Stabilized Carbon-Centered Radical-Mediated Carbosulfenylation of Styrenes: Modular Synthesis of Sulfur-Containing Glycine and Peptide Derivatives.

Sulfur-containing amino acids and peptides play critical roles in organisms. Thiol-ene reactions between the thiol residues of L-cysteine and the alkenyl fragments in the designed coupling partners serve as primary tools for constructing C─S bonds in the synthesis of unnatural sulfur-containing amino acid derivatives. These reactions are favored due to the preference for hydrogen transfer from thiol to ß-sulfanyl carbon radical intermediates. In this paper, the study proposes utilizing carbon-centered radicals stabilized by the capto-dative effect, generated under photocatalytic conditions from N-aryl glycine derivatives. The aim is to compete with the thiol hydrogen, enabling radical C─C bond formation with ß-sulfanyl carbon radicals. This protocol is robust in the presence of air and water, offers significant potential as a modular and efficient platform for synthesizing sulfur-containing amino acids and modifying peptides, particularly with abundant disulfides and styrenes.

An Aging-Related lncRNA Signature Establishing for Breast Cancer Prognosis and Immunotherapy Responsiveness Prediction.

Purpose: Emerging evidence demonstrates the vital role of aging and long non-coding RNAs (lncRNAs) in breast cancer (BC) progression. Our study intended to develop a prognostic risk model based on aging-related lncRNAs (AG-lncs) to foresee BC patients' outcomes. Patients and Methods: 307 aging-related genes (AGs) were sequenced from the TCGA project. Then, 697 AG-lncs were identified by the co-expression analysis with AGs. Using multivariate and univariate Cox regression analysis, and LASSO, 6 AG-lncs, including al136531.1, mapt-as1, al451085.2, otud6b-as1, tnfrsf14-as1, and linc01871, were validated to compute the risk score and establish a risk signature. Expression levels of al136531.1, mapt-as1, al451085.2, tnfrsf14-as1, and linc01871 were higher in low-risk BC patients, whereas otud6b-as1 expression was higher in high-risk BC patients. In the training and testing set, high-risk patients performed shorter PFI, OS, and DFS than low-risk patients. Results: Our risk signature had the highest concordance index among other established prognostic signatures and displayed ideal predictive ability for 1-, 3- and 5-year patient OS in the nomogram. Additionally, BC patients with different risk score levels showed different immune statuses and responses to immunotherapy via GSEA, ssGSEA, ESTIMATE algorithm, and TIDE algorithm analysis. Of note, the qRT-PCR analysis validated that these 6 AG-lncs expressed quite differentially in BC tissues at various clinical stages. Conclusion: The risk signature of 6 AG-lncs might offer a novel prognostic biomarker and promisingly enhance BC immunotherapy's effectiveness.

New insight into molecular mechanisms of different polyphenols affecting Sirtuin 3 deacetylation activity.

Multiple phenolic substances have been shown to promote SIRT3 expression, however, few studies have focused on the effects of these phenolics on SIRT3 enzyme activity. This study constructed a variety of reaction systems to elucidate the mechanisms by which different polyphenols affect SIRT3 enzyme activity. The results showed that acP53317-320 was the most suitable substrate among the five acetylated peptide substrates (Kcat/Km = 74.85 ± 1.86 M-1•s-1). All the phenolic compounds involved in the experiment inhibited the enzymatic activity of SIRT3, and the lowest IC50 among them was quercetin (0.12 ± 0.01 mM) and the highest was piceatannol (1.29 ± 0.08 mM). Their inhibition types were mainly competitive and mixed. In addition, piceatannol was found to be a natural SIRT3 agonist by enzyme kinetic analysis and validation of deacetylation efficiency. This study will provide a useful reference for polyphenol modulation of SIRT3 dosage, as well as the development and application of polyphenol-based SIRT3 activators and agonists.

Synthesis and Antifungal Activity of Norbornene Carboxamide/sulfonamide Derivatives as Potential Fungicides Targeting Laccase.

To explore more potential fungicides with new scaffolds, thirty-seven norbornene carboxamide/sulfonamide derivatives were designed, synthesized, and assayed for inhibitory activity against six plant pathogenic fungi and oomycetes. The preliminary antifungal assay suggested that the title derivatives showed moderate to good antifungal activity against six plant pathogens. Especially, compound 6 e presented excellent in vitro antifungal activity against Sclerotinia sclerotiorum (EC50=0.71 mg/L), which was substantially stronger than pydiflumetofen. In vivo antifungal assay indicated 6 e displayed prominent protective and curative effects on rape leaves infected by S. sclerotiorum. The preliminary mechanism research displayed that 6 e could damage the surface morphology and inhibit the sclerotia formation of S. sclerotiorum. In addition, the in vitro enzyme inhibition bioassay indicated that 6 e displayed pronounced laccase inhibition activity (IC50=0.63 µM), much stronger than positive control cysteine. Molecular docking elucidated the binding modes between 6 e and laccase. The bioassay results and mechanism investigation demonstrated that this class of norbornene carboxamide/sulfonamide derivatives could be promising laccase inhibitors for novel fungicide development.

Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors.

BACKGROUND: To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens. RESULTS: In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC50) of 0.17 mg L-1, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC50) of 1.02 µM, much stronger than that of positive control cysteine (IC50 = 35.50 µM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking. CONCLUSION: This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry.

RGIE: A Gene Selection Method Related to Radiotherapy Resistance in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Head and Neck Squamous Cell Carcinoma (HNSCC) is a malignant tumor with a high degree of malignancy, invasiveness, and metastasis rate. Radiotherapy, as an important adjuvant therapy for HNSCC, can reduce the postoperative recurrence rate and improve the survival rate. Identifying the genes related to HNSCC radiotherapy resistance (HNSCC-RR) is helpful in the search for potential therapeutic targets. However, identifying radiotherapy resistance-related genes from tens of thousands of genes is a challenging task. While interactions between genes are important for elucidating complex biological processes, the large number of genes makes the computation of gene interactions infeasible. METHODS: We propose a gene selection algorithm, RGIE, which is based on ReliefF, Gene Network Inference with Ensemble of Trees (GENIE3) and Feature Elimination. ReliefF was used to select a feature subset that is discriminative for HNSCC-RR, GENIE3 constructed a gene regulatory network based on this subset to analyze the regulatory relationship among genes, and feature elimination was used to remove redundant and noisy features. RESULTS: Nine genes (SPAG1, FIGN, NUBPL, CHMP5, TCF7L2, COQ10B, BSDC1, ZFPM1, GRPEL1) were identified and used to identify HNSCC-RR, which achieved performances of 0.9730, 0.9679, 0.9767, and 0.9885 in terms of accuracy, precision, recall, and AUC, respectively. Finally, qRT-PCR validated the differential expression of the nine signature genes in cell lines (SCC9, SCC9-RR). CONCLUSION: RGIE is effective in screening genes related to HNSCC-RR. This approach may help guide clinical treatment modalities for patients and develop potential treatments.

Potential for the development of Taraxacum mongolicum aqueous extract as a phytogenic feed additive for poultry.

Introduction: Taraxacum mongolicum (TM) is a kind of medicinal and edible homologous plant which is included in the catalogue of feed raw materials in China. It is rich in polyphenols, flavonoids, polysaccharides and other active substances, and shows many benefits to livestock, poultry and aquatic products. The study aimed to assess the potential of TM aqueous extract (TMAE) as a substitute for poultry AGPs. Methods: A total of 240 one-day-old Arbor Acker broilers were randomly assigned to four groups and fed a basal diet (Con) supplemented with 500, 1000, and 2000 mg/kg TMAE (Low, Medium, and High groups). The growth performance of the broilers was measured on day 21 and day 42. At the end of the trial, the researchers measured slaughter performance and collected serum, liver, spleen, ileum, and intestinal contents to investigate the effects of TMAE on serum biochemistry, antioxidant capacity, immune function, organ coefficient, intestinal morphology, flora composition, and short-chain fatty acids (SCFAs). Results: The results showed that broilers treated with TMAE had a significantly higher average daily gain from 22 to 42 days old compared to the Con group. Various doses of TMAE resulted in different levels of improvement in serum chemistry. High doses increased serum alkaline phosphatase and decreased creatinine. TMAE also increased the antioxidant capacity of serum, liver, and ileum in broilers. Additionally, middle and high doses of TMAE enhanced the innate immune function of the liver (IL-10) and ileum (Occludin) in broilers. Compared to the control group, the TMAE treatment group exhibited an increase in the ratio of villi length to villi crypt in the duodenum. TMAE increased the abundance of beneficial bacteria, such as Alistipes and Lactobacillus, while reducing the accumulation of harmful bacteria, such as Colidextracter and Sellimonas. The cecum's SCFAs content increased with a medium dose of TMAE. Supplementing broiler diets with TMAE at varying doses enhanced growth performance and overall health. The most significant benefits were observed at a dose of 1000 mg/kg, including improved serum biochemical parameters, intestinal morphology, antioxidant capacity of the liver and ileum, immune function of the liver and ileum, and increased SCFAs content. Lactobacillus aviarius, norank_f_norank_o__Clostridia_UCG-014, and Flavonifractor are potentially dominant members of the intestinal microflora. Conclusion: In conclusion, TMAE is a promising poultry feed additive and 1000 mg/kg is an effective reference dose.

Extracellular vesicle-derived non-coding RNAs in remodeling melanoma.

Melanoma is one of the most lethal cutaneous malignancies. Despite great advances in radiotherapy, chemotherapy, and immunotherapy, the survival rate and prognosis of patients with melanoma remain poor. The abundant and sophisticated reciprocal communication network between melanoma cells and non-tumor cells contributes to the high heterogeneity of the melanoma microenvironment and is intimately related to varying treatment responses and clinical courses. Extracellular vesicles (EVs) are membrane structures generated by nearly all cell types. EVs contain biologically active molecules, mainly comprising proteins, lipids, and RNAs, and undoubtedly play multifaceted roles in numerous diseases, represented by melanoma. Non-coding RNAs (ncRNAs) mainly encompass long non-coding RNAs, microRNAs, and circular RNAs and constitute the majority of the human transcriptome. Multiple ncRNAs encapsulated in EVs coordinate various pathophysiological processes in melanoma. This review summarizes the mechanisms by which EV-ncRNAs modulate biological behaviors and immunity, and their potential diagnostic and therapeutic applications in melanoma. Undoubtedly, further insight into EV-ncRNAs and their functions in melanoma will contribute to the clinical treatment of melanoma and the implementation of precision medicine.

SALL4 promotes cancer stem-like cell phenotype and radioresistance in oral squamous cell carcinomas via methyltransferase-like 3-mediated m6A modification.

Radioresistance imposes a great challenge in reducing tumor recurrence and improving the clinical prognosis of individuals having oral squamous cell carcinoma (OSCC). OSCC harbors a subpopulation of CD44(+) cells that exhibit cancer stem-like cell (CSC) characteristics are involved in malignant tumor phenotype and radioresistance. Nevertheless, the underlying molecular mechanisms in CD44( + )-OSCC remain unclear. The current investigation demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in CD44(+) cells and promotes CSCs phenotype. Using RNA-sequencing analysis, we further showed that Spalt-like transcription factor 4 (SALL4) is involved in the maintenance of CSCs properties. Furthermore, the overexpression of SALL4 in CD44( + )-OSCC cells caused radioresistance in vitro and in vivo. In contrast, silencing SALL4 sensitized OSCC cells to radiation therapy (RT). Mechanistically, we illustrated that SALL4 is a direct downstream transcriptional regulation target of METTL3, the transcription activation of SALL4 promotes the nuclear transport of ß-catenin and the expression of downstream target genes after radiation therapy, there by activates the Wnt/ß-catenin pathway, effectively enhancing the CSCs phenotype and causing radioresistance. Herein, this study indicates that the METTL3/SALL4 axis promotes the CSCs phenotype and resistance to radiation in OSCC via the Wnt/ß-catenin signaling pathway, and provides a potential therapeutic target to eliminate radioresistant OSCC.

Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment.

BACKGROUND: Neurofibroma type I (NF1) often presents with multiple clinical phenotypes due to mutations of NF1 gene. The aim of this study was to determine the phenotypic and therapeutic relevance of tumor microenvironment in NF1 patients. METHODS: Tumor stem cells (TSCs) from NF1 were isolated and cultured using fluorescence activated cell sorting (FACS) and colony formation experiments. Then, flow cytometry was used to detect the surface markers, osteogenic and adipogenic differentiation were performed as well. Its tumorigenesis ability was confirmed by subcutaneous tumorigenesis in nude mice. Immunohistochemical staining was performed on neurofibroma tissues from the head and trunk with different phenotypes. The expression of BDNF in neurofibroma tissues was detected by Elisa and immunohistochemical staining. Western Blotting was used to detect the expression of p38 MAPK pathway in TSCs. The effect of BDNF neutralizing antibody on the tumorigenesis of TSCs was observed. RESULTS: Herein, we advocate that NF1 contain a new subgroup of mesenchymal-like neurofibroma stem cells (MNSCs). Such colony-forming MNSCs preserved self-renewal, multiple differentiation and tumorigenic capabilities. More interestingly, the MNSCs isolated from neurofibroma tissues of the same patient with different phenotypes presented site-specific capabilities. Moreover, different levels of brain-derived neurotrophic factor (BDNF) in neurofibroma tissues can impact the MNSCs by activating the TrkB/p38 MAPK pathway. Systemic administration of BDNF neutralizing antibodies inhibited MNSCs' characteristics. CONCLUSIONS: We demonstrated that BDNF can modulate MNSCs and thereby controlling different tumor phenotypes between the head and trunk regions. Application of BDNF neutralizing antibodies may inhibit p38 MAPK pathway, therefore providing a promising strategy for managing NF1.

Wheat Alkylresorcinols Modulate Glucose Homeostasis through Improving GLP-1 Secretion in High-Fat-Diet-Induced Obese Mice.

Wheat alkylresorcinols (ARs) consumption has been evidenced to improve obesity and its associated insulin resistance. However, the effect of ARs on glucagon-like peptide 1 (GLP-1) secretion and the underlying mechanism of action are still unclear. In this study, C57BL/6J mice were fed low-fat diet (LFD), high-fat diet (HFD), and HFD supplemented with 0.4% (w/w) ARs separately for 9 weeks. The results showed that ARs intervention significantly improved glucose homeostasis and restored the serum level of GLP-1 compared with the HFD control group. Moreover, ARs treatment alleviated HFD-induced ileal epithelium damage according to TUNEL staining, immunofluorescence, and transmission electron microscopy observation. The alleviative effect was further verified by apoptosis analysis and mitochondrial function evaluation. Furthermore, palmitic acid (PA) was administered to the intestinal secretin tumor cell line (STC-1) to clarify the protective effect of ARs on GLP-1 secretion in vitro. In consistence with the results of animal studies, ARs treatment could significantly improve GLP-1 secretion in STC-1 cells compared with PA treatment alone in a dose-dependent manner, accompanied by a reduction in apoptosis and mitochondrial dysfunction. In addition, ARs treatment notably enhanced the abundance of SCFA (short-chain fatty acid)-producing bacteria, such as Bacteroides, Bifidobacterium, and Akkermansia. The increased levels of intestinal SCFAs, such as acetic acid, propionic acid, and butyric acid, improved the expression of short-chain fatty acid receptors (FFAR3) and glucagon-like peptide-1 receptor (GLP-1R), enhancing the secretion of the intestinal hormones GLP-1. Thus, this study provides potential clinical implications of whole wheat as a dietary strategy to improve glucose homeostasis for obese populations.

Design, Synthesis, and Biological Evaluation of Novel Camphor-Based Hydrazide and Sulfonamide Derivatives as Laccase Inhibitors against Plant Pathogenic Fungi/Oomycetes.

To discover novel natural product-based fungicidal agrochemicals, 41 novel camphanic acid hydrazide and camphor sulfonamide derivatives were designed, synthesized, and tested for their antifungal profile against four plant pathogenic fungi and three oomycetes. As a result, some derivatives presented pronounced inhibitory activities toward Botryosphaeria dothidea, Fusarium graminearum, Phytophthora capsici, and Phytophthora nicotianae. Especially, compound 4b demonstrated the most potent anti-B. dothidea activity (EC50 = 1.28 mg/L), much stronger than positive control chlorthalonil. The in vivo assay showed that 4b displayed significant protective and curative effects on apple fruits infected by B. dothidea. The primary antifungal mechanism study revealed that 4b could obviously enhance the cell membrane permeability, destroy the mycelial surface morphology and the cell ultrastructure, and reduce the ergosterol and exopolysaccharide contents of B. dothidea. Further, 4b showed potent laccase inhibitory activity in vitro with an IC50 value of 11.3 µM, superior to positive control cysteine. The molecular docking study revealed that 4b could dock well into the active site of laccase by forming multiple interactions with the key residues in the pocket. The acute oral toxicity test in rats presented that 4b had slight toxicity with an LD50 value of 849.1 mg/kg bw (95% confidence limit: 403.9-1785.3 mg/kg bw). This research identified that the camphanic acid hydrazide derivatives could be promising leads for the development of novel laccase-targeting fungicides.

Piceatannol Protects PC-12 Cells against Oxidative Damage and Mitochondrial Dysfunction by Inhibiting Autophagy via SIRT3 Pathway.

Oxidative stress has been identified as a major cause of cellular injury in a variety of neurodegenerative disorders. This study aimed to investigate the cytoprotective effects of piceatannol on hydrogen peroxide (H2O2)-induced pheochromocytoma-12 (PC-12) cell damage and explore the underlying mechanisms. Our findings indicated that piceatannol pre-treatment significantly attenuated H2O2-induced PC-12 cell death. Furthermore, piceatannol effectively improved mitochondrial content and mitochondrial function, including enhancing mitochondrial reactive oxygen species (ROS) elimination capacity and increasing mitochondrial transcription factor (TFAM), peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondria Complex IV expression. Meanwhile, piceatannol treatment inhibited mitochondria-mediated autophagy as demonstrated by restoring mitochondrial membrane potential, reducing autophagosome formation and light chain 3B II/I (LC3B II/I) and autophagy-related protein 5 (ATG5) expression level. The protein expression level of SIRT3 was significantly increased by piceatannol in a concentration-dependent manner. However, the cytoprotective effect of piceatannol was dramatically abolished by sirtuin 3 (SIRT3) inhibitor, 3-(1H-1,2,3-Triazol-4-yl) pyridine (3-TYP), which led to an exacerbated mitochondrial dysfunction and autophagy in PC-12 cells under oxidative stress. In addition, the autophagy activator (rapamycin) abrogated the protective effects of piceatannol on PC-12 cell death. These findings demonstrated that piceatannol could alleviate PC-12 cell oxidative damage and mitochondrial dysfunction by inhibiting autophagy via the SIRT3 pathway.

Synthesis and Antifungal Activity of Novel L-Menthol Hydrazide Derivatives as Potential Laccase Inhibitors.

To discover novel laccase inhibitors as potential fungicides, twenty-six novel L-menthol hydrazide derivatives were designed and synthesized. In the in vitro antifungal assay, most of the target compounds displayed pronounced antifungal activity against Sclerotinia sclerotiorum, Fusarium graminearum, and Botryosphaeria dothidea. Especially, the EC50 of compounds 3 b and 3 q against B. dothidea was 0.465 and 0.622 mg/L, which was close to the positive compound fluxapyroxad (EC50 =0.322 mg/L). Scanning electron microscopy (SEM) analysis showed that compound 3 b could significantly damage the mycelial morphology of B. dothidea. In vivo antifungal experiments on apple fruits showed that 3 b exhibited excellent protective and curative effects. Furthermore, in the in vitro laccase inhibition assay, 3 b showed outstanding inhibitory activity with the IC50 value of 2.08 µM, which is much stronger than positive control cysteine and PMDD-5Y. These results indicated that this class of L-menthol derivatives could be promising leads for the discovery of laccase-targeting fungicides.

The development of radioresistant oral squamous carcinoma cell lines and identification of radiotherapy-related biomarkers.

BACKGROUND: In the treatment of oral squamous cell carcinoma (OSCC), radiation resistance remains an important obstacle to patient outcomes. Progress in understanding the molecular mechanisms of radioresistance has been limited by research models that do not fully recapitulate the biological features of solid tumors. In this study, we aimed to develop novel in vitro models to investigate the underlying basis of radioresistance in OSCC and to identify novel biomarkers. METHODS: Parental OSCC cells (SCC9 and CAL27) were repeatedly exposed to ionizing radiation to develop isogenic radioresistant cell lines. We characterized the phenotypic differences between the parental and radioresistant cell lines. RNA sequencing was used to identify differentially expressed genes (DEGs), and bioinformatics analysis identified candidate molecules that may be related to OSCC radiotherapy. RESULTS: Two isogenic radioresistant cell lines for OSCC were successfully established. The radioresistant cells displayed a radioresistant phenotype when compared to the parental cells. Two hundred and sixty DEGs were co-expressed in SCC9-RR and CAL27-RR, and thirty-eight DEGs were upregulated or downregulated in both cell lines. The associations between the overall survival (OS) of OSCC patients and the identified genes were analyzed using data from the Cancer Genome Atlas (TCGA) database. A total of six candidate genes (KCNJ2, CLEC18C, P3H3, PIK3R3, SERPINE1, and TMC8) were closely associated with prognosis. CONCLUSION: This study demonstrated the utility of constructing isogenic cell models to investigate the molecular changes associated with radioresistance. Six genes were identified based on the data from the radioresistant cells that may be potential targets in the treatment of OSCC.

[Progression and reflection on the mechanism study of acupuncture and moxibustion in treatment of Crohn's disease].

Crohn's disease (CD) is a common chronic non-specific gastrointestinal inflammatory disease. Studies showed that acupuncture-moxibustion (A&M) can effectively relieve the symptoms of CD and its clinical efficacy has been confirmed in patients. In this paper, by reviewing the relevant articles for the mechanism studies on CD treated with A&M in recent years, it is discovered that the effect mechanism of A&M on CD includes two aspects, i.e. the local regulation inside the intestines and the neuromodulation outside intestines. The former one refers to the regulation of intestinal microflora, intestinal epithelial cell function and the regulation of intestinal local immune cells. The latter points to the modulation of brain function effect and the modulation of "brain-gut axis" related neurotransmitters. This paper also introduces the differences in intervention modes and acupoint selection between clinical trial and animal experiment, the suggestions on elucidating the nerve-immunity mechanism for CD treatment with A&M in view of "brain-gut axis" system, and its prospects. It is anticipated that this review may be conductive to the effect mechanism research of A&M for CD so that the evidences may be provided for optimizing the clinical regimen of A&M in treatment of this disease.

Clinical characteristics and prognostic characterization of endometrial carcinoma: a comparative analysis of molecular typing protocols.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies in China and globally, accounting for the fourth-prevalent cancer in women. Although numerous studies have confirmed prognostic value of The Cancer Genome Atlas (TCGA) molecular subgroups, it is unclear how they are combined with histological features. The main objective of this study was to compare ProMisE and TCGA classification for the rapid and accurate prediction of prognosis within EC patients, together with the provision of a revised strategy for individualized diagnosis and treatment of patients. METHODS: Within this study, 70 patients with EC from Beijing Tsinghua Changgeng Hospital (affiliated to Tsinghua University) were retrospectively examined between July 2015 and December 2021. Samples were processed for determination of clinical markers, together with ProMisE and TCGA classification. RESULTS: Comparative analysis across four TCGA types (POLE, Low-CN, High-CN, and MSI-H) and age, was statistically significant (χ²= 7.000, p = 0.029). There was no significant difference observed among the four TCGA types and FIGO stage, vascular invasion and depth of invasion, or lymph node metastasis and tumor area. There was no significant association between the expression of Vimentin, Ki-67, PTEN, MSH2, PAX-8, ß-catenin, CD10, ER, PR, P16, MLH1, and PMS2 with the four TCGA types. In addition, p63 expression (χ²= 11.09, p = 0.029) and p53 expression (χ²= 11.585, p = 0.005) were statistically significant. Numerous models demonstrated that patients with POLE mutations and low-CN had higher progression free survival (PFS) and overall survival (OS), whereas those with high-CN had lowest values. The log-rank test revealed that the survival rate of PR-positive and ER-positive patients was significantly higher (p < 0.001). CONCLUSION: Overall, these results can be of additional benefit for clinical applications, in comparison to the ProMisE classification method. In addition, PR, ER, vascular infiltration, hyperlipidemia and atherosclerosis were found to be the key factors affecting EC prognosis.

Design, synthesis and antifungal evaluation of novel nopol derivatives as potent laccase inhibitors.

BACKGROUND: To explore further potential natural product-based antifungal agents, a series of novel nopol-based carboxamide and hydrazide derivatives containing a natural pinene structure were designed, synthesized, and evaluated for their inhibitory activities against seven phytopathogenic fungi and oomycetes. RESULTS: The bioassay results indicated that some compounds exhibited good inhibitory activities against Gibberella zeae, Sclerotinia sclerotiorum, and Phytophthora capsici. Among them, compound 3h displayed excellent in vitro activities against G. zeae, with EC50 values of 1.09 mg L-1 , which was comparable with the commercial fungicides bixafen and carbendazim (median effective concentration [EC50 ] = 1.21 and 0.89 mg L-1 , respectively). Notably, in vivo bioassay results suggested that compound 3h also showed prominent protective and curative effects (95.6% and 94.2%) at 200 mg L-1 against G. zeae. The scanning electron microscopy study indicated that compound 3h could destroy the morphological integrity of G. zeae hyphae. The in vitro enzyme inhibitory bioassay revealed that compound 3h exhibited potent inhibitory activity against laccase with median inhibitory concentration (IC50 ) values of 4.93 µm, superior to positive control cysteine (IC50  = 35.50 µm), and its binding modes with laccase were elucidated by molecular docking study. In addition, the fluorescent imaging of the dansylamide-labeled derivatives 8 on wheat leaf epidermal cells and the hyphae of G. zeae revealed that this class of hydrazide derivatives could readily permeate into wheat leaves and reached the laccase target in fungal cells. CONCLUSION: Some nopol-based hydrazide derivatives exhibited excellent anti-G. zeae activity and laccase inhibitory activity, which merits further development as a new fungicide candidate for controlling Fusarium head blight. © 2023 Society of Chemical Industry.

Acupuncture for Fibromyalgia: A Review Based on Multidimensional Evidence.

Fibromyalgia (FM) is a complicated syndrome characterized by widespread chronic pain, fatigue, sleep disturbances, cognitive dysfunction, and other complications. There is currently no specific treatment available. No comprehensive surveys have been published to summarize the mechanism of acupuncture in FM management. Although several studies have shown that acupuncture can benefit FM patients, their clinical findings are inconsistent. Here, we summarize the operation method of acupuncture for FM. For the first time, we conducted a comprehensive review of the mechanisms of acupuncture for FM, and integrated evidence-based scientific findings with the most comprehensive and updated literature. According to studies conducted using FM patients and animal models, acupuncture may improve symptoms in FM patients by regulating the afferent pain pathway and descending inhibitory pain pathways of various molecules, such as ASIC3, Nav1.7, Nav1.8, and TRPV1, as well as peripheral inflammation and the autonomic nervous system. Furthermore, we discussed the epidemiology, pathophysiology, diagnosis, and management of FM, and reviewed acupuncture-related clinical studies. This review fills a previously unknown gap in knowledge of the mechanism of acupuncture for FM. Although there is growing evidence that acupuncture may be a promising therapy for treating symptoms in FM patients, further investigation is needed.

The GAL/GALR2 axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial-to-mesenchymal transition.

BACKGROUND: Perineural invasion (PNI) is a typical pathological characteristic of salivary adenoid cystic carcinoma (SACC) and other neurotrophic cancers. The mechanism of the neural microenvironment controlling tumor progression during the PNI process is unclear. In the present study, we investigated the role and molecular mechanisms of nerve-derived neuropeptide galanin (GAL) and its receptor (GALR2) in the regulation of PNI in SACC. METHODS: Immunohistochemistry staining and clinical association studies were performed to analyze the expression of GAL and GALR2 in SACC tissues and their clinical value. Dorsal root ganglion or SH-SY5Y cells were co-cultured with SACC cells in vitro to simulate the interactions between the neural microenvironment and tumor cells, and a series of assays including transcriptome sequencing, Western blot, and Transwell were performed to investigate the role and molecular mechanism of GAL and GALR2 in the regulation of SACC cells. Moreover, both the in vitro and in vivo PNI models were established to assess the potential PNI-specific therapeutic effects by blocking the GAL/GALR2 axis. RESULTS: GAL and GALR2 were highly expressed in SACC tissues, and were associated with PNI and poor prognosis in SACC patients (p < 0.05). Nerve-derived GAL activated GALR2 expression in SACC cells and induced epithelial-to-mesenchymal transition (EMT) in SACC cells. Adding human recombinant GAL to the co-culture system promoted the proliferation, migration, and invasion of SACC cells significantly, but inhibited the apoptosis of SACC cells. Adding M871, a specific antagonist of GALR2, significantly blocked the above effects (p < 0.05) and inhibited the PNI of SACC cells in vitro and in vivo (p < 0.05). CONCLUSIONS: This study demonstrated that nerve-derived GAL activated GALR2 expression, and promoted EMT in SACC cells, thereby enhancing the PNI process. Interruption of the GAL/GALR2 axis might be a novel strategy for anti-PNI therapy for SACC.