Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors.

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.

Municipal pipeline networks as preferential vapor intrusion pathways: A review.

Recent reports show a rise in instances where municipal networks, such as sewer lines, serve as pathways for vapor intrusion (VI), enabling volatile organic compounds (VOCs) vapors to travel along these networks. These VOCs pose potential health risks to occupants of buildings connected to these networks. Currently, there's a lack of specific technical or regulatory guidance on identifying and assessing the VI risk associated with sewer as preferential VI pathways. This critical review summarizes key findings from studies and site investigations related to sewer VI pathways. These findings cover background VOCs concentration levels in sewers, updates to site conceptual models, advances in sewer sampling techniques, innovative tools for identifying and characterizing sewer VI, and practices for assessing and mitigating sewer VI risk. While significant improvements have been made towards understanding how municipal pipeline networks act as VI pathways, more research is still needed to develop strategies for investigating sites and assessing risks associated with "pipeline VI pathways". Future research could focus on the development of "pipeline VI pathways" data set, the improvement and validation of investigation tools, and improving the understanding of VOCs transportation mechanisms within these "pipeline VI pathways".

Ethnobotanical study of medicinal plants used by the Yi people in Mile, Yunnan, China.

BACKGROUND: The Yi people are a sociolinguistic group living in Mile City, which is their typical settlement in southeastern Yunnan, China. Over the long history of using medicinal plants, the Yi people have accumulated and developed a wealth of traditional medicinal knowledge, which has played a vital role in their health care. However, only a few studies have been performed to systematically document the medicinal plants commonly used by the Yi people. This study provides fundamental data for the development and application of ethnomedicine as well as supports the conservation of the traditional medical knowledge of the Yi people. METHODS: This study was conducted from May 2020 to August 2022 and involved five townships in Mile. Information regarding medicinal plants was obtained through semistructured interviews, key informant interviews, and participatory observation. The collected voucher specimens were identified using the botanical taxonomy method and deposited in the herbarium. Ethnobotanical data were analyzed using informant consensus factor, relative frequency of citation, and fidelity level. RESULTS: In total, 114 informants distributed in five townships of Mile were interviewed. The Yi people used 267 medicinal plant species belonging to 232 genera and 104 families to treat various diseases. Asteraceae, Lamiaceae, and Fabaceae were the most commonly used plant families by the Yi people. In addition, herbs were most commonly used by the Yi people. Whole plants and roots were the preferred medicinal parts. Decoctions were the most common method of herbal medicine preparation. There are 49 different recorded diseases treated by Yi medicinal plants, and among them, respiratory diseases, rheumatism, traumatic injury, fractures, and digestive system diseases have the largest number of species used. A quantitative analysis demonstrated that plants such as Zingiber officinale, Lycopodium japonicum, Aconitum carmichaelii, Panax notoginseng, Cyathula officinalis, and Leonurus japonicus played crucial roles in disease prevention and treatment. CONCLUSION: Traditional knowledge of medicinal plants is closely associated with the social culture of the local Yi people. The medicinal plants used for health care in the study area were diverse. Local healers were skilled at using medicinal plants to treat various diseases. Their treatment methods were convenient and unique, exhibiting distinctive regional characteristics. However, the inheritance of their traditional medicinal knowledge and protection of wild medicinal plant resources are facing serious challenges, including the decreasing number of local healers, aging of healers, lack of successors, and excessive harvesting of medicinal plant resources. This ethnobotanical survey provides a useful reference for the sustainable utilization and protection of medicinal plant resources in Mile and the inheritance of traditional medicinal knowledge of the Yi people.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study.

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab-chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA-IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9-81.0%). For patients with ctDNA- vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Universal DNA-Based Sensing Toolbox for Programming Cell Functions.

By recombining natural cell signaling systems and further reprogramming cell functions, use of genetically engineered cells and bacteria as therapies is an innovative emerging concept. However, the inherent properties and structures of the natural signal sensing and response pathways constrain further development. We present a universal DNA-based sensing toolbox on the cell surface to endow new signal sensing abilities for cells, control cell states, and reprogram multiple cell functions. The sensing toolbox contains a triangular-prismatic-shaped DNA origami framework and a sensing core anchored inside the internal confined space to enhance the specificity and efficacy of the toolbox. As a proof of principle, the sensing toolbox uses the customizable sensing core with signal sensing switches and converters to recognize unconventional signal inputs, deliver functional components to cells, and then control cell responses, including specific tumor cell death, immune cell disinhibition and adhesion, and bacterial expression. This work expands the diversity of cell sensing signals and reprograms biological functions by constructing nanomechanical-natural hybrid cells, providing new strategies for engineering cells and bacteria in diagnosis and treatment applications.

Association between sodium and potassium intake levels and body compositions of Chinese college students.

BACKGROUND AND OBJECTIVES: To investigate the relationship between sodium (Na) and potassium (K) nutritional condition and body compositions in youth aiming to give target population reasonable diet recommendations. METHODS AND STUDY DESIGN: The cross-sectional study was conducted involving 512 healthy youth aged 18 to 31 years from universities in Beijing. Food frequency questionnaire (FFQ) and bioelectrical impedance analyzer (BIA) were used to collect dietary intake information and body compositions. RESULTS: There was an increasing tendency in fat-related indicators and muscle-related indicators of the dietary Na tertile group (p <0.05). Additionally, Weight, body mass index (BMI), waist circumference (WC), and muscle-related indicators increased with the dietary K tertile group (p <0.05). Across increasing tertiles of dietary Na intake, the odds ratio (OR) was increased significantly (p < 0.05) in fat-related indicators. On the contrary, with the increased dietary Na intake, the OR decreased (p < 0.05) in appendicular skeletal muscle mass index (ASMI) and body lean mass. As tertiles of dietary K intake increased, the OR in both skeletal muscle mass index (SMMI) and lean mass index (LMI) decreased. CONCLUSIONS: High dietary Na is a risk factor for abnormal lipid distribution in college students. High dietary K can maintain skeletal muscle mass and reduce the risk of obesity. Na in the diet has a greater impact on the body composition of young people than K. Low dietary Na and high dietary K still need to be strengthened in science popularization and practice among more college students.

HOXC13 promotes cell proliferation, metastasis and glycolysis in breast cancer by regulating DNMT3A.

Breast cancer (BC) is a life-threatening malignant tumor that affects females more commonly than males. The mechanisms underlying BC proliferation, metastasis and glycolysis require further investigation. Homeobox C13 (HOXC13) is highly expressed in BC; however, the specific mechanisms in BC are yet to be fully elucidated. Therefore, the aim of the present study was to investigate the role of HOXC13 in BC proliferation, migration, invasion and glycolysis. In the present study, the UALCAN database was used to predict the expression levels of HOXC13 in patients with BC. Western blot analysis and reverse transcription-quantitative PCR were used to determine the expression levels of HOXC13 in BC cell lines. Moreover, HOXC13 knockdown was induced using cell transfection, and the viability, proliferation and apoptosis of cells were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining and flow cytometry. Migration, invasion and epithelial-mesenchymal transition (EMT) were measured using wound healing assay, Transwell assay and western blotting. In addition, XF96 extracellular flux analyzer and corresponding kits were used to detect glycolysis. The JASPAR database was used to predict promoter binding sites for the transcription factors HOXC13 and DNA methyltransferase 3α (DNMT3A). HOXC13 expression was silenced and DNMT3A was simultaneously overexpressed using cell transfection. The results of the present study revealed that HOXC13 expression was significantly elevated in BC tissues and cells. Following HOXC13 knockdown in BC cells, the viability, proliferation, glycolysis, migration, invasion and EMT were significantly decreased, and apoptosis was significantly increased. In addition, HOXC13 positively regulated the transcription of DNMT3A in BC cells, thus playing a regulatory role in the malignant progression of cells. In conclusion, HOXC13 promoted cell viability, proliferation, migration, invasion, EMT and glycolysis in BC by regulating DNMT3A.

Bioinformatics analysis to identify breast cancer-related potential targets and candidate small molecule drugs.

OBJECTIVE: The purpose of this study is to identify potential targets associated with breast cancer and screen potential small molecule drugs using bioinformatics analysis. METHODS: DEGs analysis of breast cancer tissues and normal breast tissues was performed using R language limma analysis on the GSE42568 and GSE205185 datasets. Functional enrichment analysis was conducted on the intersecting DEGs. The STRING analysis platform was used to construct a PPI network, and the top 10 core nodes were identified using Cytoscape software. QuartataWeb was utilized to build a target-drug interaction network and identify potential drugs. Cell survival and proliferation were assessed using CCK8 and colony formation assays. Cell cycle analysis was performed using flow cytometry. Western blot analysis was conducted to assess protein levels of PLK1, MELK, AURKA, and NEK2. RESULTS: A total of 54 genes were consistently upregulated in both datasets, which were functionally enriched in mitotic cell cycle and cell cycle-related pathways. The 226 downregulated genes were functionally enriched in pathways related to hormone level regulation and negative regulation of cell population proliferation. Ten key genes, namely CDK1, CCNB2, ASPM, AURKA, TPX2, TOP2A, BUB1B, MELK, RRM2, and NEK2 were identified. The potential drug Fostamatinib was predicted to target AURKA, MELK, CDK1, and NEK2. In vitro experiments demonstrated that Fostamatinib inhibited the proliferation of breast cancer cells, induced cell arrest in the G2/M phase, and down-regulated MELK, AURKA, and NEK2 proteins. CONCLUSION: In conclusion, Fostamatinib shows promise as a potential drug for the treatment of breast cancer by regulating the cell cycle and inhibiting the proliferation of breast cancer cells.

Triterpenoid saponins from Psammosilene tunicoides and their antinociceptive activities.

Herein, five undescribed oleanane-type triterpenoid saponins, namely, psammosaponins A-E, along with nine known compounds, were isolated from the roots of Psammosilene tunicoides. Moreover, part of the ethanolic extract of P. tunicoides was acid-hydrolyzed and three aglycones were isolated from the resulting hydrolysate. The structures of all compounds were established through extensive analysis involving 1D and 2D NMR experiments, HRESIMS measurements, chemical derivatization, and comparison of spectroscopic data with the values reported in the literature. In all, 10 of the isolated saponins and the three aglycones were evaluated in the acetic acid-induced writhing model for their antinociceptive activity. At a dose of 40 mg/kg, these compounds exhibited significant inhibitory effects on the mouse writhing response, with inhibitions ranging from 31.9% to 79.3%. In addition, the structure-activity relationships of the isolates were discussed. Among the isolates, quillaic acid 3-O-glucuronide and 16α-hydroxygypsogenic acid showed better antinociceptive activity with inhibitions of 79.3% and 73.7%, respectively. Both isolates also exhibited antinociceptive activities in hot plate and formalin tests on mice. Their antinociceptive mechanism was explored in lipopolysaccharide-stimulated RAW 264.7 cells. These isolates could significantly inhibit the production of nitric oxide and interleukin-6 and downregulate the expression levels of inducible NO synthase, COX-1, and COX-2.

A Bifunctional Catalyst for Green Ammonia Synthesis from Ubiquitous Air and Water.

Ammonia (NH3 ) is essential for modern agriculture and industry, and, due to its high hydrogen density and no carbon emission, it is also expected to be the next-generation of "clean" energy carrier. Herein, directly from air and water, a plasma-electrocatalytic reaction system for NH3 production, which combines two steps of plasma-air-to-NOx - and electrochemical NOx - reduction reaction (eNOx RR) with a bifunctional catalyst, is successfully established. Especially, the bifunctional catalyst of CuCo2 O4 /Ni can simultaneously promote plasma-air-to-NOx - and eNOx RR processes. The easy adsorption and activation of O2 by CuCo2 O4 /Ni greatly improve the NOx - production rate at the first step. Further, CuCo2 O4 /Ni can also resolve the overbonding of the key intermediate of * NO, and thus reduce the energy barrier of the second step of eNOx RR. Finally, the "green" NH3 production achieves excellent FENH3 (96.8%) and record-high NH3 yield rate of 145.8 mg h-1  cm-2 with large partial current density (1384.7 mA cm-2 ). Moreover, an enlarged self-made H-type electrolyzer improves the NH3 yield to 3.6 g h-1 , and the obtained NH3 is then rapidly converted to a solid of magnesium ammonium phosphate hexahydrate, which favors the easy storage and transportation of NH3 .

Role of soy lecithin combined with soy isoflavone on cerebral blood flow in rats of cognitive impairment and the primary screening of its optimum combination.

BACKGROUND/OBJECTIVES: Soy isoflavone (SIF) and soy lecithin (SL) have beneficial effects on many chronic diseases, including neurodegenerative diseases. Regretfully, there is little evidence to show the combined effects of these soy extractives on the impairment of cognition and abnormal cerebral blood flow (CBF). This study examined the optimal combination dose of SIF + SL to provide evidence for improving CBF and protecting cerebrovascular endothelial cells. MATERIALS/METHODS: In vivo study, SIF50 + SL40, SIF50 + SL80 and SIF50 + SL160 groups were obtained. Morris water maze, laser speckle contrast imaging (LSCI), and hematoxylin-eosin staining were used to detect learning and memory impairment, CBF, and damage to the cerebrovascular tissue in rat. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) and the oxidized glutathione (GSSG) were detected. The anti-oxidative damage index of superoxide dismutase (SOD) and glutathione (GSH) in the serum of an animal model was also tested. In vitro study, an immortalized mouse brain endothelial cell line (bEND.3 cells) was used to confirm the cerebrovascular endothelial cell protection of SIF + SL. In this study, 50 µM of Gen were used, while the 25, 50, or 100 µM of SL for different incubation times were selected first. The intracellular levels of 8-OHdG, SOD, GSH, and GSSG were also detected in the cells. RESULTS: In vivo study, SIF + SL could increase the target crossing times significantly and shorten the total swimming distance of rats. The CBF in the rats of the SIF50 + SL40 group and SIF50 + SL160 group was enhanced. Pathological changes, such as attenuation of the endothelium in cerebral vessels were much less in the SIF50 + SL40 group and SIF50 + SL160 group. The 8-OHdG was reduced in the SIF50 + SL40 group. The GSSG showed a significant decrease in all SIF + SL pretreatment groups, but the GSH showed an opposite result. SOD was upregulated by SIF + SL pretreatment. Different combinations of Genistein (Gen)+SL, the secondary proof of health benefits found in vivo study, showed they have effective anti-oxidation and less side reaction on protecting cerebrovascular endothelial cell. SIF50 + SL40 in rats experiment and Gen50 + SL25 in cell test were the optimum joint doses on alleviating cognitive impairment and regulating CBF through protecting cerebrovascular tissue by its antioxidant activity. CONCLUSIONS: SIF+SL could significantly prevent cognitive defect induced by ß-Amyloid through regulating CBF. This kind of effect might be attributed to its antioxidant activity on protecting cerebral vessels.

An Outstandingly Rare Occurrence of Mycoviruses in Soil Strains of the Plant-Beneficial Fungi from the Genus Trichoderma and a Novel Polymycoviridae Isolate.

In fungi, viral infections frequently remain cryptic causing little or no phenotypic changes. It can indicate either a long history of coevolution or a strong immune system of the host. Some fungi are outstandingly ubiquitous and can be recovered from a great diversity of habitats. However, the role of viral infection in the emergence of environmental opportunistic species is not known. The genus of filamentous and mycoparasitic fungi Trichoderma (Hypocreales, Ascomycota) consists of more than 400 species, which mainly occur on dead wood, other fungi, or as endo- and epiphytes. However, some species are environmental opportunists because they are cosmopolitan, can establish in a diversity of habitats, and can also become pests on mushroom farms and infect immunocompromised humans. In this study, we investigated the library of 163 Trichoderma strains isolated from grassland soils in Inner Mongolia, China, and found only four strains with signs of the mycoviral nucleic acids, including a strain of T. barbatum infected with a novel strain of the Polymycoviridae and named and characterized here as Trichoderma barbatum polymycovirus 1 (TbPMV1). Phylogenetic analysis suggested that TbPMV1 was evolutionarily distinct from the Polymycoviridae isolated either from Eurotialean fungi or from the order Magnaportales. Although the Polymycoviridae viruses were also known from Hypocrealean Beauveria bassiana, the phylogeny of TbPMV1 did not reflect the phylogeny of the host. Our analysis lays the groundwork for further in-depth characterization of TbPMV1 and the role of mycoviruses in the emergence of environmental opportunism in Trichoderma. IMPORTANCE Although viruses infect all organisms, our knowledge of some groups of eukaryotes remains limited. For instance, the diversity of viruses infecting fungi-mycoviruses-is largely unknown. However, the knowledge of viruses associated with industrially relevant and plant-beneficial fungi, such as Trichoderma spp. (Hypocreales, Ascomycota), may shed light on the stability of their phenotypes and the expression of beneficial traits. In this study, we screened the library of soilborne Trichoderma strains because these isolates may be developed into bioeffectors for plant protection and sustainable agriculture. Notably, the diversity of endophytic viruses in soil Trichoderma was outstandingly low. Only 2% of 163 strains contained traces of dsRNA viruses, including the new Trichoderma barbatum polymycovirus 1 (TbPMV1) characterized in this study. TbPMV1 is the first mycovirus found in Trichoderma. Our results indicate that the limited data prevent the in-depth study of the evolutionary relationship between soilborne fungi and is worth further investigation.

Phytol from Faeces Bombycis alleviated migraine pain by inhibiting Nav1.7 sodium channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Faeces Bombycis (silkworm excrement, called Cansha in Chinese), is the dried faeces of the larvae of silkworm. According to the theories of traditional Chinese medicine recorded in "Compendium of Materia Medica", Faeces Bombycis has often been prescribed in traditional Chinese medicine for the treatment of recurrent headache, rheumatalgia, rubella and itching et al. However, the bioactive components and their exact mechanisms underlying the pain-relieving effects remain to be revealed. AIM OF THE STUDY: The present study aimed to evaluate the analgesic effect of Faeces Bombycis extract (FBE) on migraine, explore the main active constituents and investigate the pharmacological mechanisms for its pain relief. MATERIALS AND METHODS: The bioactivity of different extracts from Faeces Bombycis was tracked by the nitroglycerin (NTG)-induced migraine model on rats and identified by NMR spectroscopic data. Whole-cell patch clamp technique, an electrophysiological method, was used to screen the potential targets and study the mechanism of action for the bioactive compound. The following targets have been screened and studied, including Nav1.7 sodium channels, Nav1.8 sodium channels, TRPV1 channels and TRPA1 channels. The trigeminal ganglion neurons were further used to study the effects of the identified compound on neuronal excitability. RESULTS: By testing the bioactivity of the different extracts proceedingly, fraction petroleum ether showed higher anti-migraine activity. Through further step-by-step isolations, 7 compounds were isolated. Among them, phytol was identified with the highest yield and displayed a potent anti-migraine effect. By screening the potential ion channel targets for migraine, phytol was found to preferentially block the inactivated state of Nav1.7 sodium channels with half-inhibition concentration 0.32 ± 0.05 µM. Thus, the effects of phytol on the biophysical properties of Nav1.7 sodium channels were further characterized. Phytol induced a hyperpolarizing shift of voltage-dependent inactivation and slowed the recovery from inactivation. The affinity of phytol became weaker in the inactivation-deficient Nav1.7 channels (Nav1.7-WCW). And such an effect was independent on the local anesthetic site (Nav1.7 F1737A). Consistent with the data from recombinant channels, the compound also displayed state-dependent inhibition on neuronal sodium channels and further decreased the neuronal excitability in trigeminal ganglion neurons. Moreover, besides Nav1.7 channel, phytol also antagonized the activation of TRPV1 and TRPA1 channels at micromolar concentrations with a weaker affinity. CONCLUSION: Our results demonstrated that phytol is the major anti-migraine ingredient of Faeces Bombycis and alleviates migraine behaviors by acting on Nav1.7 sodium channels in the trigeminal ganglion neurons. This study provided evidences for the therapeutic application of Faeces Bombycis and phytol on migraine disease.

Umifenovir Epigenetically Targets the IL-10 Pathway in Therapy against Coxsackievirus B4 Infection.

Umifenovir, a broad-spectrum nonnucleoside antiviral drug, has a promising efficacy against coxsackievirus B4 (CVB4) infection, but its mechanism remains unclear. CVB4 is a common human single-stranded RNA virus that belongs to the Picornaviridae family and the Enterovirus genus. Enterovirus can cause severe diseases, such as meningitis, myocarditis, pancreatitis, insulin-dependent diabetes, and several other diseases, in both adults and children. We have previously demonstrated the critical role of interleukin 10 (IL-10) in promoting CVB4 infection and the downregulation of IL-10 by umifenovir. To further explore the underlying mechanisms of umifenovir, we characterized the epigenetic regulation of IL-10 in IL-10 knockout RAW264.7 cells and a BALB/c mouse splenocyte model. Mechanistically, we found that umifenovir inhibited CVB4-activated IL-10 by enhancing the methylation level of the repressive histones H3K9me3 and H3K27me3 while reducing the acetylation level of the activating histone H3K9ac in the promoter region of the IL-10 gene. Furthermore, using a chromosome conformation capture approach, we discovered that CVB4 infection activated the IL-10 gene by forming an intrachromosomal interaction between the IL-10 gene promoter and an intronic enhancer of the downstream MK2 (mitogen-activated protein kinase [MAPK]-activated protein kinase 2 [MAPKAPK2]) gene, a critical component of the p38-MAPK signaling pathway, which is required for IL-10 gene expression. However, umifenovir treatment abolished this spatial conformation and chromatin interaction, thus reducing the continuous expression of IL-10 and subsequent CVB4 replication. In conclusion, this study reveals a novel epigenetic mechanism by which umifenovir controls CVB4 infections, thus laying a theoretical foundation for therapeutic use of umifenovir. IMPORTANCE Viral infections are major threats to human health because of their strong association with a variety of inflammation-related diseases, especially cancer. Many antiviral drugs are performing poorly in treating viral infections. This is probably due to the immunosuppressive effect of highly expressed IL-10, which is caused by viral infection. Umifenovir is a broad-spectrum antiviral drug. Our recent studies showed that umifenovir has a significant inhibitory effect on CVB4 infection and can reduce IL-10 expression caused by CVB4. However, another antiviral drug, rupintrivir, showed good antiviral activity but had no effect on the expression of IL-10. This suggests that the regulation of IL-10 expression is a key part of the antiviral mechanism of umifenovir. Therefore, due to the dual function of the inhibition of CVB4 replication and the regulation of immune antiviral pathway, the mechanism of umifenovir is of great value to study.

The combined analgesic, sedative, and anti-gastric cancer mechanisms of Tinospora sagittata var. yunnanensis (S. Y. Hu) H. S. Lo based on integrated ethnopharmacological data.

ETHNOPHARMACOLOGY RELEVANCE: As a Yi medicine for eliminating wind to relieve pain, Tinospora sagittata var. yunnanensis (S. Y. Hu) H. S. Lo (TSY) is widely used to treat sore throat, stomach pain, bone and muscle injuries, and tumors; however, the material basis and mechanism of action remain unclear. AIM OF THE STUDY: This study aims to investigate the potential active compounds of TSY and related pharmacological mechanisms against gastric cancer using a multitarget strategy. MATERIALS AND METHODS: The main chemical components of TSY were collected through a literature review and database searches. The components were further screened for ADMET properties, and their targets were predicted using network pharmacology (admetSAR) and substructure-drug-target network-based inference (SDTNBI) approaches in silico. The pharmacological mechanism of action of TSY extract for pain relief, sedation, and anti-gastric cancer activities were identified via in vivo and in vitro biochemical analyses. RESULTS: Here, 28 chemical components were identified, 7 active compounds were selected, and 75 targets of TSY extract were predicted. A compound-target-disease network topological approach revealed that the predicted targets are highly related to the digestive system and nervous system. Network pharmacology results suggested that the anti-gastric cancer activity of TSY was highly correlated with its analgesic and sedative targets and MAPK. In vivo experiments confirmed that TSY extract not only reduced the number of voluntary activities in the mouse model but also exhibited a synergistic effect on sodium pentobarbital-induced sleep, reduced the number of mice exhibiting writhing responses to acetic acid, and increased the hot plate pain threshold of mice. Thus, TSY extract exhibits good analgesic and sedative effects. The TSY extract inhibited HGC-27 cell proliferation and induced apoptosis by regulating apoptotic proteins (BAX, BCL-2 and BCL-XL) in vitro. CONCLUSIONS: TSY exhibits combined analgesic, sedative, and anti-gastric cancer activities.

Single-cell profile of tumor and immune cells in primary breast cancer, sentinel lymph node, and metastatic lymph node.

PURPOSE: Little is known about the host-tumor interaction in the lymph-node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastases of a patient with triple-negative breast cancer. METHODS: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during surgery. Single-cell sequencing was performed on all four specimens. RESULTS: 14,016 cells were clustered into 6 cell subpopulations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor-associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8 + and CD4 + T lymphocytes concentrated more in sentinel lymph node and mainly stratified into two transcriptional states. The immune-cell amount variation among primary tumor, sentinel and normal lymph nodes showed a similar tendency between the sc-RNA-seq profile of TNBC samples and a previous reported bulk RNA-seq profile of a breast cancer cohort, including all four breast cancer subtype samples. DISCUSSION: Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity, while other T cells exhibit an exhausted state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between SLND and ALND.

Correlation between Mild Cognitive Impairment and Sarcopenia: The Prospective Role of Lipids and Basal Metabolic Rate in the Link.

There is evidence of correlation between mild cognitive impairment (MCI) and sarcopenia (SA). However, the influencing factors and the mechanism, such as age-related lipid redistribution, remain unknown. This study aimed to clarify the role of dietary fats and erythrocyte lipids profile combined with basal metabolic rate (BMR) in the link between MCI and SA. A total of 1050 participants aged 65 to 85 were divided into control, MCI, SA and MCI and SA groups. Bioelectrical impedance analysis was used to evaluate appendicular lean mass and BMR. Cognition and dietary nutrition were detected by neuropsychological tests and food frequency questionnaires. UHPLC-QExactive-MS/MS and UHPLC-Qtrap-MS/MS were used to conduct the lipidomics analysis. Lower dietary intake of different phospholipids, unsaturated fatty acids and kinds of choline were significantly associated with MCI and SA. Least absolute shrinkage and selection operator, multivariate logistic regression, receiver operating characteristic curve and validation tests provided evidence that specific phospholipids, unsaturated fatty acids and BMR might be the critical factors in the processing of MCI and SA, as well as in their link. The lipidomic analysis observed a clear discrimination of the lipid profiles in the individuals who are in MCI, SA, or MCI and SA, compared with the control. Lower expressions in certain phospholipid species, such as sphingomyelin and phosphatidylethanolamines, decreased phosphatidylcholine with more unsaturated double bonds, lower level of lipids with C20:5 and C20:4, higher level of lipids with C18:2 and lipids with a remodeled length of acyl chain, might be closely related to the link between MCI and SA. Inadequate dietary intake and lower concentrations of the erythrocyte lipid profile of phospholipids and unsaturated fatty acids with a lower level of BMR might be the key points that lead to progress in MCI and SA, as well as in their link. They could be used as the prospective biomarkers for the higher risk of cognitive decline and/or SA in elderly population.

The Role of Dietary Patterns and Dietary Quality on Body Composition of Adolescents in Chinese College.

There is limited evidence regarding the effects of dietary pattern and dietary quality on the risk of unhealthy weight status and related body composition in Chinese adolescence. In particular, studies using bioelectrical impedance analyzer (BIA) in these subjects are rare. The aim of this study was to evaluate the role of diet in body composition, to find a healthy dietary pattern for Chinese youth, and to promote the application of BIA among this population. A total of 498 participants aged from 18 to 22 years old were included. Dietary patterns were identified by principal components analysis. Energy-adjusted dietary inflammatory index (DII) and diet balance index (DBI) were calculated based on semi-quantitative food frequency questionnaire. Multivariate linear regression and logistic regression analysis were used to examine the relationship of dietary patterns, dietary quality with body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and the effect of dietary factors on BMI levels. The majority of participants with overweight and obesity had abdominal obesity, and there was 3.7% abdominal obesity in normal BMI individuals. Four dietary patterns were detected in the subjects. The pattern with the higher energy intake, which was close to the Western diet, was positively correlated with BMI (ß = 0.326, p = 0.018) and FMI (ß = 0.201, p = 0.043), while being negatively correlated with FFMI (ß = −0.183, p = 0.021). Individuals who followed the pattern similar to the Mediterranean diet had a higher basal metabolic rate (BMR), and the highest fat free mass, soft lean mass, and skeletal muscle mass (p < 0.05) but the lowest FMI, visceral fat area (VFA), waist−hip ratio, and FMI/FFMI ratio (p < 0.05). Higher energy-adjusted DII was associated with high BMI. Higher bound score (HBS) (ß = −0.018, p = 0.010) and diet quality distance (DQD) (ß = −0.012, p = 0.015) were both negatively correlated with FFMI. In conclusion, fat or muscle indexes, such as BMR, FMI, and FFMI, had an important role in predicting overweight and obesity, which suggested the importance of applying BIA among Chinese college students. Students who followed healthful dietary patterns or the high-quality diet that is similar to the Mediterranean diet but not close to the Western diet were more likely to have a healthy BMI and normal body composition.

Two new monoterpene esters from Illigera paviflora Dunn roots.

Two new monoterpene esters, illigerates H and I (1 and 2), and six known compounds actinodaphine (3), bulbocupnine (4), stephanine (5), hypserpanine B (6), betulinic acid (7) and gallic acid (8) were obtained from the root of Illigera paviflora Dunn. Their structures were elucidated by spectroscopic analysis. Anti-inflammatory and α-glucosidase inhibitory activity of some isolated compounds were assessed. Two monoterpenes 1 and 2 exhibited weak in vitro anti-inflammatory activity (IC50 64.5 ± 5.3 and 79.2 ± 7.5 µM) while compounds 3-6 showed inhibition of α-glucosidase with IC50 values ranged from 87.17 to 118.74 µM.

The Protective Effects of Zeaxanthin on Amyloid-ß Peptide 1-42-Induced Impairment of Learning and Memory Ability in Rats.

Background and Objectives: Zeaxanthin (ZEA) as one of the biologically active phytochemicals presents a neuroprotective effect. Since ZEA may play its anti-oxidative role in neurodegenerative diseases including Alzheimer's disease (AD), we hypothesized cognitive defects could be prevented or deferred by ZEA pre-treatment. Methods and Study Design: All the rats were randomly divided into four groups (control, Aß1-42, ZEA, and ZEA + Aß groups). Learning and memory ability of rats, cerebrovascular ultrastructure changes, the redox state, endothelin-1 (ET-1) level, and amyloid-ß peptide (Aß) level in plasma and the Aß transport receptors which are advanced glycation end products (RAGEs) and LDL receptor-related protein-1 (LRP-1) and interleukin-1ß (IL-1ß) expressions in the cerebrovascular tissue were measured in the present study. Results: The escape latency and frequency of spanning the position of platform showed significant differences between the Aß group and ZEA treatment groups. ZEA could prevent the ultrastructure changes of cerebrovascular tissue. In addition, ZEA also showed the protective effects on regulating redox state, restraining ET-1 levels, and maintaining Aß homeostasis in plasma and cerebrovascular. Moreover, the disordered expressions of RAGE and LRP-1 and IL-1ß induced by Aß1-42 could be prevented by the pre-treatment of ZEA. Conclusion: ZEA pre-treatment could prevent learning and memory impairment of rats induced by Aß1-42. This neuroprotective effect might be attributable to the anti-oxidative and anti-inflammatory effects of ZEA on maintaining the redox state and reducing the Aß level through regulating the Aß transport receptors and inflammatory cytokine of the cerebrovascular tissue.