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Abstract Background Chemoresistance is associated with tumor relapse and unfavorable prognosis. Multiple mechanisms underlying chemoresistance have been elucidated, including stemness and DNA damage repair. Here, the involvement of the WNT receptor, FZD5, in ovarian cancer (OC) chemoresistance was investigated. Methods OC cells were analyzed using in vitro techniques including cell transfection, western blot, immunofluorescence and phalloidin staining, CCK8 assay, colony formation, flowcytometry, real-time PCR, and tumorisphere formation. Pearson correlation analysis of the expression levels of relevant genes was conducted using data from the CCLE database. Further, the behavior of OC cells in vivo was assessed by generation of a mouse xenograft model. Results Functional studies in OC cells showed that FZD5 contributes to epithelial phenotype maintenance, growth, stemness, HR repair, and chemoresistance. Mechanistically, FZD5 modulates the expression of ALDH1A1, a functional marker for cancer stem-like cells, in a β-catenin-dependent manner. ALDH1A1 activates Akt signaling, further upregulating RAD51 and BRCA1, to promote HR repair. Conclusions Taken together, these findings demonstrate that the FZD5-ALDH1A1-Akt pathway is responsible for OC cell survival, and targeting this pathway can sensitize OC cells to DNA damage-based therapy.

The objective of this study was to optimize the extraction process of total flavonoids from Haloragis micrantha (Thunb.) R. Brown. and explore its antioxidant activity. With the yield of total flavonoids as an evaluation index, single factor tests were used to investigate the effects of ethanol volume fraction, solid-liquid ratio, ultrasonic temperature and extraction time on the total flavonoids content of Haloragis micrantha (Thunb.) R. Brown., and the Box-Behnken method was used to optimize the extraction process. The scavenging ability and total reducing power of total flavonoids of Haloragis micrantha (Thunb.) R. Brown. to DPPH and ABTS+ free radicals were detected. The results showed that optimum extraction process was ethanol volume fraction of 76.15%, liquid to material ratio of 1:39.66 g/mL, ultrasonic time of 41.14 min. The yield of total flavonoids from Haloragis micrantha (Thunb.) R. Brown. was 28.61±0.05 mg/g. The total flavonoids of Haloragis micrantha (Thunb.) R. Brown. could effectively scavenge DPPH and ABTS+ free radicals. Within a certain range, the scavenging ability increased with the increasing of mass concentration, and the total flavonoids of Haloragis micrantha (Thunb.) R. Brown. had high reducing power and better antioxidant activity. The total flavonoids of Haloragis micrantha (Thunb.) R. Brown. had the strongest ability to scavenge ABTS+ free radicals. When the concentration of total flavonoids was 3 mg/mL, the clearance rate of ABTS+ were 98.28%, which was equivalent to 3 mg/mL vitamin C (clearance rate was 99.81%). This process would be simple and feasible, and the extracted total flavonoids have good antioxidant activity.

To study the effect of Annulohypoxylon stygium fermented tea aqueous extracts (ASTAE) on blood lipids and liver protection in mice, 80 male KM mice were established hyperlipidemic model by high-fat diet induction, and then randomly divided into eight groups: blank control group (CK), model group (HF), positive control group (UA, 200 mg/kg), green tea group (GT, 400 mg/kg), Annulohypoxylon stygium group (AS, 400 mg/kg), and high (HA, 400 mg/kg), medium (MA, 200 mg/kg) and low (LA, 100 mg/kg) dose Annulohypoxylon stygium fermented tea aqueous extracts groups. After 5 weeks, serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (Scr), blood urea nitrogen (BUN) and adiponectin (ADPN) levels were detected. Detect the organ index, and liver fat lesions and distribution were observed by HE and oil red O staining. The results showed that compared with the HF group, the HA group could extremely significantly reduce the levels of TC, TG, LDL-C, AST, ALT, BUN and Scr in hyperlipidemia mice (P

In comparison to metal complexes, organic photosensitive dyes employed in photocatalytic hydrogen production exhibit promising developmental prospects. Utilizing the organic dye molecule TA+0 as the foundational structure, a series of innovative organic dyes, denoted as TA1-1 to TA2-6, were systematically designed. Employing first-principles calculations, we methodically explored the modifying effects of diverse electron-donating groups on the R1 and R2 positions to assess their application potential. Our findings reveal that, relative to the experimentally synthesized TATA+03, the TA2-6 molecule boasts a spatial structure conducive to intramolecular electron transfer, showcasing the most negative reduction potential (Ered = −2.11 eV) and the maximum reaction driving force (△G02 = −1.26 eV). This configuration enhances its compatibility with the reduction catalyst, thereby facilitating efficient hydrogen evolution. The TA2-6 dye demonstrates outstanding photophysical properties and a robust solar energy capture capacity. Its maximum molar extinction coefficient (ε) stands at 2.616 × 104 M−1·cm−1, representing a remarkable 292.8% improvement over TATA+03. In conclusion, this research underscores the promising potential of the TA2-6 dye as an innovative organic photosensitizer, positioning it as an efficacious component in homogeneous photocatalytic systems.

In order to evaluate the effect of RRE on reducing blood lipid and protecting liver, a model of nonalcoholic fatty liver disease (NAFLD) mice induced by high-fat diet was used, and then the body weight, liver weight and liver coefficient of each group were calculated, and the TC、TG、HDL-C、LDL-C、AST、ALT、AKP were checked by sample test. The liver tissue was stained with HE and oil Red O for pathological observation and fat particles observation; Animal experiment results showed that RRE intervention could effectively improve the process of liver pathological changes, alleviate inflammatory injury and reduce the accumulation of liver fat particles in NAFLD mice; both high and medium doses of RRE could significantly reduce the levels of TC, TG and LDL-C in serum of NAFLD mice (P0.05); Through network pharmacology, the intersection of Rhinacanthus nasutus and NAFLD disease-related targets was carried out, and the effective active substances and action mechanism of RRE were predicted combined with molecular docking technology, which showed that rhinacanthin-C had good binding potential with the intersection targets. The experimental results showed that the RRE could reduce blood lipid, improved liver lipid deposition and inflammatory injury in NAFLD mice, so as to protect the liver. Its mechanism may be that the active substance rhinacanthin-C can improve liver lipid deposition and metabolic disorder through AMPK-SREBP1c-SIRT1 signal pathway. The experimental results can provide a scientific basis for the development of Zhuang medicine Rhinacanthus nasutus as a national drug for reducing blood lipid and improving fatty liver.

Abstract Chemoresistance represents a major obstacle to the treatment of human cancers. Increased DNA repair capacity is one of the important mechanisms underlying chemoresistance. In silico analysis indicated that YTHDF1, an m6A binding protein, is a putative tumor promoter in breast cancer. Loss of function studies further showed that YTHDF1 promotes breast cancer cell growth in vitro and in vivo. YTHDF1 facilitates S-phase entry, DNA replication and DNA damage repair, and accordingly YTHDF1 knockdown sensitizes breast cancer cells to Adriamycin and Cisplatin as well as Olaparib, a PARP inhibitor. E2F8 is a target molecule by YTHDF1 which modulates E2F8 mRNA stability and DNA damage repair in a METTL14-dependent manner. These data demonstrate that YTHDF1 has a tumor-promoting role in breast cancer, and is a novel target to overcome chemoresistance.

Cadmium (Cd), widely present in food and drinking water at low doses, can cause health risks. However, the mechanistic effects of long-term Cd exposure at low dose through dietary intake is poorly studied. The aim of this study is to elucidate whether the dysbiosis of gut microbiota caused by Cd at an environmental low dose can aggravate the injury of mice liver, and the possible mechanism is investigated. In order to explore the potential underlying mechanism, the analyses of the variation of gut microbiota composition, intestinal permeability, and hepatic transcriptome were conducted. Our results showed that gut microbiota was disturbed. The rise of intestinal permeability induced by the dysbiosis of gut microbiota resulted in more Cd ions accumulating in mice liver, but it could be restored partly through depleting gut microbiota by antibiotics cocktail. Transcriptomic analyses indicated that 162 genes were significantly differentially expressed including 59 up-regulated and 103 down-regulated in Cd treatment. These genes were involved in several important pathways. Our findings provide a better understanding about the health risks of cadmium in the environment.

Under the new educational philosophy, the comprehensive quality evaluation of students in sports colleges is increasingly receiving attention from educators and society. Because comprehensive quality not only covers professional knowledge and skills, but also includes moral qualities, innovative spirit, teamwork ability, etc., which are all urgent needs for talents in sports colleges and universities in society. However, the comprehensive quality evaluation system for students in sports colleges and universities seems to be unable to fully meet this demand, and there are some problems that cannot be ignored, such as excessive emphasis on grades, fixed evaluation systems, lack of student participation in the evaluation process, and fuzzy evaluation standards. The existence of these problems not only affects the fairness and effectiveness of evaluation, but also hinders the comprehensive development of students and the process of educational reform. Therefore, how to optimize the comprehensive quality evaluation system of students in sports colleges and universities to better adapt to the needs of social development has become an important topic in current sports education research. The comprehensive quality evaluation of physical education institutions is multi-attribute decision-making (MADM). Exponential TODIM (ExpTODIM) and improved grey relational analysis (IGRA) approaches were used to address MADM issues in this context. Hesitant Triangular Fuzzy Sets (HTFSs) have been employed as a tool for characterizing the uncertain information inherent in the comprehensive quality evaluation of physical education institutions. In this paper, we develop a Hesitant Triangular Fuzzy Number Exponential TODIM-IGRA (HTFN-ExpTODIM-IGRA) approach to illustrate the MADM problem under the framework of HTFSs. Finally, numerical study for the comprehensive quality evaluation of physical education institutions, along with comparative analysis, is provided to validate the HTFN-ExpTODIM-IGRA approach.

Abstract This study systematically investigates the spatio-temporal distribution, influential factors, and conservation significance of 413 traditional villages in Xiangxi, China. Employing methods such as ArcGIS spatial analysis, geographic statistical analysis, and historical literature review, this work meticulously delineates the intricate interplay of natural, societal, and cultural elements in shaping the evolution of village distributions. As pillars of China's rich traditional culture, these villages encapsulate profound historical, folkloric, and architectural values. Their spatial and temporal transformations are instrumental in unraveling Xiangxi’s historical and cultural tapestry, thereby informing strategic conservation efforts. The research findings are as follows: (1) from a spatial perspective, traditional villages in Xiangxi, China, exhibit an overall clustering tendency, characterized by a distribution pattern of "more in the core, fewer on the periphery, with small clusters and significant dispersion." These villages are distributed in multiple bands along ancient postal routes, the Wuling Mountains, the Xuefeng Mountains, and river basins. (2) Traditional villages in Xiangxi primarily originated prior to the Yuan Dynasty, with a predominant north–south spatial orientation. Over successive dynasties, the distribution center gradually shifted northeastward, resulting in an expansion of the spatial distribution range and a decrease in directional bias. (3) The formation and distribution evolution of traditional villages are influenced by a combination of natural factors, socio-economic factors, and historical-cultural factors. Natural factors and cultural elements influence the selection and layout of traditional village sites, while socio-economic and historical-cultural factors impact their development and evolution. In conclusion, the distribution evolution of traditional villages in Xiangxi, China, underscores the intricate interplay of diverse factors, spanning the realms of nature, society, and culture. Recognizing this complexity is essential in comprehending the historical and cultural tapestry of Xiangxi and in formulating strategies for the preservation of these invaluable cultural and historical assets. The preservation of traditional villages transcends mere heritage conservation; it represents a pivotal step towards safeguarding the multifaceted heritage of Xiangxi.

In this work, a magnetic covalent organic frameworks (COFs) named Fe3O4@TpBD was rapidly synthesized by an ultrasonic method, which reduced the synthesis time to 1.5 h. Fe3O4@TpBD was used as a magnetic solid-phase extraction (MSPE) adsorbent for the extraction and enrichment of five common sulfonamides, and there were different enrichment multiples ranging from 5 to 30. The limits of detection (LODs) of this method were 0.31–0.73 ng mL−1, the limits of quantitation were 1.03–2.44 ng mL−1, and the intraday and interday relative standard deviations (RSDs) were

Background: The success of embryo transfer cycle depends mainly on the quality of embryo and endometrial receptivity. Ultrasound examination is still the most widely used non-invasive evaluation method for its advantages of convenience, non-invasiveness and repeatability. Ultrasound-measured endometrial blood flow is one of the important evaluation indicators of morphology.Aims: To investigate the effect of the number of endometrial blood flow branches on pregnancy outcome of frozen-thawed embryo transfer cycles which have undergoing hormone replacement therapy (HRT-FET).Material and methods: A retrospective cohort study was performed looking at a total of 1390 HRT-FET cycles from our reproductive medicine center between January 2017 to December 2021, which transferred one blastocyst frozen on day 5 with good quality in morphology. Associations between endometrial blood flow branches and pregnancy outcomes were evaluated with multivariable linear regression analysis.Results: The number of endometrial blood flow branches was independently associated with clinical pregnancy (OR 1.10; 95% CI 1.02–1.20). After adjusting for potential confounders, the effect size (odds ratio) was 1.09 (95% CI 1.00–1.19), and the results showed that the clinical pregnancy rate and live birth rate of T2 and T3 groups were significantly higher than those in group T1 (p < 0.05). Subgroup analysis showed that a consistent association between the endometrial blood flow branches and clinical pregnancy in all subgroups.Conclusion: Our study provided evidence for the influence of endometrial blood flow on pregnancy outcomes. There may be an independent association between the number of endometrial blood flow branches and pregnancy outcomes in frozen-thawed single blastocyst transfer cycles.

Mussels can form tough and long-lasting adhesions to organic and inorganic surfaces in saline and impactive severe aquatic environments. Similar to mussel adhesion, dentin bonding occurs in a wet environment. However, unlike mussels, it is difficult to achieve long-lasting bonds with dentin. Moreover, water is considered a major hindrance in dentin bonding. Inspired by the synergistic effect of cationic lysine (Lys) and catechol on the elimination of the hydration layer during mussel adhesion, a catechol- and Lys-functionalized polymerizable polymer (catechol–Lys–methacrylate [CLM]) was synthesized to replicate the complex synergy between amino acids and catechol. The bond-promoting potential of 5 ​mg/mL CLM primer was confirmed using an in vitro wet dentin-bonding model, which was characterized by an improvement in bond strength and durability. CLM can adhere to wet demineralized dentin, with Lys acting as a molecular vanguard to expel water. Subsequently, a myriad of interfacial interactions can be obtained by introducing the catechol group into the interface. Additionally, tough and long-lasting adhesion, similar to that formed by mussels, can be achieved by grafting CLM onto type I collagen via covalent bonds, hydrogen bonds, Van der Waals interactions, and cation–π interactions, which can enhance the mechanical and chemical stability of collagen, increase the enzymatic resistance of collagen, and provide additional physical/chemical adhesion to dentin bonds. Catechol- and cationic Lys-functionalized polymers can improve the stability of the resin–dentin interface under wet conditions.

Abstract Background FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. However, few studies have investigated the role of FAT4 in the development of colorectal cancer (CRC). The current study aimed to detect the role of FAT4 in the invasion, migration, proliferation and autophagy of CRC and elucidate the probable molecular mechanisms through which FAT4 interacts with these processes. Methods Transwell invasion assays, MTT assays, transmission electron microscopy, immunohistochemistry and western blotting were performed to evaluate the migration, invasion, proliferation and autophagy abilities of CRC cells, and the levels of active molecules involved in PI3K/AKT signaling were examined through a western blotting analysis. In addition, the function of FAT4 in vivo was assessed using a tumor xenograft model. Results FAT4 expression in CRC tissues was weaker than that in nonmalignant tissues and could inhibit cell invasion, migration, and proliferation by promoting autophagy in vitro. Furthermore, the regulatory effects of FAT4 on autophagy and the EMT were partially attributed to the PI3K-AKT signaling pathway. The results in vivo also showed that FAT4 modulated CRC tumorigenesis. Conclusion FAT4 can regulate the activity of PI3K to promote autophagy and inhibit the EMT in part through the PI3K/AKT/mTOR and PI3K/AKT/GSK-3β signaling pathways.

The metabotropic glutamate subtype 1 (mGluR1), a member of the metabotropic glutamate receptors, is a therapeutic target for neurological disorders. However, due to the lower subtype selectivity of mGluR1 orthosteric compounds, a new targeted strategy, known as allosteric modulators research, is needed for the treatment of mGluR1-related diseases. Recently, the structure of the seven-transmembrane domain (7TMD) of mGluR1 has been solved, which reveals the binding site of allosteric modulators and provides an opportunity for future subtype-selectivity drug design. In this study, a series of computer-aided drug design methods were utilized to discover potential mGluR1 negative allosteric modulators (NAMs). Pharmacophore models were constructed based on three different structure types of mGluR1 NAMs. After validation using the built-in parameters and test set, the optimal pharmacophore model of each structure type was selected and utilized as a query to screen the Traditional Chinese Medicine Database (TCMD). Then, three different hit lists of compounds were obtained. Molecular docking was used based on the latest crystal structure of mGluR1-7TMD to further filter these hits. As a compound with high QFIT and LibDock Score was preferred, a total of 30 compounds were retained. MD simulation was utilized to confirm the stability of potential compounds binding. From the computational results, thesinine-4ʹ-O-β-d-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGluR1. This paper indicates the applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs.

Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. In the event of serious human orthopoxvirus infections, it is important to have treatments available for individual patients as well as their close contacts. The smallpox vaccine and vaccinia immune globulin (VIG) were used in the past as therapeutics for patients exposed to smallpox. VIG was also used in patients who were at high risk of developing complications from smallpox vaccination. Thus post-exposure vaccination and VIG treatments may again become important therapeutic modalities. This paper summarizes some of the historic use of the smallpox vaccine and immunoglobulins in the post-exposure setting in humans and reviews in detail the newer animal studies that address the use of therapeutic vaccines and immunoglobulins in orthopoxvirus infections as well as the development of new therapeutic monoclonal antibodies.

Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.