical, sensing, and body-compatible devices.

Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice.

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring's PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection.

Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome.

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.

Nitrate promotes the growth and the production of short-chain fatty acids and tryptophan from commensal anaerobe Veillonella dispar in the lactate-deficient environment by facilitating the catabolism of glutamate and aspartate.

Veillonella spp. are nitrate-reducing bacteria with anaerobic respiratory activity that reduce nitrate to nitrite. They are obligate anaerobic, Gram-negative cocci that ferment lactate as the main carbon source and produce short-chain fatty acids (SCFAs). Commensal Veillonella reside in the human body site where lactate level is, however, limited for Veillonella growth. In this study, nitrate was shown to promote the anaerobic growth of Veillonella in the lactate-deficient media. We aimed to investigate the underlying mechanisms and the metabolism involved in nitrate respiration. Nitrate (15 mM) was demonstrated to promote Veillonella dispar growth and viability in the tryptone-yeast extract medium containing 0.5 mM L-lactate. Metabolite and transcriptomic analyses revealed nitrate enabled V. dispar to actively utilize glutamate and aspartate from the medium and secrete tryptophan. Glutamate or aspartate was further supplemented to a medium to investigate individual catabolism during nitrate respiration. Notably, nitrate was demonstrated to elevate SCFA production in the glutamate-supplemented medium, and further increase tryptophan production in the aspartate-supplemented medium. We proposed that the increased consumption of glutamate provided reducing power for nitrate respiration and aspartate served as a substrate for fumarate formation. Both glutamate and aspartate were incorporated into the central metabolic pathways via reverse tricarboxylic acid cycle and were linked with the increased production of acetate, propionate, and tryptophan. This study provides further understanding of the promoted growth and metabolic mechanisms by commensal V. dispar utilizing nitrate and specific amino acids to adapt to the lactate-deficient environment.IMPORTANCENitrate is a pivotal ecological factor influencing microbial community and metabolism. Dietary nitrate provides health benefits including anti-diabetic and anti-hypertensive effects via microbial-derived metabolites such as nitrite. Unraveling the impacts of nitrate on the growth and metabolism of human commensal bacteria is imperative to comprehend the intricate roles of nitrate in regulating microbial metabolism, community, and human health. Veillonella are lactate-utilizing, nitrate-reducing bacteria that are frequently found in the human body site where lactate levels are low and nitrate is at millimolar levels. Here, we comprehensively described the metabolic strategies employed by V. dispar to thrive in the lactate-deficient environment using nitrate respiration and catabolism of specific amino acids. The elevated production of SCFAs and tryptophan from amino acids during nitrate respiration of V. dispar further suggested the potential roles of nitrate and Veillonella in the promotion of human health.

Iodomethane in C1 chemistry: application in palladium-catalyzed [2 + 2 + 1] annulation.

An efficient palladium-catalyzed [2 + 2 + 1] annulation of 3-iodochromones, bridged olefins, and iodomethane is described, affording a range of chromone-containing polycyclic compounds. Additionally, the corresponding deuterated products were smoothly obtained with iodomethane-d3 instead of iodomethane. Moreover, the synthetic utility of this method is further substantiated by gram scale preparation and application to late-stage modification of estrone.

EGR1 transcriptionally regulates SVEP1 to promote proliferation and migration in human coronary artery smooth muscle cells.

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1) is associated with the risk of coronary artery disease, as determined by a genome-wide association study. SVEP1 induces vascular smooth muscle cell proliferation and an inflammatory phenotype to promote atherosclerosis. In the present study, qRT‒PCR demonstrated that the mRNA expression of SVEP1 was significantly increased in atherosclerotic plaques compared to normal tissues. Bioinformatics revealed that EGR1 was a transcription factor for SVEP1. The results of the luciferase reporter assay, siRNA interference or overexpression assay, mutational analysis and ChIP confirmed that EGR1 positively regulated the transcriptional activity of SVEP1 by directly binding to its promoter. EGR1 promoted human coronary artery smooth muscle cell (HCASMC) proliferation and migration via SVEP1 in response to oxidized low-density lipoprotein (ox-LDL) treatment. Moreover, the expression level of EGR1 was increased in atherosclerotic plaques and showed a strong linear correlation with the expression of SVEP1. Our findings indicated that EGR1 binding to the promoter region drive SVEP1 transcription to promote HCASMC proliferation and migration.

Disease Duration Affects the Clinical Phenotype of Primary Sjögren Syndrome: A Medical Records Review Study of 952 Cases.

OBJECTIVES: To investigate the impact of disease duration on clinical phenotypes in Chinese patients with primary Sjögren syndrome (pSS) and examine the correlation between clinical phenotypes and onset age, age at diagnosis, and disease duration. METHODS: Data from 952 patients diagnosed with pSS in China between January 2013 and March 2022 were analyzed based on medical records. Patients were categorized into 3 groups based on disease duration: short (<5 years), moderate (≥5 and <10 years), and long (≥10 years) group. Clinical characteristics were compared among the 3 groups, and pSS patients with a long disease duration were compared with the other patients after matching age at diagnosis and age at onset. RESULTS: Among the patients, 20.4% had a disease duration over 10 years. After matching for age at onset and age at diagnosis, pSS patients with a long disease duration exhibited a significantly higher prevalence of dry mouth ( p <0.001), dry eyes ( p <0.001), fatigue ( p <0.001), arthralgia ( p <0.001), and dental caries ( p <0.001) and higher rates of anti-Sjögren syndrome A ( p < 0.05), anti-Ro52 ( p < 0.05), and anti-SSB ( p < 0.05) positivity than their control groups, with prevalence increasing with disease duration ( ptrend < 0.001). However, no differences were noted in the prevalence of interstitial lung disease and leukopenia between different disease duration groups after matching for age at onset, although differences were shown when matching for age at diagnosis. CONCLUSION: Longer disease duration in pSS patients correlates with increased prevalence of sicca symptoms, fatigue, and arthralgia and higher positivity of autoantibodies associated with pSS. However, the prevalence of interstitial lung disease and leukopenia did not correlate with disease duration after matching for age at onset.

Fibroblast growth factor 5 as a target for atrial fibrillation treatment: Evidence from mendelian randomization.

BACKGROUND: Previous studies have found that inflammatory proteins are involved in the pathogenesis of atrial fibrillation (AF). We used mendelian randomization to explore the potential pathogenic inflammatory proteins of AF. METHODS: This study adopts a Mendelian randomization design to primarily assess causal associations using the Wald ratio and the inverse variance weighting method. It leverages protein quantitative trait locus (pQTL) data encompassing 91 types of inflammatory proteins from 14,824 participants of European ancestry. The primary analysis phase utilizes AF GWAS data from 55,106 participants, with an additional 237,690 participants included in the validation stage. Sensitivity analyses, including reverse causality analysis, Bayesian colocalization analysis, and phenotype scanning, were conducted. Finally, the study explores potential targeted drugs. RESULTS: The findings highlight a causal link between 7 inflammatory proteins and AF, with 2 showing positive correlations and 5 exhibiting negative correlations. Among these, fibroblast growth factor 5 (FGF5) emerges as particularly robust in sensitivity analysis. Colocalization analysis indicates a shared genetic variation between FGF5 and AF, supporting its potential as a targeted therapy for AF. Importantly, this causal relationship remains unaffected by reverse causality. Furthermore, significant pleiotropic effects were observed in phenotype scanning. Finally, the causal association between FGF5 and AF was successfully replicated during the validation phase. CONCLUSION: FGF5 may become an intervention target for AF targeted therapy.

Preparation of catalyst for CO2 hydrogenation reaction based on the idea of element sharing and preliminary exploration of catalytic mechanism.

Under the background of the continuous rise of CO2 annual emissions, the development of CO2 capture and utilization technology is urgent. This study focuses on improving the catalytic capacity of the catalyst for CO2 hydrogenation, improving the efficiency of CO2 conversion to methanol, and converting H2 into chemical substances to avoid the danger of H2 storage. Based on the concept of element sharing, the ASMZ (Aluminum Shares Metal Zeolite catalysts) series catalyst was prepared by combining the CuO-ZnO-Al2O3 catalyst with the ZSM-5 zeolite using the amphoteric metal properties of the Al element. The basic structural properties of ASMZ catalysts were compared by XRD, FTIR, and BET characterization. Catalytic properties of samples were measured on a micro fixed-bed reactor. The catalytic mechanism of the catalyst was further analyzed by SEM, TEM, XPS, H2-TPR, and NH3-TPD. The results show that the ASMZ3 catalyst had the highest CO2 conversion rate (26.4%), the highest methanol selectivity (76.0%), and the lowest CO selectivity (15.3%) in this study. This is mainly due to the fact that the preparation method in this study promotes the exposure of effective weakly acidic sites and medium strength acidic sites (facilitating the hydrogenation of CO2 to methanol). At the same time, the close binding of Cu-ZnO-Al2O3 (CZA) and ZSM-5 zeolite also ensures the timely transfer of catalytic products and ensures the timely play of various catalytic active centers. The preparation method of the catalyst in this study also provides ideas for the preparation of other catalysts.

Precision targeting in oncology: The future of conjugated drugs.

Coupled drugs, especially antibody-coupled drugs (ADCs), are a hot topic in oncology. As the development of ADCs has progressed, different coupling modes have emerged, inspired by their structural design have emerged. Technological advances have led to interweaving and collision of old and new concepts of coupled drugs, and have even challenged the concepts and techniques of coupled drugs at this stage. For example, antibody-oligonucleotide conjugates are a new class of chimeric biomolecules synthesized by coupling oligonucleotides with monoclonal antibodies through linkers, offering precise targeting and improved pharmacokinetic properties. This study aimed to elucidate the mechanism of action of coupled drugs and their current development status in antitumor therapy to provide better strategies for antitumor therapy.

Comparative effectiveness of ehealth self-management interventions for patients with heart failure: A Bayesian network meta-analysis.

OBJECTIVE: This study evaluated the effectiveness of electronic self-management support interventions in reducing all-cause mortality, cardiovascular mortality, readmission rates, and HF-related readmission in heart failure patients. METHODS: Following the PRISMA-P guidelines and PRISMS taxonomy, we searched Pubmed, Cochrane Library, and Embase for RCTs and trials of electronic health technologies for heart failure interventions. Develop support programs in advance for education, monitoring, reminders, or a combination of these to screen and categorize studies. The Cochrane ROB2 tool was used to assess the risk of bias. RESULTS: The monitoring interventions may improve all-cause mortality (OR 0.77, 95% CI 0.63 to 0.93) and cardiovascular mortality (OR 0.75, 95% CI 0.61 to 0.93) compared to usual care. Reminder interventions were associated with significantly reducing readmission rates (OR 0.07, 95% CI 0.00 to 0.94). Mixed interventions were most effective in reducing HF-related readmission rates (OR 0.75, 95% CI 0.56 to 0.99). CONCLUSION: Electronic self-management interventions, particularly monitoring and reminders, can potentially improve outcomes of heart failure patients, including reducing all-cause mortality, cardiovascular mortality, and readmission rates. PRACTICE IMPLICATIONS: The eHealth model and the combination of self-management are significant for long-term intervention in patients with HF to improve their quality of life and prognosis.

Mutualistic interactions of lactate-producing lactobacilli and lactate-utilizing Veillonella dispar: Lactate and glutamate cross-feeding for the enhanced growth and short-chain fatty acid production.

The human gut hosts numerous ecological niches for microbe-microbe and host-microbe interactions. Gut lactate homeostasis in humans is crucial and relies on various bacteria. Veillonella spp., gut lactate-utilizing bacteria, and lactate-producing bacteria were frequently co-isolated. A recent clinical trial has revealed that lactate-producing bacteria in humans cross-feed lactate to Veillonella spp.; however, their interspecies interaction mechanisms remain unclear. Veillonella dispar, an obligate anaerobe commonly found in the human gut and oral cavity, ferments lactate into acetate and propionate. In our study, we investigated the interaction between V. dispar ATCC 17748T and three representative phylogenetically distant strains of lactic acid bacteria, Lactobacillus acidophilus ATCC 4356T, Lacticaseibacillus paracasei subsp. paracasei ATCC 27216T, and Lactiplantibacillus plantarum ATCC 10241. Bacterial growth, viability, metabolism and gene level adaptations during bacterial interaction were examined. V. dispar exhibited the highest degree of mutualism with L. acidophilus. During co-culture of V. dispar with L. acidophilus, both bacteria exhibited enhanced growth and increased viability. V. dispar demonstrated an upregulation of amino acid biosynthesis pathways and the aspartate catabolic pathway. L. acidophilus also showed a considerable number of upregulated genes related to growth and lactate fermentation. Our results support that V. dispar is able to enhance the fermentative capability of L. acidophilus by presumably consuming the produced lactate, and that L. acidophilus cross-feed not only lactate, but also glutamate, to V. dispar during co-culture. The cross-fed glutamate enters the central carbon metabolism in V. dispar. These findings highlight an intricate metabolic relationship characterized by cross-feeding of lactate and glutamate in parallel with considerable gene regulation within both L. acidophilus (lactate-producing) and V. dispar (lactate-utilizing). The mechanisms of mutualistic interactions between a traditional probiotic bacterium and a potential next-generation probiotic bacterium were elucidated in the production of short-chain fatty acids.

Computed tomography-based radiomics combined with machine learning allows differentiation between primary intestinal lymphoma and Crohn's disease.

BACKGROUND: Due to similar clinical manifestations and imaging signs, differential diagnosis of primary intestinal lymphoma (PIL) and Crohn's disease (CD) is a challenge in clinical practice. AIM: To investigate the ability of radiomics combined with machine learning methods to differentiate PIL from CD. METHODS: We collected contrast-enhanced computed tomography (CECT) and clinical data from 120 patients form center 1. A total of 944 features were extracted single-phase images of CECT scans. Using the last absolute shrinkage and selection operator model, the best predictive radiographic features and clinical indications were screened. Data from 54 patients were collected at center 2 as an external validation set to verify the robustness of the model. The area under the receiver operating characteristic curve, accuracy, sensitivity and specificity were used for evaluation. RESULTS: A total of five machine learning models were built to distinguish PIL from CD. Based on the results from the test group, most models performed well with a large area under the curve (AUC) (> 0.850) and high accuracy (> 0.900). The combined clinical and radiomics model (AUC = 1.000, accuracy = 1.000) was the best model among all models. CONCLUSION: Based on machine learning, a model combining clinical data with radiologic features was constructed that can effectively differentiate PIL from CD.

A Report of Two Cases of Meningoencephalitis Caused by Streptococcus intermedius.

Objective: In this paper, we analyzed the clinical data of patients with meningoencephalitis caused by Streptococcus intermedius to understand better the clinical characteristics of the disease and recommend auxiliary diagnostic mode as well as treatment experience. Methods: We reviewed the clinical data of two patients admitted to our department in 2019 with meningoencephalitis caused by S. intermedius. Results: Two female patients were examined, one of whom had a history of radiotherapy for nasopharyngeal carcinoma while the other had no underlying disease. These two patients were admitted with symptoms of meningoencephalitis. Cerebrospinal fluid examinations revealed elevated levels of leukocytes and protein. After treatment with meropenem, the condition improved for a brief time, but then worsened with a decline in mental status and limb movement. Blood and cerebrospinal fluid cultures demonstrated the absence of pathogenic bacteria, while genome sequencing of cerebrospinal fluids revealed the presence of S. intermedius. Cranial magnetic resonance imaging revealed multiple cerebral abscesses (CAs). After coadministration of linezolid as an anti-infective, clinical symptoms gradually improved, and the CAs shrank on follow-up imaging. The condition exhibited a pattern of improvement-deterioration-improvement. Conclusion: Meningoencephalitis caused by S. intermedius is complex and prone to fluctuation and formation of multiple CAs. The definitive clinical diagnosis of this disease can be aided by genome sequencing technology, and early clarification of the etiology combined with the use of potent antibiotics is effective.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

Improving sarcopenia in older adults: a systematic review and meta-analysis of randomized controlled trials of whey protein supplementation with or without resistance training.

OBJECTIVES: The aim of the study was to comprehensively analyze the effects of whey protein (WP)-enriched supplement intake with or without resistance training (RT) in older patients, either from the community or hospital, who were diagnosed with sarcopenia according to the EWGSOP or AWGS criteria. METHODS: This meta-analysis study was registered in PROSPERO (CRD42023407885). We searched the PubMed, Embase, Web of Science, and Cochrane Library databases for RCTs up to June 1, 2023. Standardized mean differences (SMD) with 95% confidence intervals (CI) were used to estimate the pooled results. RESULTS: Ten RCT studies, including 1154 participants, were included and analyzed. The primary outcomes were the changes in muscle mass, strength, and physical performance. In WP group versus (vs.) Isocaloric placebo (PLA)/Routine consultation (RC) group, WP significantly increased the appendicular skeletal muscle mass index (SMD: 0.47, 95%CI: 0.23, 0.71), appendicular skeletal muscle mass (SMD: 0.28, 95%CI: 0.11, 0.45) and gait speed (SMD: 1.13, 95%CI: 0.82, 1.44) in older patients with sarcopenia. In WP with RT group vs. PLA/ RC group, there was significant increase in handgrip strength (SMD: 0.67, 95%CI: 0.29, 1.04). In addition, in the secondary outcomes, WP significantly reduced interleukin-6, significantly increased insulin-like growth factor-1 and albumin, promoted participants' intake of total energy and protein, enhanced activities of daily living scores in patients, and had no significant effect on BMI, weight, or fat mass. CONCLUSION: This review confirms that WP can improve various aspects of older adult with sarcopenia, thereby enhancing their overall physical condition. More studies should be conducted to validate this result and further explore the effects of WP and RT in patients with sarcopenia.

Synthesis and antiproliferative evaluation of new hybrids of piperine and acylhydrazone.

Piperine, a natural amide isolated from the genus of Piper, serves as a pharmacophore in medicinal chemistry. In this study, we synthesised and evaluated 18 novel piperine-acylhydrazone hybrids (4a-4r) for their antiproliferative activities in vitro. The structures of these hybrids were validated using 1H,13C NMR, and HR-ESI-MS data. Furthermore, we screened all synthesised compounds for their antiproliferative activities against three human cancer cell lines: FaDu (laryngeal carcinoma cells), HepG2 (hepatoblastoma carcinoma cells), and MGC803 (gastric carcinoma cells). Among them, compound 4o exhibited significantly inhibitory activities against FaDu, HepG2, and MGC803 with IC50 values of 13.85 ± 0.19, 11.02 ± 1.45, and 13.47 ± 3.43 µM, respectively, which was approximately two-fold lower than the positive control cisplatin. These findings suggest that compound 4o has the potential to be promising leads for the design of anti-cancer drugs.

ETS1 and RBPJ transcriptionally regulate METTL14 to suppress TGF-ß1-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling. Epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is considered to be a crucial player in asthma. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, is implicated in multiple pathological processes, including EMT, cell proliferation and migration. However, the role of METTL14 in asthma remains uncertain. This research aimed to explore the biological functions of METTL14 in asthma and its underlying upstream mechanisms. METTL14 expression was down-regulated in asthmatic from three GEO datasets (GSE104468, GSE165934, and GSE74986). Consistent with this trend, METTL14 was decreased in the lung tissues of OVA-induced asthmatic mice and transforming growth factor-ß1 (TGF-ß1)-stimulated human bronchial epithelial cells (Beas-2B) in this study. Overexpression of METTL14 caused reduction in mesenchymal markers (FN1, N-cad, Col-1 and α-SMA) in TGF-ß1-treated cells, but caused increase in epithelial markers (E-cad), thus inhibiting EMT. Also, METTL14 suppressed the proliferation and migration ability of TGF-ß1-treated Beas-2B cells. Two transcription factors, ETS1 and RBPJ, could both bind to the promoter region of METTL14 and drive its expression. Elevating METTL14 expression could reversed EMT, cell proliferation and migration promoted by ETS1 or RBPJ deficiency. These results indicate that the ETS1/METTL14 and RBPJ/METTL14 transcription axes exhibit anti-EMT, anti-proliferation and anti-migration functions in TGF-ß1-induced bronchial epithelial cells, implying that METTL14 may be considered an alternative candidate target for the treatment of asthma.

[Effects of Organic Fertilizer of Kitchen Waste on Soil Microbial Activity and Function].

Changes in soil microbial activity and ecological function can be used to assess the level of soil fertility and the stability of ecosystems. To assess the fertility and safety of organic fertilizer of kitchen waste (OFK), soils containing 0% (CK), 1%, 3%, and 5% OFK were cultured, and the physical, chemical, and microbial properties of the soils were measured dynamically with routine agrochemical analysis measures and amplicon sequencing. The results showed that compared with those in CK, the contents of organic matter, available phosphorus, available potassium, NH4+-N, and NO3--N in soils with OFK increased by 23.80%-35.13%, 13.29%-29.72%, 16.91%-39.37%, 164.7%-340.2%, and 28.56%-32.71%, respectively. The activities of hydrolases related to the cycle of carbon, nitrogen, and phosphorus (α-glucosidase, leucine aminopeptidase, acid phosphatase, etc.) were also significantly higher than those of the CK treatment. OFK stimulated the growth of soil microorganisms and increased the carbon content of the microbial biomass. The amplicon sequencing analysis found that the microbial community structures of different treatments were significantly different at both the class and genus levels. In addition, it was found that the abundance of beneficial microbes in the soils with OFK increased, whereas pathogenic microbes decreased. RDA results confirmed that soil properties (including soil pH, organic matter, available nutrients, and microbial biomass) had a significant impact on microbial community structure. The results of investing bacterial community based on PICRUSt and FAPROTAX revealed that the function of the soil bacterial community was similar in the four treatments, but OFK supply significantly improved the microbial carbon utilization and metabolic ability. Moreover, by using the FUNGuild software, we found that the application of OFK increased the proportion of saprotroph-symbiotroph and symbiotroph and stimulated the growth of ectomycorrhizal fungi-undefined saprophytic fungi but inhibited plant and animal pathogenic fungi in soil. These results implied that OFK could promote the establishment of symbiotic relationships and inhibit the growth of pathogenic fungi. In summary, OFK could improve soil fertility and hydrolase activity, stimulate the growth of beneficial microorganisms, and defend against pathogens, indicating a promising use as safe and efficient organic fertilizer.