Resistance Signaling Pathways Research Articles

The role of circRNA in breast cancer drug resistance

Among women with cancer, breast cancer has surpassed lung cancer to become the most prevalent type of cancer globally. High-throughput sequencing of breast cancer tissues from many patients has revealed significant variations in circRNA expression across different types of breast cancer. Chemotherapy is currently a very important method for treating breast cancer; however, as the number of chemotherapy sessions increases and considering factors such as the patient’s immune response, drug resistance has become a challenging issue in treating breast cancer. It is well known that drug resistance is associated with multiple factors, and different resistance mechanisms involve different roles of circRNA. This review consolidates literature from the past 5 years and addresses the shortcomings in the broad description of circRNA’s role in breast cancer drug resistance. It categorizes and describes the drug resistance and its mechanisms in different types of breast cancer, as well as the roles of circRNA and signaling pathways in drug resistance.

Gut microbiota may mediate the causality of statins on diabetic nephropathy: a mediation Mendelian randomization study.

Increasing evidence indicates that statins may increase the risk of developing diabetic nephropathy (DN). As the gut-kidney axis concept gains traction, it remains unclear whether statins contribute to the onset and progression of DN by modulating gut microbiota. To investigate the association between statins and DN and the proportion of this association mediated through gut microbiota. This study utilized a two-sample Mendelian randomization (MR) approach and a cross-sectional observational design to investigate the causal relationships among statins, 473 gut microbiota, and DN. Furthermore, mediation MR analysis was employed to explore the potential mediating effects of gut microbiota in the statins-DN relationship. HMGCR inhibitors were causally linked to the increased incidence of DN (odds ratio [OR]: 0.732, 95% confidence interval [CI] 0.647, 0.828, PFDR = 0.000004). Supporting results from a cross-sectional study based on the Medical Information Marketplace in Intensive Care (MIMIC-IV) database also indicated this association (OR: 0.74, 95% CI: 0.61, 0.91, P = 0.004). Among the 473 identified gut microbiota species, 13 (PFDR < 0.05) were causally associated with DN. The mediation MR analysis revealed that 10 gut microbiota mediated the relationship between statins and DN, acting as either protective or risk factors (P < 0.05). In addition, HMGCR and related proteins may be involved in lipid metabolism, insulin resistance, and AMPK signaling pathway. Statins may become a risk factor for DN by increasing or decreasing the abundance of specific gut microbiota. These specific gut bacteria have the potential to become a new indicator for guiding the clinical use of statins in diabetic patients.

Exploration of the key active ingredients and mechanisms of Sparganii Rhizoma-Curcumae Rhizoma compatible formulation against human colorectal cancer through network pharmacology and in vitro experiments

IntroductionSparganii Rhizoma-Curcumae Rhizoma (SR-CR) formulation may offer an effective treatment for human colorectal cancer (CRC). However, the active ingredients and underlying mechanisms of this herbal formulation remain unclear. MethodsThis study integrates network pharmacology, molecular docking and experimental verification to identify key active ingredients and elucidate the mechanisms of SR-CR in CRC treatment. ResultsTwenty-three active components of SR-CR were identified using the TCMSP, UniProt and Gene Cards databases. These components were associated with 178 targets, of which 118 are directly related to CRC. Protein-protein interaction (PPI) network analysis identified protein kinase B (AKT) 1, epidermal growth factor receptor (EGFR), SRC, Bcl2 and CASP3 as core anti-CRC targets. Gene Ontology (GO) and KEGG pathway analyses were performed on these 178 intersecting targets, and the results showed that these targets are involved in EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. At the same time, five compounds, including bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, were selected based on the target number of effective components and tested for cytotoxicity against human CRC cell lines HT-29, HCT-8 and HCT-116 in vitro. The results showed that bisdemethoxycurcumin exhibited significant anti-proliferative activity against HCT-116 cells. Molecular docking results indicated that bisdemethoxycurcumin effectively binds with AKT, EGFR, Bcl-2 and CASP3. Further pharmacological experiments demonstrated that bisdemethoxycurcumin inhibits HCT-116 cell proliferation and migration via inhibiting EGFR-AKT pathway, and induces apoptosis by up-regulating Bcl-2 expression. DiscussionBased on our study, inhibiting the EGFR-AKT pathway and upregulating Bcl2 may be one of the mechanisms by which SR-CR inhibits the growth of CRC. The main active ingredients of SR-CR include bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, which may exert anti-colon cancer activity by targeting the regulation of AKT, EGFR, Bcl-2 and CASP3. However, we need more in vitro and in vivo evidence to confirm this conclusion. This study lays the foundation for further research on the pharmacological mechanism of SR-CR in the treatment of CRC.

Phyllanthi Fructus ameliorates hyperuricemia and kidney injure via inhibiting uric acid synthesis, modulating urate transporters, and alleviating inflammation

Phyllanthi Fructus, known as Yuganzi (YGZ), is a unique medicine and food homologous fruit with both medicinal and nutritional properties. Its historical use in treating hyperuricemia (HUA) and gout is well-documented. However, the precise therapeutic effects and potential molecular mechanisms remain unclear. In this study, an experimental rat modelling by a high-fat/high-sugar diet and potassium oxonate/adenine oral administration was used to evaluate the pharmacodynamic effects of YGZ. Network pharmacology, molecular docking and molecular dynamics simulation were utilized to elucidate the potential mechanisms. Supplementation with YGZ effectively ameliorated HUA by inhibiting xanthine oxidase activity, and enhancing uric acid excretion through up-regulating of OAT1 and ABCG2, while down-regulating of URAT1. Furthermore, YGZ supplementation enhanced superoxide dismutase activity, reduced malondialdehyde content, and inhibited the secretion of IL1B, IL6, TNFα, ICAM1, VCAM1, TGFβ1, and NF-κB protein expression. Network pharmacology analysis indicated that YGZ influences 138 targets, modulating the disease network via lipid and atherosclerosis, insulin resistance, HIF-1, TNF, IL-17, TLRS, and NF-κB signaling pathways. Molecular docking analysis suggested that organic acids (e.g. ellagic acid, gallic acid) and flavonoids (e.g. quercetin, delphinidin, luteolin, epigallocatechin gallate) exhibited superior binding abilities to key targets (e.g. XDH, ABCG2, URAT1, OAT1, IRS1, PTGS2, TLR4). Noteworthy, molecular dynamics simulations confirmed that epigallocatechin gallate binds to URAT1 with the greatest stability. These results provide substantial evidence for the therapeutic efficacy of YGZ and establish a theoretical foundation for the development of natural products in treating hyperuricemia.

Network Pharmacology and Molecular Dynamics Simulations Reveal the Mechanism of Total Alkaloid Components in Anisodus Tanguticus (Maxim.) Pascher in Treating Inflammation and Pain.

This study aimed to elucidate the mechanism that total alkaloids in Anisodus tanguticus (AT)(Maxim.) Pascher played anti-inflammatory and analgesic effects. In this paper, the anti-inflammatory effect in the total alkaloids of AT was confirmed via lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 cells and the main components of AT were immediately analyzed by UPLC/MS. Disease targets were obtained in GeneCards and DisGeNET. Targets of major compounds were searched in ETCM, TCMSP and other databases. The protein-protein interaction (PPI) network was constructed using STRING database, and Cytoscape was used for core targets screening. GO and KEGG enrichment analysis were performed using Daivid database. Sailvina was used for molecular docking. Molecular dynamics simulation analysis was performed using the Amber 20 program. The results showed that the main components in AT were anisodamine, atropine, fabiatrin, scopolamine, scopoletin and scopolin, possibly exerting anti-inflammatory and analgesic effects through pathways such as EGFR tyrosine kinase inhibitor resistance and IL-17 signaling pathway. Fabiatrin and scopolin could be potential drugs with good anti-inflammatory and analgesic effects.

Effect of Rhei Radix Et Rhizome on treatment of polycystic ovary syndrome by regulating PI3K/AKT pathway and targeting EGFR/ALB in rats

Ethnopharmacological relevanceAbnormal endocrine metabolism caused by polycystic ovary syndrome (PCOS) poses a serious risk to reproductive health in females. According to Traditional Chinese Medicine (TCM) theories, the leading causes of PCOS include turbid phlegm, blood stasis and stagnation of liver Qi. Rhei Radix Et Rhizome is widely used in TCM to attack stagnation, clear damp heat, relieve fire. Rhei Radix Et Rhizome is an important part of the TCM formulas for the treatment of PCOS, which has a long history of medicinal use. However, the specific effect and mechanisms of Rhei Radix Et Rhizome on PCOS have yet to be elucidated. Aim of the studyThe object of this study aimed to investigate the effect and its pharmacological mechanism of Rhei Radix Et Rhizome on the treatment of polycystic ovary syndrome. MethodsPCOS was induced in female Sprague Dawley (SD) rats by administering letrozole (1 mg/kg, per orally, p.o.) for 21 days, then treated with Rhei Radix Et Rhizome at doses of 0.6 g/kg or 1.2 g/kg. Rats weight, blood glucose and estrus period are measured, and serum hormone include free testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and ovarian lesions were observed to determine the effects of Rhei Radix Et Rhizome. Network pharmacology and molecular docking predicted the targets of Rhei Radix Et Rhizome on PCOS. Epidermal growth factor receptor (EGFR), albumin (ALB), PI3K and P-AKT/AKT protein expression levels in ovarian tissues were assessed by Western blot. ResultsRhei Radix Et Rhizome reduce abnormal weight and fasting blood glucose induced by letrozole (n = 5, p < 0.01), and improve the disturbed estrus cycle, reduce T, LH levels and LH/FSH ratio of PCOS rats (n = 4, p < 0.01). In addition, it alleviates the polycystic changes of ovaries in PCOS rats and reduces ovarian histopathological damage (n = 4, p < 0.01). Additionally, the core active components of Rhei Radix Et Rhizome for PCOS include Sennoside D_qt, Procyanidin B-5,3′-O-gallate, and Mutatochrome, which strongly bind to core therapeutic targets ALB and EGFR. Furthermore, the treatment reduces the increase of EGFR and ALB induced by letrozole (n = 4, p < 0.01). KEGG pathway enrichment analysis highlights endocrine resistance and prolactin signaling pathway, in both of which the PI3K/AKT pathway plays a crucial role. Our results show Rhei Radix Et Rhizome rescue the abnormal expression of PI3K/AKT pathway in PCOS rats (n = 4, p < 0.01). However, no significant dose-dependent relationship was observed in the tested dose range for the above experiments. ConclusionThese findings suggest that Rhei Radix Et Rhizome can regulate the PI3K/AKT pathway and target EGFR and ALB to treat polycystic ovary syndrome in rats. This study provides a scientific basis for the use of Rhei Radix Et Rhizome in the treatment of PCOS and highlights its potential mechanism through modulation of the PI3K/AKT pathway.

Transglutaminase 2 in breast cancer metastasis and drug resistance.

Transglutaminase 2 (TG2) is a widely distributed multifunctional protein with various enzymatic and non-enzymatic activities. It is becoming increasingly evident that high levels of TG2 in tumors induce the occurrence of epithelial to mesenchymal transition (EMT) and the acquisition of stem cell-like phenotypes, promoting tumor metastasis and drug resistance. By regulating intracellular and extracellular signaling pathways, TG2 promotes breast cancer metastasis to lung, brain, liver and bone, as well as resistance to various chemotherapy drugs including docetaxel, doxorubicin, platinum and neratinib. More importantly, recent studies described the involvement of TG2 in PD-1/PD-L1 inhibitors resistance. An in-depth understanding of the role that TG2 plays in the progression of metastasis and drug resistance will offer new therapeutic targets for breast cancer treatment. This review covers the extensive and rapidly growing field of the role of TG2 in breast cancer. Based on the role of TG2 in EMT, we summarize TG2-related signaling pathways in breast cancer metastasis and drug resistance and discuss TG2 as a therapeutic target.

Insights into the DNA methylation of Portunus trituberculatus in response to Vibrio parahaemolyticus infection

Vibrio parahaemolyticus is the main pathogen causing acute hepatopancreatic necrotic disease in crustaceans. To elucidate the epigenetic regulatory mechanism of crustacean resistance to V. parahaemolyticus infection, we conducted artificial infection studies on Portunus trituberculatus. The results showed that the mortality rate reached the highest at 12 h of artificial infection, which was 23.69 %. At 72 h after V parahaemolyticus infection, the expression level of DNA demethylase (ten-eleven-translocation protein) Tet was significantly decreased, the expression of DNA methyltransferase Dnmt3B fluctuated significantly. Based on the differential expression levels of Tet and Dnmt3B. We depict for DNA methylation profiles of the whole genome of P. trituberculatus at single-base resolution by using whole-genome bisulfite sequencing (WGBS) on hemolymph tissues. The overall DNA methylation level was low at 2.16 % in P. trituberculatus hemolymph. A total of 2590 differentially methylated regions (DMRs) were identified, of which 1329 were hypermethylated and 1261 were hypomethylated, and 1389 genes were annotated in these DMRs. Differently methylated genes (DMGs) were significantly enriched in ribosomes (KO03010), protein kinases (KO01001), cell cycle (HSA04110), endocrine resistance (HSA01522) and FoxO signaling pathway (KO04068). Finally, we selected six differentially methylated genes for quantitative analysis. The results showed that DNA methylation not only has a negative regulatory effect on gene expression, but also has a positive regulatory effect. These results indicated that DNA methylation in the regulation of genes involved in immune responses contributes to the resistance of P. trituberculatus to V. parahaemolyticus, which is valuable for understanding how crustaceans regulate the innate immune system to defend against bacterial infections.

Pharmacological targets and validation of remdesivir for the treatment of COVID-19-associated pulmonary fibrosis: A network-based pharmacology and bioinformatics study.

The objective of this study was to employ bioinformatics and network pharmacology methodologies to investigate the targets and molecular mechanisms of remdesivir in the treatment of coronavirus disease 2019 (COVID-19)-associated pulmonary fibrosis (PF). Several open-source databases were utilized to confirm the shared targets of remdesivir, COVID-19, and PF. Following this, a comprehensive analysis incorporating function enrichment, protein-protein interaction (PPI), transcription factor (TF), and molecular docking was conducted to investigate the potential mechanisms underlying the effectiveness of remdesivir in the treatment of COVID-19-associated PF. The initial validation of these findings was performed using publicly available histological and single-cell sequencing databases. The functional enrichment analysis revealed a strong association between remdesivir and viral defense, inflammatory response, and immune response. The key pathways identified in the study were transforming growth factor (TGF-β), PI3K-Akt, mTOR, MAPK, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, HIF-1, and Toll-like receptor signaling pathways. Additionally, the PPI analysis demonstrated the network relationships of 13 important targets, while the TF analysis provided valuable insights into the regulatory networks of these targets. Among the identified TFs, RELA was found to be the most significant. To validate our findings, we utilized publicly available histological and single-cell sequencing databases, successfully confirming the involvement of 8 key targets, including AKT1, EGFR, RHOA, MAPK1, PIK3R1, MAPK8, MAPK14, and MTOR. Furthermore, molecular docking studies were conducted to assess the interaction between remdesivir and the identified key targets, thus confirming its effective targeting effects. Remdesivir has the potential to exert antiviral, anti-inflammatory, and immunomodulatory effects in the context of COVID-19-associated PF.

A combined model of six serum microRNAs as diagnostic markers for hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and its poor prognosis is mainly due to the lack of an effective means of early diagnosis. This study aimed to identify a group of serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of HCC. MethodsWe collected 190 HCC cases, 109 benign lesions of the liver, 40 cases of non-HCC tumors, and 130 healthy controls. The 469 participants were divided into training and validation sets. A literature search revealed 12 miRNAs closely associated with HCC. In the training set, significantly differentially expressed miRNAs (DEmiRNAs) were screened using real-time quantitative PCR, and a diagnostic model of HCC was constructed using logistic regression analysis. An independent validation was performed using a validation set. The identified DE miRNAs were subjected to target gene prediction and functional analyses. ResultsCompared to the controls, the levels of miR-21, miR-221, miR-801, and miR-1246 significantly decreased in HCC (P < 0.05), while the levels of miR-26a and miR-122 significantly increased (P < 0.05). A diagnostic model based on the six DE miRNAs was successfully constructed, with AUC values of 0.953 for the training set and 0.952 for the verification set. Finally, 100 target genes of the DE miRNAs were predicted and were significantly enriched in the B cell receptor, neurotrophin, ferroptosis, and EGFR tyrosine kinase inhibitor resistance signaling pathways. ConclusionsThe constructed diagnostic model based on six DE miRNA combinations has important clinical value for the early diagnosis of HCC

Abstract C110: The role of the S100 family signaling pathway proteins in Hispanic colorectal cancer disparities

Abstract Colorectal cancer (CRC) is a global health concern, ranking as the second deadliest and third most diagnosed cancer. In the United States alone, it is estimated that there will be 152,810 new cases of CRC in 2024. CRC has an overall survival rate of 90% when detected in its early stages (Stage I/II). However, due to low screening rates, only 39% of CRC patients in the U.S. are diagnosed during the early stage, particularly among the minority groups like Hispanics. This disparity can be attributed to various factors, including limited access to health care facilities and socio-economic barriers. Among Hispanics, CRC diagnosis and screening rate are lower, resulting in a higher incidence of late-stage (Stage III/IV) diagnosis compared to Non-Hispanic Whites (NHW). Only 33% of Hispanics receive timely diagnosis, and merely 49% undergo recommended screening protocols, in comparison to a diagnosis rate of 35% and screening rate of 58% in NHW. Addressing this health disparity emphasizes the urgent need for targeted interventions to improve early screening and diagnosis within the Hispanic population. We hypothesize that genetic factors across different ethnicities/races may influence gene expression patterns during various stages, thereby contributing to CRC tumorigenesis and progression. To enhance the chances of identifying markers for early detection and diagnosis among Hispanics, we aim to identify new ethnicity-specific transcriptomic profiles. RNA sequencing of Hispanic CRC, NHW CRC and their respective normal tissues adjacent to the tumor (NAT), revealed unique sets of differentially expressed genes (DEGs) with a log2 foldchange of ≥ 2.0 and ≤ -2.0 and p-adjusted value ≤ 0.05 in Hispanic (1831) and NHW (1225) CRC populations compared to their respective NATs. Further analysis identified DEGs specific to early (1012) and late (765) stages of CRC within the Hispanic population, as compared to the respective stages in the NHW. Ingenuity Pathway Analysis (IPA) was used to uncover significant DEGs associated with the S100 family signaling pathway in Hispanic CRC samples. Previous studies have indicated the involvement of the S100 family proteins and their signaling pathways in CRC development, progression, metastasis, and drug resistance through interactions with WNT/β-catenin, RAGE, MAPK and NF-κβ signaling pathways. Our investigation of DEGs within the S100 signaling pathway and their interaction with downstream effectors suggests differential expression of genes crucial in cellular processes, including matrix metallopeptidases (MMP), mitogen-activated protein kinases (MAP2K) and Wingless-related integration site (WNT) family proteins. Exploring these proteins and their downstream effectors in Hispanic CRC tissues and organoids would elucidate specific functional attributes influencing CRC progression. Understanding the interaction of proteins identified in this study may serve as potential ethnicity-specific biomarkers or targets for the development of novel therapeutic interventions for early-stage CRC diagnosis in Hispanics. Citation Format: Soumya Nair, Brian I Grajeda, Sourav Roy. The role of the S100 family signaling pathway proteins in Hispanic colorectal cancer disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C110.

189 Association of the liver phosphoproteome with divergent dry matter intake in finishing beef steers

Abstract As the need for improving the sustainability of the beef industry increases, optimizing feed efficiency is of the utmost importance. The liver has a central role in nutrient metabolism, and for ruminants particularly, it is essential for providing glucose through gluconeogenesis via substrates such as propionate, lactate, and glycerol. Further, through cell signaling and vagal afferent signals, the liver acts to stimulate and inhibit dry matter intake (DMI). Thus, the objective of this study was to investigate alterations in the phosphoproteome of finishing beef steers in relation to divergent DMI to identify changes in the abundance of signaling proteins. Angus steers [n = 57; initial body weight (BW) = 518 ± 27 kg] underwent a 63-d intake trial utilizing an Insentec Roughage Intake Control System (Hokofarm Group, Emmeloord, The Netherlands). Prior to beginning the trial, liver biopsy samples were collected from all steers. Samples from steers with the greatest and least DMI (n = 8 each) were utilized for phosphoproteomic analysis. Liver protein was isolated and labeled with isobaric tandem mass tagging reagents. Samples were enriched for phosphopeptides using immobilized metal affinity chromatography and subsequently analyzed using high-performance liquid chromatography tandem mass spectrometry. Spectral data were searched in the National Center for Biotechnology Information Bos taurus protein database using MaxQuant (version 2.2.0.0; Max Planck Inst., Munich, Germany), and the data were analyzed using Perseus (version 2.0.10.0; Max Planck Inst.). Two sample t-tests were conducted to determine the difference in phosphopeptide abundance between steers with high and low DMI. A total of 16,365 phosphopeptides were identified, and 287 were differentially expressed (False Discovery Rate &amp;lt; 0.05). In addition, 2,777 phosphopeptides were differentially expressed based on an unadjusted P &amp;lt; 0.05 which were used for enrichment analysis of Gene Ontology processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using the Database for Annotation, Visualization, and Integrated Discovery. The background for this analysis was all identified phosphopeptides. Gene ontology terms enriched included processes related to phosphorylation activity, intracellular signal transduction, response to insulin, kinase activity, and signaling protein binding. Enriched KEGG pathways included pathways related to insulin signaling, such as AMPK signaling, mTOR signaling, and MAPK signaling. Further, pathways related to glycolysis and gluconeogenesis, glucagon signaling, insulin resistance, carbon metabolism, and various other signaling pathways were also enriched. These results suggest a link between the liver phosphoproteome and DMI, indicating that divergent DMI is associated with alterations in signaling pathways related to nutrient uptake and metabolic processes.

Compositional Analysis and Network Pharmacological Strategy for the Treatment of Diabetic Kidney Disease by Shengjiang Powder Based on UHPLC-Q-TOF-MS

Objective: Shengjiang Powder (SJP) is a traditional Chinese medicine compound formula commonly used in the treatment of diabetic kidney disease (DKD). However, its material basis and mechanism of action are still unclear. Methods: In this study, the aqueous extract of SJP was obtained by aqueous decoction method, and the in vivo and in vitro constituents of SJP were analysed by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), and a network pharmacological strategy was established in conjunction with molecular docking in order to investigate the mechanism of action of SJP in the treatment of DKD. Results: The results identified 162 components, of which 28 could be absorbed into the blood and exert therapeutic effects in vivo. The main active ingredients were CT-1, CT-2, CT-7, BJC-2, and BJC-5, and the main targets in vivo were related to AKT1, MAPK1, MAPK3, MAPK8, and MAPK14, which could exert their therapeutic effects through the PI3K-Akt signaling pathway, Insulin resistance, and AGE-RAGE signaling pathway in diabetic complications, etc Conclusion: The present study adopts a comprehensive analytical strategy to reveal the pharmacodynamic material basis and mechanism of action of SJP in the treatment of DKD, and to provide a scientific basis for its clinical application.

Profiling of chromatin accessibility and regulatory elements toward understanding the mechanisms underlying growth regulation in the Pacific oyster (Crassostrea gigas)

Changes in phenotype are precisely controlled by transcriptional regulators, which depend on chromatin remodeling. Although artificial genetic breeding has significantly improved the growth performance of the Pacific oyster (Crassostrea gigas), the identification of gene regulatory elements and transcription factors related to growth is obscure. In this study, we performed a genome-wide characterization of chromatin accessibility using two strains of C. gigas that exhibit significant differences in growth. The results showed that accessible chromatin regions were mainly distributed in the noncoding regions of the genome, with a greater proportion of distal intergenic regions than that of promoters and introns. A total of 2044 differentially accessible regions and 2574 differentially expressed genes were identified through comparative analysis. Genes annotated from regions with differential chromatin accessibility were enriched in cell adhesion molecules, JAK-STAT, insulin resistance, HIF-1α, and platelet activation signaling pathways. Correlation analysis of ATAC-seq and RNA-seq data showed that differential gene expression was positively correlated with differential chromatin accessibility. Furthermore, motif screening and identification of accessible chromatin regions revealed a set of transcription factors, including LHX3, TCF7L2, and LEF1, that may play important roles in the growth of C. gigas. Integrated analysis with public Hi-C datasets allowed the identification of a differential peak located 47 kb upstream of angiopoietin-2, which may act as a potential enhancer that affects the growth of C. gigas. In summary, our work contributes to a better understanding of growth-related regulation in C. gigas and provides valuable information for deciphering the economic traits underlying growth, which is conducive to the development of the breeding industry of C. gigas in the future.

Exploring the action mechanism of Oxalis corniculata L. decoction in treating osteoarthritis utilizing liquid chromatography-mass spectrometry technology combined with network pharmacology.

This study aimed to identify the chemical constituents of Oxalis corniculata L. decoction. Furthermore, the mechanism of action of O corniculata L. decoction in treating osteoarthritis (OA) was investigated utilizing network pharmacology. The chemical composition of the O corniculata L. decoction was analyzed by employing UHPLC-Q-Exactive-MS/MS. Subsequently, a "compound-target-pathway" network was established through network pharmacology, offering a novel approach to identify the molecular mechanism underlying the treatment of OA with O corniculata L. decoction. Ultimately, the molecular docking technique was employed to validate the binding ability of the active ingredients with therapeutic targets. A total of 539 compounds were identified in O corniculata L. decoction. Topological analysis of the protein-protein interaction network indicated that compounds, including guanosine, naringenin-7-O-beta-D-glucuronide, noroxyhydrastinine, and chrysophanol 8-O-glucoside, have therapeutic potential for OA. In addition, GAPDH, TNF, TP53, epidermal growth factor receptor, and ESR1 may be key targets for the treatment of OA, primarily involving lipid and atherosclerosis, cellular senescence, IL-17 signaling pathway, and epidermal growth factor receptor tyrosine kinase inhibitor resistance signaling pathways. This method preliminarily identified the chemical composition of O corniculata L. decoction and predicted the active ingredients, potential targets, and signaling pathways of O corniculata L. decoction in treating OA. The findings of this research revealed the potential function of O corniculata L. decoction in anti-inflammation, alongside its ability to promote osteoblast proliferation and differentiation, providing new ideas for the processing of O corniculata L. herbs and related drug development.

Mechanism of inhibition of TLR4/NFκB/NLRP3 inflammatory pathway against AD based on the network pharmacology of Erjing Pills.

Alzheimer disease is an irreversible neurodegenerative disease, and its pathogenesis involves various mechanisms such as neuroinflammation and β-amyloid deposition. Erjing Pills can inhibit neuroinflammation by inhibiting toll-like receptor 4/nuclear factor kappa-B/nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3; however, qualitative analysis of the material basis is lacking. Therefore, it is necessary to analyze and explore the material basis of network pharmacology research. This study employed a multifaceted approach, including drug-like screening, molecular docking, and bioinformatic analysis. Preliminary screening identified 59 drug ingredients in Erjing Pills that met the Absorption, Distribution, Metabolism, Excretion and Toxicity screening criteria. Among these, 7 ingredients, including diosgenin, exhibited superior binding properties compared with the positive drugs in molecular docking. Gene ontology annotation and pathway analysis revealed their involvement in crucial biological processes, such as hormone response, insulin resistance, and steroid hormone biosynthesis signaling pathways, which are known for their anti-inflammatory and cognitive enhancement effects. A meta-analysis of relevant literature corroborated the anti-inflammatory activities of diosgenin and 5 other ingredients. These 5 ingredients, with diosgenin as a prominent candidate, exert anti-inflammatory effects by targeting key components of the toll-like receptor 4/nuclear factor kappa-B/nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3 inflammatory pathway, thereby presenting potential efficacy in the treatment of Alzheimer disease.

Recent Advances in Biomaterials for mRNA Delivery to Immune Cells.

Modulating the function of immune cells by targeting the cells themselves has become a key strategy in immunotherapy for combating various diseases such as cancer, autoimmune disorders, and infectious ailments. The use of mRNA (mRNA) is a powerful tool for transiently inducing protein expression, which is often used for genetic manipulation. However, its inherent instability and inability to precisely reach target cells necessitate the use of biomaterials for safe and effective delivery. Additionally, transfecting immune cells is difficult and complex due to their resistance mechanisms, signaling pathways, and cellular interactions. This review focuses on the recent development of biomaterials for mRNA delivery to immune cells, including lipid nanoparticles and polymeric carriers. It also outlines the challenges of targeting and delivering therapeutic payloads to immune cells, providing commentary and outlook on the design of next-generation materials. Finally, this approach has the potential to significantly enhance the precision and effectiveness of therapeutic interventions for various diseases, shaping the future of mRNA delivery for immune conditions.

Activation of the helper NRC4 immune receptor forms a hexameric resistosome

Innate immune responses to microbial pathogens are regulated by intracellular receptors known as nucleotide-binding leucine-rich repeat receptors (NLRs) in both the plant and animal kingdoms. Across plant innate immune systems, "helper" NLRs (hNLRs) work in coordination with "sensor" NLRs (sNLRs) to modulate disease resistance signaling pathways. Activation mechanisms of hNLRs based on structures are unknown. Our research reveals that the hNLR, known as NLR required for cell death 4 (NRC4), assembles into a hexameric resistosome upon activation by the sNLR Bs2 and the pathogenic effector AvrBs2. This conformational change triggers immune responses by facilitating the influx of calcium ions (Ca2+) into the cytosol. The activation mimic alleles of NRC2, NRC3, or NRC4 alone did not induce Ca2+ influx and cell death in animal cells, suggesting that unknown plant-specific factors regulate NRCs' activation in plants. These findings significantly advance our understanding of the regulatory mechanisms governing plant immune responses.

Study on the Effect of Rhubarb and Its Active Components on Pyroptosis in DKD by Regulating STAT3/Caspase-11 Axis

Rhubarb has been found to have a certain protective effect on improving the kidney function. However, the specific mechanism is still unclear. In this study, network pharmacology, molecular docking spontaneous binding technology and molecular biology experiments were used to verify the mechanism of rhubarb and its active ingredients in the treatment of DKD. A total of 10 active compounds and 121 (larger than average) target proteins were collected. The target proteins with higher degree value were screened by PPI according to degree value as follows: AKT1, STAT3, EGFR, NFKB1, SRC, etc. GO and KEGG enrichment analysis suggest that rhubarb therapy for DKD mainly involves Pathways in cancer, Prostate cancer, Proteoglycans in cancer, Chemokine signaling pathway, PI3K-Akt signaling pathway, PD-L1 expression and PD-1 checkpoint pathway in cancer, EGFR tyrosine kinase inhibitor resistance signaling pathway and so on. Furthermore, molecular docking results suggest that hydrogen bonding, salt bridge and hydrophobic interactions contribute to spontaneous binding of the compound to the target protein. Experimental verification shows that rhubarb and aloe emodin affect the mechanism of pyroptosis in diabetic kidney disease by regulating STAT3/Caspase11 axis. In conclusion, this study comprehensively elaborated the active compounds, potential targets and molecular experimental mechanisms of rhubarb to provide the basic experimental theory for clinical treatment of DKD.

Euonymus alatus delays progression of diabetic kidney disease in mice by regulating EGFR tyrosine kinase inhibitor resistance signaling pathway

To explore the therapeutic mechanism of Euonymus alatus for diabetic kidney disease (DKD). TCMSP, PubChem and Swiss Target Prediction databases were used to obtain the active ingredients in Euonymus alatus and their targets. GEO database and R language were used to analyze the differentially expressed genes in DKD. The therapeutic targets of DKD were obtained using GeneCards, DisGeNet, OMIM and TTD databases. The protein-protein interaction network and the "drug-component-target-disease" network were constructed for analyzing the topological properties of the core targets, which were functionally annotated using GO and KEGG pathway enrichment analyses. Molecular docking was performed for the core targets and the main pharmacologically active components, and the results were verified in db/db mice. Analysis of GSE96804, GSE30528 and GSE30529 datasets (including 60 DKD patients and 45 normal samples) identified 111 differentially expressed genes in DKD. Network pharmacology analysis obtained 161 intersecting genes between the target genes of Euonymus alatus and DKD, including the key core target genes SRC, EGFR, and AKT1. The core active ingredients of Euonymus alatus were quercetin, kaempferol, diosmetin, and naringenin, which were associated with responses to xenobiotic stimulionus and protein phosphorylation and regulated EGFR tyrosine kinase inhibitor resistance pathways. Molecular docking suggested good binding activities of the core active components of Euonymus alatus with the core targets. In db/db mouse models of DKD, treatment with Euonymus alatus obviously ameliorated kidney pathologies, significantly inhibited renal expressions of SRC, EGFR and AKT1, and delayed the progression of DKD. Euonymus alatus contains multiple active ingredients such as quercetin, kakaferol, diosmetin, naringenin, which regulate the expressions of SRC, EGFR, and AKT1 to affect the EGFR tyrosine kinase inhibitor resistance signaling pathway to delay the progression of DKD.