The lncRNA LINC00339-encoded peptide promotes trophoblast adhesion to endometrial cells via MAPK and PI3K-Akt signaling pathways.

BACKGROUND: Endometrial receptivity (ER), a pivotal event for successful embryo implantation, refers to the capacity of endometrium to allow the adhesion of the trophectoderm of the blastocyst to endometrial cells. In this paper, we set to elucidate whether the peptides encoded by lncRNAs could influence trophoblast cells' adhesion to endometrial cells. METHODS: WGCNA construction and bioinformatics were used to find out the ER-related lncRNAs with coding potential. Protein analysis was done by immunoblotting and immunofluorescence (IF) microscopy. CCK-8 and Calcein-AM/PI double staining assays were employed to evaluate cell viability. The effect of the peptide on trophoblast spheroids' adhesion to endometrial cells was evaluated. The RNA sequencing (RNA-seq) analysis was applied to identify downstream molecular processes. RESULTS: lncRNA LINC00339 was found to be related to ER development and it had been predicted to have protein-coding potential. LINC00339 had high occupancy of ribosomes and was confirmed to encode a 49-aa peptide (named LINC00339-205-49aa). LINC00339-205-49aa could promote the attachment of JAR trophoblast spheroids to Ishikawa endometrial cells in vitro. LINC00339-205-49aa also upregulated the expression of E-cadherin in Ishikawa cells. Mechanistically, MAPK and PI3K-Akt signaling pathways were involved in the modulation of LINC00339-205-49aa, which were activated by LINC00339-205-49aa in Ishikawa cells. CONCLUSION: These data demonstrate that a previously uncharacterized peptide encoded by lncRNA LINC00339 has the ability to enhance JAR trophoblast spheroids' adhesion to Ishikawa endometrial cells, highlighting a new opportunity for the development of drugs to improve ER.

Biocompatible Electrical and Optical Interfaces for Implantable Sensors and Devices.

Implantable bioelectronics hold tremendous potential in the field of healthcare, yet the performance of these systems heavily relies on the interfaces between artificial machines and living tissues. In this paper, we discuss the recent developments of tethered interfaces, as well as those of non-tethered interfaces. Among them, systems that study neural activity receive significant attention due to their innovative developments and high relevance in contemporary research, but other functional types of interface systems are also explored to provide a comprehensive overview of the field. We also analyze the key considerations, including perforation site selection, fixing strategies, long-term retention, and wireless communication, highlighting the challenges and opportunities with stable, effective, and biocompatible interfaces. Furthermore, we propose a primitive model of biocompatible electrical and optical interfaces for implantable systems, which simultaneously possesses biocompatibility, stability, and convenience. Finally, we point out the future directions of interfacing strategies.

Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells.

Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 µM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.

Anti-inflammatory Potential of Saponins from Aster tataricus via NF-κB/MAPK Activation.

Four new aster saponins (1-4) together with five known analogues (5-9) were isolated from Aster tataricus. The chemical structures of 1-4 were elucidated based on spectrometric and spectroscopic analysis and comparison with reported data. The potential anti-inflammatory activities of aster saponins 1-9 were evaluated subsequently by measuring lipopolysaccharide (LPS)-enhanced nitric oxide (NO) formation in murine macrophages. Among these, aster saponin B (6) exhibited the most potent inhibitory activity (IC50: 1.2 µM). Additionally, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels were dose-dependently suppressed by 6 in LPS-activated RAW 264.7 cells. Investigation of the anti-inflammatory mechanism indicated that 6 attenuated the phosphorylation and degradation of the inhibitor of NF-κB (IκB), which led to the blocking of NF-κB p65 translocation to the nucleus.

Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation.

A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 µM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.

Therapeutic effect of human umbilical cord mesenchymal stem cells and their conditioned medium on LPS-induced endometritis in mice.

AIM: To explore the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) and their conditioned medium (MSC-CM) in repairing the endometritis mouse model in vivo. METHODS: Lipopolysaccharide (LPS) was used to induce acute inflammation in endometritis mouse model. Mice were treated in six groups: control group (PBS), model group (LPS), LPS+MSC-CM (6 h) group, LPS+MSC-CM (12 h) group, LPS+MSCs (6 h) group and LPS+MSCs (12 h) group. Morphological and histological changes of mouse uterus were observed, and mouse uterine inflammation index myeloperoxidase (MPO) and related immune index TNF-α, IL-6 and IL-1ß levels were detected by ELISA. RESULTS: There exist remarkable inflammatory response and an obvious increase in the value of MPO, TNF-α, IL-1ß and IL-6 in the endometritis mouse model compared with the control group. Morphological and histological appearances were relieved after treated with hUC-MSCs and MSC-CM. Besides, the value of MPO, TNF-α, IL-1ß and IL-6 showed different degrees of decline. In comparison with LPS+MSC-CM (12 h) and LPS+MSCs (12 h) group, there was significant decrease in inflammatory indicators in LPS+MSC-CM (6 h) and LPS+MSCs (6 h) group. CONCLUSIONS: Intrauterine infusion of hUC-MSCs and MSC-CM can alleviate LPS induced endometritis.

Alkaloids from Corydalis saxicola and their antiproliferative activity against cancer cells.

Eight undescribed alkaloids named corydalisine D-K (1-7), including one isoquinoline benzopyranone alkaloid (1), one benzocyclopentanone alkaloid (2), four benzofuranone alkaloids (3, 4, and 5a/5b) and two protoberberine alkaloids (6 and 7), along with fourteen known ones, were isolated from the Corydalis saxicola. Their structures, including absolute configurations, were unambiguously identified using spectroscopic techniques, single-crystal X-ray diffraction and electron circular dichroism calculation. Compounds 2, 14 and 21 exhibit antiproliferative activity against five cancer cell lines. The aporphine alkaloid demethylsonodione (compound 14), which exhibited the best activity (IC50 = 3.68 ± 0.25 µM), was subjected to further investigation to determine its mechanism of action against the T24 cell line. The molecular mechanism was related to the arrest of cell cycle S-phase, inhibition of CDK2 expression, accumulation of reactive oxygen species (ROS), induction of cell apoptosis, inhibition of cell migration, and activation of p38 MAPK signaling pathway. The results indicated that 14 could be used as a potential candidate agent for further development of anti-bladder transitional cell carcinoma.

Interplay of sleep patterns and oxidative balance score on total cardiovascular disease risk: Insights from the National Health and Nutrition Examination Survey 2005-2018.

Background: Unhealthy lifestyle and diet may contribute to the development of cardiovascular disease (CVD), but limited evidence exists regarding the association between sleep patterns, oxidative stress-related exposures to diet and lifestyle, and CVD risk. Methods: We analysed data from 10 212 adults in the National Health and Nutrition Examination Survey (NHANES) database (2005-2018). Self-report questionnaires were used to collect data on sleep duration, sleepiness, and trouble sleeping, classified into three categories: healthy, intermediate, and poor sleep patterns. Healthy sleep was defined as sleeping seven to nine hours per night with no self-reported sleepiness or trouble sleeping, while intermediate and poor sleep patterns indicated one and two to three sleep problems, respectively. The oxidative balance score (OBS) was calculated based on twenty oxidative stress-related exposures to dietary and lifestyle factors, with a higher score indicating greater antioxidant exposure. Survey-based multivariable-adjusted regression analysis was conducted to examine the association of sleep patterns or OBS alone and combined with the total and specific CVD risk. Results: Participants with poor sleep patterns had a higher likelihood of developing CVD (odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.26-2.45, P < 0.05), while an inverse association was found between OBS and CVD risk (quartile (Q) 4 vs Q1: OR = 0.67; 95% CI = 0.47-0.94, P = 0.02, P for trend <0.05). There was an interaction between sleep patterns and OBS (P for interaction = 0.03). Participants with unhealthy (intermediate and poor) sleep patterns and pro-oxidant OBS (Q1 and Q2) were significantly associated with increased risk of total CVD (OR = 2.31; 95% CI = 1.42-3.74, P < 0.05), as well as angina and congestive heart failure, but not coronary heart disease (CHD). Stratified analysis showed that among individuals without hyperlipidaemia, participants with both unhealthy sleep patterns and pro-oxidant OBS exhibited a higher risk of CHD compared to those with healthy sleep patterns and antioxidative OBS. Conclusions: Unhealthy sleep patterns and reduced oxidative balance are positively associated with an increased risk of overall and specific CVD. Interventions that target healthy sleep habits and antioxidant-rich diets and lifestyles may be important for reducing the risk of CVD.

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

Anti-inflammatory activity of isobutylamides from zanthoxylum nitidum var. tomentosum.

Inflammation is a very common and important basic pathological process. There is still a great need for the isolation of effective anti-inflammatory agents from plants. In this paper, five new isobutylamides, zanthoxylumamides E-I (1-5), and four known isobutylamides (6-9) were isolated from Zanthoxylum nitidum var. tomentosum (Rutaceae). Chiral resolution of seven racemic isobutylamides (1-4 and 6-8) was successfully performed, and the absolute configurations of two stereoisomers of 1-4 were validated by ECD and NMR. The obtained isobutylamides were evaluated in vitro anti-inflammatory activity with the lipopolysaccharide (LPS)-stimulated production of nitric oxide (NO) in murine macrophage RAW264.7 cells. Compound 8 exhibited significant inhibition of LPS-induced NO production. The underlying molecular mechanisms of the anti-inflammatory activity of 8 revealed that it suppressed the NO production through the modulation of myeloid differentiation factor 88 (MyD88) and interferon regulatory factor 3 (IRF3) signaling pathways.

Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disorders.

Iron is required for hemoglobin production, and it plays a key role during erythropoiesis. Systemic iron homeostasis is mainly negatively regulated by the peptide hormone hepcidin, coded by the gene HAMP. Hepcidin excess may cause iron deficiency, iron-restricted erythropoiesis, and anemia. Conversely, hepcidin insufficiency leads to iron overload and oxidative damage in multiple tissues. During regulation of hepcidin synthesis, multiple promoter elements in the HAMP gene respond to variable signaling pathways corresponding to different extracellular situations. It has been reported that hepcidin expression can be suppressed by secreted erythroid factors, including GDF15, TWSG1, GDF11, and ERFE, thereby increasing iron availability for hemoglobin synthesis. These potential erythroid factors act via intricate mechanisms that remain controversial. However, it is clear that hepcidin affects erythropoiesis, and promising therapies targeting hepcidin have been developed to treat erythroid disorders. These therapeutic strategies include suppressing or activating HAMP gene expression, mimicking or activating hepcidin activity, and blocking the ability of hepcidin to bind to its target ferroportin.

4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies.

BACKGROUND: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties. OBJECTIVE: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs. METHOD: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR. RESULTS: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1. CONCLUSION: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.