Resistance Signaling Pathways Research Articles

Abstract PO1-23-10: Multi-omics analysis identifies the mechanism in cross-resistance to endocrine therapy and CDK4/6 inhibitor in breast cancer

Abstract Background In advanced/metastatic breast cancer (MBC) or recurrent breast cancer on prior endocrine therapy (ET), selective estrogen receptor downregulator (SERD) of fulvestrant and CDK4/6i are the mainstream therapy regimen. In the clinical, fulvestrant combined with CDK4/6i is the second-line therapy for breast cancer (BC) that had progressed during previous endocrine therapy. The alternation of backbone from aromatase inhibitor or tamoxifen (endocrine sensitive) to fulvestrant (endocrine resistance) partially comes from the mechanism of ET resistance. Moreover, in the PALOMA-2 trial, approximately 30% of patients developed into recurrence after two years of CDK4/6i treatment, indicating that the ET backbone may affect CDK4/6i efficacy, bringing an emerging clinical issue of cross-resistance. However, whether the cross-resistance of ET would be more sensitive to CDK4/6i or impair the efficacy of CDK4/6i is still an ambiguous and heterogeneous issue. Also, in CDK4/6i resistance, whether the mechanism of ET resistance is associated with the dysregulation of the cell cycle or activation of other “bypass” signaling pathways is not fully understood. Methods We use a 3D and 2D culture of ET-sensitive cell S0.5, tamoxifen-resistant cell TAM, and fulvestrant-resistant cell 182R6 as our model. The 3D culture was performed by using the Tools 3d culture plus kit. Drug responses to fulvestrant and ribociclib were conducted by using CCK-8 assay. The potential target and pathway involved in the mechanisms of cross-resistance were analyzed by using multi-omics analysis of sequential window acquisition of all theoretical mass spectra (SWATH-MS), RNA-seq, micro-western array (MWA), traditional western blots, and open access database. Results In comparison with S0.5, the sensitivity to fulvestrant was indeed reduced in 182R6 cell; however, we found the sensitivity to ribociclib was also reduced in 182R6 cell, which was in contrast to the ribociclib-sensitive TAM cell. The different response to ribociclib between 182R6 and TAM, indicating that cross-resistance between fulvestrant and ribociclib existed in the model of 182R6 and TAM would be another control for 182R6 to find the target with or without cross-resistance. With multi-omics analysis of SWATH-MS, RNA-seq, MWA, western blots, and open access database, we found some unique or high expression of targets and pathways including EGFR, HER2, CDK6, CDK2, MAPK, and TNF-α pathways in cross-resistance R6 cell than in parental and TAM cell. We reconfirmed the above targets by 3D culture and found MAPK signaling pathway of p-ERK was not affected under ribociclib treatment, indicating the important role of the MAPK signaling pathway in ribociclib resistance. Conclusion To our knowledge, these results provide the first preliminary mechanism of cross-resistance between fulvestrant and ribociclib. We found fulvestrant resistant cell R6 exhibited the phenomenon of cross-resistance to ribociclib, which was in contrast to ribociclib-sensitive TAM cell. We also found some unique or high expression of target and pathway in cross-resistance R6 cells than in parental and TAM cells. In the future, with compound library screening and in vivo animal models, we expect to discover an FDA-approved drug or potential compound to overcome the cross-resistance between fulvestrant and ribociclib. Citation Format: Ming-Feng Hou, Chung-Liang Li, Chih-Po Chiang. Multi-omics analysis identifies the mechanism in cross-resistance to endocrine therapy and CDK4/6 inhibitor in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-10.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets

BackgroundThe major facilitator superfamily glucose transporters (GLUTs), encoded by solute carrier 2A (SLC2A) genes, mediate the transmembrane movement and uptake of glucose. To satisfy the improved energy demands, glycolysis flux is increased in cancers compared with healthy tissues. Multiple diseases, including cancer, have been associated with GLUTs. Nevertheless, not much research has been done on the functions of SLC2As in pan-cancer prognosis or their clinical treatment potential. MethodsThe SLC2A family genes' level of expression and prognostic values were analyzed in relation to pan-cancer. We then examined the association among SLC2As expression and TME, Stemness score, clinical characteristics, immune subtypes, and drug sensitivity. We merged bioinformatics analysis techniques with up-to-date public databases. Additionally, SLC2As from the KOBAS database were subjected to enrichment analysis. ResultsWe discovered that SLC2As' gene expression differed significantly between normal tissues and many malignancies. A number of tumors from various databases demonstrate a relationship between prognosis and SLC2A family gene expression. For instance, SLC2A2 and SLC2A5 were associated with the overall survival (OS) of hepatocellular carcinoma. SLC2A1 was associated with the OS of lung adenocarcinoma and pancreatic adenocarcinoma. Moreover, the SLC2A family gene expression is significantly correlated with the pan-cancer stromal and immune scores, and the RNA and DNA stemness scores. Furthermore, we found that the majority of SLC2As had a strong correlation with the tumor stages in KIRC. The immunological subtypes and all members of the SLC2A gene family exhibited a substantial correlation. Moreover, pathways containing insulin resistance and adipocytokine signaling pathway may influence the progression of some cancers. Finally, there is a significant positive or negative connection between drug sensitivity and SLC2A1 expression. ConclusionOur research highlights the significant promise of SLC2As as prognostic indicators and offers insightful approaches for upcoming exploration of SLC2As as putative therapeutic targets in malignancies.

Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy.

TFP5 is a Cdk5 inhibitor peptide, which could restore insulin production. However, the role of TFP5 in diabetic nephropathy (DN) is still unclear. This study aims to characterize the transcriptome profiles of mRNA and lncRNA in TFP5-treated DN mice to mine key lncRNAs associated with TFP5 efficacy. We evaluated the role of TFP5 in DN pathology and performed RNA sequencing in C57BL/6Jcontrol mice, C57BL/6J db/db model mice, and TFP5 treatment C57BL/6J db/db model mice. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were analyzed. WGCNA was used to screen hub-gene of TFP5 in treatment of DN. Our results showed that TFP5 therapy ameliorated renal tubular injury in DN mice. In addition, compared with the control group, the expression profile of lncRNAs in the model group was significantly disordered, while TFP5 alleviated the abnormal expression of lncRNAs. A total of 67 DElncRNAs shared among the three groups, 39 DElncRNAs showed a trend of increasing in the DN group and decreasing after TFP treatment, while the remaining 28 showed the opposite trend. DElncRNAs were enriched in glycosphingolipid biosynthesis signaling pathways, NF-κB signaling pathways, and complement activation signaling pathways. There were 1028 up-regulated and 1117 down-regulated DEmRNAs inthe model group compared to control group, and 123 up-regulated and 153 down-regulated DEmRNAs in theTFP5 group compared to themodel group. The DEmRNAs were involved in PPAR and MAPK signaling pathway. We confirmed that MSTRG.28304.1 is a key DElncRNA for TFP5 treatment of DN. TFP5 ameliorated DN maybe by inhibiting MSTRG.28304.1 through regulating the insulin resistance and PPAR signaling pathway. The qRT-PCR results confirmed the reliability of the sequencing data through verifying the expression of ENSMUST00000211209, MSTRG.31814.5, MSTRG.28304.1, and MSTRG.45642.14. Overall, the present study provides novel insights into molecular mechanisms of TFP5 treatment in DN.

Network pharmacology and experimental evaluation strategies to decipher the underlying pharmacological mechanism of Traditional Chinese Medicine CFF-1 against prostate cancer.

Prostate cancer (PCa) is a common malignancy in elderly men. We have applied Traditional Chinese Medicine CFF-1 in clinical treatments for PCa for several years. Here, we aimed to identify the underlying mechanism of CFF-1 on PCa using network pharmacology and experimental validation. Active ingredients, potential targets of CFF-1 were acquired from the public databases. Subsequently, protein-protein interaction (PPI) and the herbs-active ingredients-target network was constructed. A prognostic model for PCa was also constructed based on key targets. In vitro experiments using PCa cell lines CWR22Rv1 and PC-3 were carried out to validate the potential mechanism of CFF-1 on PCa. A total of 112 bioactive compounds and 359 key targets were screened from public databases. PPI and herbs-active ingredients-target network analysis determined 12 genes as the main targets of CFF-1 on PCa. Molecular docking studies indicated that the primary active ingredients of CFF-1 possess strong binding affinity to the top five hub targets. DNMT3B, RXRB and HPRT1 were found to be involved in immune regulation of PCa. In vitro, CFF-1 was found to inhibit PCa cell proliferation, migration, invasion and induce apoptosis via PI3K-Akt, HIF-1, TNF, EGFR-TKI resistance and PD-1 checkpoint signaling pathways. This study comprehensively elucidates the underlying molecular mechanism of CFF-1 against PCa, offering a strong rationale for clinical application of CFF-1 in PCa treatment.

Explore the active ingredients and potential mechanism of action on Actinidia arguta leaves against T2DM by integration of serum pharmacochemistry and network pharmacology

BackgroundActinidia arguta leaves (AAL) are traditionally consumed as a vegetable and as tea in folk China and Korea. Previous studies have reported the anti-diabetic effect of AAL, but its bioactive components and mechanism of action are still unclear. Aim of the studyThis study aims to identify the hypoglycemic active components of AAL by combining serum pharmacochemistry and network pharmacology and to elucidate its possible mechanism of action. MethodsFirstly, the effective components in mice serum samples were characterized by UPLC-Q/TOF-MSE. Furthermore, based on these active ingredients, network pharmacology analysis was performed to establish an “H-C-T-P-D” interaction network and reveal possible biological mechanisms. Finally, the affinity between serum AAL components and the main proteins in the important pathways above was investigated through molecular docking analysis. ResultsSerum pharmacochemistry analysis showed that 69 compounds in the serum samples were identified, including 23 prototypes and 46 metabolites. The metabolic reactions mainly included deglycosylation, dehydration, hydrogenation, methylation, acetylation, glucuronidation, and sulfation. Network pharmacology analysis showed that the key components quercetin, pinoresinol diglucoside, and 5-O-trans-p-coumaroyl quinic acid butyl ester mainly acted on the core targets PTGS2, HRAS, RELA, PRKCA, and BCL2 targets and through the PI3K-Akt signaling pathway, endocrine resistance, and MAPK signaling pathway to exert a hypoglycemic effect. Likewise, molecular docking results showed that the three potential active ingredients had good binding effects on the five key targets. ConclusionThis study provides a basis for elucidating the pharmacodynamic substance basis of AA against T2DM and further exploring the mechanism of action.

Yinchen gongying decoction mitigates CCl4-induced chronic liver injury and fibrosis in mice implicated in inhibition of the FoxO1/TGF-β1/ Smad2/3 and YAP signaling pathways

Ethnopharmacological relevanceLiver fibrosis (LF) is a common reversible consequence of chronic liver damage with limited therapeutic options. Yinchen Gongying decoction (YGD) composed of two homologous plants: (Artemisia capillaris Thunb, Taraxacum monochlamydeum Hand.-Mazz.), has a traditionally application as a medicinal diet for acute icteric hepatitis. However, its impact on LF and underlying mechanisms remain unclear. Aim of the studyThis study aims to assess the impact of YGD on a carbon tetrachloride (CCl4) induced liver fibrosis and elucidate its possible mechanisms. The study seeks to establish an experimental foundation for YGD as a candidate drug for hepatic fibrosis. Materials and methodsLC-MS/MS identified 11 blood-entry components in YGD, and network pharmacology predicted their involvement in the FoxO signaling pathway, insulin resistance, and PI3K-AKT signaling pathway. Using a CCl4-induced LF mouse model, YGD's protective effects were evaluated in comparison to a positive control and a normal group. The underlying mechanisms were explored through the assessments of hepatic stellate cells (HSCs) activation, fibrotic signaling, and inflammation. ResultsYGD treatment significantly improved liver function, enhanced liver morphology, and reduced liver collagen deposition in CCl4-induced LF mice. Mechanistically, YGD inhibited HSC activation, elevated MMPs/TIMP1 ratios, suppressed the FoxO1/TGF-β1/Smad2/3 and YAP pathways, and exhibited anti-inflammatory and antioxidant effects. Notably, YGD improved the insulin signaling pathway. ConclusionYGD mitigates LF in mice by modulating fibrotic and inflammatory pathways, enhancing antioxidant responses, and specifically inhibiting FoxO1/TGF-β1/Smad2/3 and YAP signal pathways.

Cellular and Molecular Mechanisms of Insulin Resistance

Abstract Purpose of Review Although the molecular mechanism of insulin resistance involves multiple factors and several intrinsic and extrinsic mechanisms have been identified, this comprehensive review provides key information on some of the core mechanisms and complex interactions of the molecules involved in the signaling pathways of insulin resistance. Recent Findings Diabetes Mellitus, the most common metabolic disorder, is one of the greatest global medical challenges at present. There has been a significant increase in complications associated with diabetes such as heart disorders, stroke, neuropathy, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and nephropathy. This calls for immediate strategic action to combat this complex metabolic disorder. Insulin resistance, a characteristic marker of type 2 diabetes is a condition in which the regulation of glucose metabolism in body tissues, such as the liver, adipose tissue, and skeletal muscle, becomes disrupted. It is generally associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and impaired glucose homeostasis. Summary Understanding the pathophysiological molecular mechanisms involved in insulin resistance is critical for developing new therapeutic strategies to treat this polygenic multifactorial condition. Impairment of insulin action is caused by several factors such as lipotoxicity, increased adiposity, enhanced inflammatory signaling, endoplasmic reticulum stress, adipokines, mitochondrial dysfunction, increased free fatty acids, and dysfunctional insulin signaling.

Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cells

BackgroundOsteosarcoma (OS) is one of the most common aggressive bone malignancy tumors in adolescents. With the application of new chemotherapy regimens, finding new and effective anti-OS drugs to coordinate program implementation is urgent for the patients of OS. Oridonin had been proved to mediate anti-tumor effect on OS cells, but its mechanism has not been fully elucidated.MethodsThe effects of oridonin on the viability, clonal formation and migration of 143B and U2OS cells were detected by CCK-8, colony formation assays and wound-healing test. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the mechanism of oridonin on OS. Western blot (WB), real-time quantitative PCR (qRT-PCR) were used to detect the expression levels of apoptosis and ferroptosis-relative proteins and genes. Annexin V-FITC apoptosis detection kit and flow cytometry examination were used to detect the level of apoptosis. Iron assay kit was used to evaluate the relative Fe2+ content. The levels of mitochondrial membrane potential and lipid peroxidation production was determined by mitochondrial membrane potential detection kit and ROS assay kit.ResultsOridonin could effectively inhibit the survival, clonal formation and metastasis of OS cells. The KEGG results indicated that oridonin is associated with the malignant phenotypic signaling pathways of proliferation, migration, and drug resistance in OS. Oridonin was capable of inhibiting expressions of BAX, cl-caspase3, SLC7A11, GPX4 and FTH1 proteins and mRNA, while promoting the expressions of Bcl-2 and ACSL4 in 143B and U2OS cells. Additionally, we found that oridonin could promote the accumulation of reactive oxygen species (ROS) and Fe2+ in OS cells, as well as reduce mitochondrial membrane potential, and these effects could be significantly reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1).ConclusionOridonin can trigger apoptosis and ferroptosis collaboratively in OS cells, making it a promising and effective agent for OS therapy.

Integrated UPLC/Q-TOF-MS/MS Analysis and Network Pharmacology to Reveal the Neuroprotective Mechanisms and Potential Pharmacological Ingredients of Aurantii Fructus Immaturus and Aurantii Fructus.

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) have been used for thousands of years as traditional Chinese medicine (TCM) with sedative effects. Modern studies have shown that Citrus plants also have protective effects on the nervous system. However, the effective substances and mechanisms of action in Citrus TCMs still remain unclear. In order to explore the pharmacodynamic profiles of identified substances and the action mechanism of these herbs, a comprehensive approach combining ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) analysis and network pharmacology was employed. Firstly, UNIFI 2.1.1 software was used to identify the chemical characteristics of AF and AFI. Secondly, the SwissTargetPrediction database was used to predict the targets of chemical components in AF and AFI. Targets for neuroprotection were also collected from GeneCards: The Human Gene Database (GeneCards-Human Genes|Gene Database|Gene Search). The networks between targets and compounds or diseases were then constructed using Cytoscape 3.9.1. Finally, the Annotation, Visualization and Integrated Discovery Database (DAVID) (DAVID Functional Annotation Bioinformatics Microarray Analysis) was used for GO and pathway enrichment analysis. The results showed that 50 of 188 compounds in AF and AFI may have neuroprotective biological activities. These activities are associated with the regulatory effects of related components on 146 important signaling pathways, derived from the KEGG (KEGG: Kyoto Encyclopedia of Genes and Genomes), such as neurodegeneration (hsa05022), the Alzheimer's disease pathway (hsa05010), the NF-kappa B signaling pathway (hsa04064), the hypoxia-inducible factor (HIF)-1 signaling pathway (hsa04066), apoptosis (hsa04210), the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance signaling pathway (hsa01521), and others, by targeting 108 proteins, including xanthine dehydrogenase (XDH), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), and glucose-6-phosphate dehydrogenase (G6PD), among others. These targets are thought to be related to inflammation, neural function and cell growth.

MTOR inhibitor introduce disitamab vedotin (RC48-ADC) rechallenge microtubule-chemotherapy resistance in HER2-low MBC patients with PI3K mutation.

This study aimed to explore the efficacy and potential mechanisms of rechallenge therapy with microtubule-targeting agents (MTAs) in patients with HER2-low metastatic breast cancer (MBC). We performed a systematic review to investigate the rechallenge treatment concept in the field of HER2-low MBC treatment and utilized a series of cases identified in the literature to illustrate the concept. Here we reported two clinical cases of HER2-low MBC patients whose disease progressed after prior treatment with MTAs such as docetaxel and vincristine. When rechallenged with disitamab vedotin ((RC48-antibody-drug conjugate (ADC), a monomethyl auristatin (MMAE) MTA)), both patients achieved a partial response and the final progression-free survival (PFS) was 13.5 and 9 months, respectively. Genomic profiling detected a PIK3CA H1047R mutation in the patients. The patients were treated with everolimus before being rechallenged with RC48, which may lead to a better response. This study further summarizes and analyzes the potential mechanism of the PI3K-AKT signaling pathway in MTA resistance and reveals that the PIK3CA H1047R mutation may be a potential molecular marker for the efficacy prediction of mTOR inhibitors, providing new insights and potential therapeutic strategies for the application of MTAs to MBC patients.

Revealing the Antiperspirant Components of Floating Wheat and Their Mechanisms of Action through Metabolomics and Network Pharmacology.

Floating wheat is a classical herbal with potential efficacy in the treatment of hyperhidrosis. Aiming at revealing the main components and potential mechanisms of floating wheat, a comprehensive and unique phytopharmacology profile study was carried out. First, common wheat was used as a control to look for chemical markers of floating wheat. In the screening analysis, a total of 180 shared compounds were characterized in common wheat and floating wheat, respectively. The results showed that floating wheat and common wheat contain similar types of compounds. In addition, in non-targeted metabolomic analysis, when taking the contents of the constituents into account, it was found that there indeed existed quite a difference between floating wheat and common wheat and 17 potential biomarkers for floating wheat. Meanwhile, a total of seven components targeted for hyperhidrosis were screened out based on network pharmacology. Seven key differential components were screened, among which kaempferol, asiatic acid, sclareol, enoxolone, and secoisolariciresinol had higher degree values than the others. The analysis of interacting genes revealed three key genes, namely, MAP2K1, ESR1, and ESR2. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses showed that various signaling pathways were involved. Prolactin signaling, thyroid cancer, endocrine resistance, gonadotropin secretion, and estrogen signaling pathways were the main pathways of the intervention of floating wheat in excessive sweating, which was associated with the estrogenic response, hormone receptor binding, androgen metabolism, apoptosis, cancer, and many other biological processes. Molecular docking showed that the screened key components could form good bindings with the target proteins through intermolecular forces. This study reveals the active ingredients and potential molecular mechanism of floating wheat in the treatment of hyperhidrosis and provides a reference for subsequent basic research.

The potential mechanism of Aidi injection against neuroblastoma-an investigation based on network pharmacology analysis.

Background: Aidi injection, a classic traditional Chinese medicine (TCM) formula, has been used on a broader scale in treating a variety of cancers. In this study, we aimed to explore the potential anti-tumor effects of Aidi injection in the treatment of neuroblastoma (NB) using network pharmacology (NP). Methods: To elucidate the anti-NB mechanism of Aidi injection, an NP-based approach and molecular docking validation were employed. The compounds and target genes were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) database. The protein-protein interaction network was constructed using the STRING database. clusterProfiler (R package) was utilized to annotate the bioinformatics of hub target genes. The gene survival analysis was performed on R2, a web-based genomic analysis application. iGEMDOCK was used for molecular docking validation, and GROMACS was utilized to validate molecular docking results. Furthermore, we investigated the anticancer effects of gomisin B and ginsenoside Rh2 on human NB cells using a cell viability assay. The Western blot assay was used to validate the protein levels of target genes in gomisin B- and ginsenoside Rh2-treated NB cells. Results: A total of 2 critical compounds with 16 hub target genes were identified for treating NB. All 16 hub genes could potentially influence the survival of NB patients. The top three genes (EGFR, ESR1, and MAPK1) were considered the central hub genes from the drug-compound-hub target gene-pathway network. The endocrine resistance and estrogen signaling pathways were identified as the therapeutic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gomisin B and ginsenoside Rh2 showed a good binding ability to the target protein in molecular docking. The results of cell experiments showed the anti-NB effect of gomisin B and ginsenoside Rh2. In addition, the administration of gomisin B over-regulated the expression of ESR1 protein in MYCN-amplified NB cells. Conclusion: In the present study, we investigated the potential pharmacological mechanisms of Aidi against NB and revealed the anti-NB effect of gomisin B, providing clinical evidence of Aidi in treating NB and establishing baselines for further research.

Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.

Exploring the potential mechanism of Simiao Yongan decoction in the treatment of diabetic peripheral vascular disease based on network pharmacology and molecular docking technology

The study aims to investigate the potential action targets and molecular mechanisms of Simiao Yongan decoction (SMYAD) in treating diabetic peripheral vascular disease (DPVD) by utilizing network pharmacology analysis and molecular docking technology. The components and targets of SMYAD were screened using the TCMSP database, while DPVD-related genes were obtained from the GeneCards, OMIM, and Disgenet databases. After intersecting the gene sets, a Protein-Protein Interaction (PPI) network was established, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out. The practical chemical components and core targets identified were molecularly docked using AutoDock software. A total of 126 active compounds were screened from which 25 main components included quercetin, rutoside, hesperidin, naringin, and β-sitosterol were determined to be the active components most associated with the core targets. A total of 224 common target genes were obtained. Among them, JUN, AKT1, MAPK3, TP53, STAT3, RELA, MAPK1, FOS, and others are the expected core targets of traditional Chinese medicine. The top-ranked GO enrichment analysis results included 727 biological processes (BP), 153 molecular functions (MF), and 102 cellular components (CC). KEGG pathway enrichment analysis involved mainly 178 signaling pathways, such as cancer signaling pathway, AGE-RAGE signaling pathway, interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, endocrine resistance signaling pathway, cell aging signaling pathway, and so on. The molecular docking results demonstrate that the principal chemical components of SMYAD exhibit considerable potential for binding to the core targets. SMYAD has the potential to treat DPVD through various components, targets, and pathways. Its mechanism of action requires further experimental investigation.

Physiological and transcriptomic analyses of response of walnuts (Juglans regia) to Pantoea agglomerans infection.

Walnut blight is a serious bacterial disease that affects the yield and quality of walnuts. Pantoea agglomerans is one of the main causative agents of walnut blight. However, there have been few studies on the response of walnuts to P. agglomerans infection. In this study, the soluble sugar, photosynthesis, antioxidant enzyme activities, and secondary metabolites were measured, and the transcriptomic analysis was performed to determine the response of walnut tissue cultures to P. agglomerans infection. After pathogen inoculation, the soluble sugar content decreased, and photosynthesis was inhibited. Antioxidant enzyme (superoxide dismutase and peroxidase) activities and secondary metabolites (phenol and flavonoid) contents increased, especially in the early stages of inoculation. Transcriptomic analysis revealed that the phenylpropanoid biosynthesis pathway is induced after infection, and pathogen infection promotes ABA and ethylene signal transduction and inhibits auxin signaling. In addition, SA and JA-related gene expression was altered after inoculation with P. agglomerans, and the FLS- and calcium-mediated disease resistance signaling pathways were activated. Furthermore, our results suggested an involvement of the R-protein RPM-mediated disease resistance pathway in the response of walnuts to bacterial infections. Our findings indicated that phenylpropanoid biosynthesis, hormone signal transduction, and plant-pathogen interaction have key roles in pathogenic inoculation, which provide insights into the molecular mechanisms in the response of walnuts to P. agglomerans infection.

Seed Soaking Using Methanol Kalanchoe pinnata Leaf Extracts Induces Rice Resistance against Bacterial Leaf Blight

Bacterial leaf blight (Xanthomonas oryzae pv. oryzae) is a significant rice disease. Aqueous crude extracts of Kalanchoe pinnata were shown to induce rice resistance against the disease. This study aims at testing the disease-reducing effects of K. pinnata leaf extracts using the liquid–liquid extraction method with three different solvents (dichloromethane, methanol, and water). This serves as a basis to select appropriate extracts for effective disease control. Three concentrations (1, 1.5, and 2%) of each extract were tested using seed soaking. The extracts did not show adverse effects on seed germination and seedling growth. Methanol extracts showed significantly different effects compared to those of the untreated control. The involvement of induced resistance in the disease reduction was shown through activities of the four defense-related and antioxidant enzymes, i.e., peroxidase (POX), catalase (CAT), polyphenol oxidase (PPO), and phenylalanine ammonia lyase (PAL). Using 1% methanol extract, activities of POX and CAT involved in hydrogen peroxide production in rice tissues increased 1–4 days after pathogen inoculation (DAI) and remained at high levels until 6 DAI. Activities of PPO and PAL involved in resistance signaling pathways significantly increased after pathogen inoculation. Activities of the four enzymes generally increased after pathogen inoculation and reached higher levels with extract applications.

An update on Mycobacterium tuberculosis lipoproteins.

Almost 3% of theproteins of Mycobacterium tuberculosis (M. tuberculosis), the main causative agent of human tuberculosis, are lipoproteins. These lipoproteins are characteristic of the mycobacterial cell envelope and participate in many mechanisms involved in the pathogenesis of M. tuberculosis. In this review, the authors provide anupdatedanalysis of M. tuberculosis lipoproteins and categorize them according to their demonstrated or predicted functions, including transport of compounds to and from the cytoplasm, biosynthesis of the mycobacterial cell envelope, defense and resistance mechanisms, enzymatic activities and signaling pathways. In addition, this updated analysis revealed that at least 40% of M.tuberculosis lipoproteins are glycosylated.

Study on resistance of MdMYB gene family in apple

The growth and development of apples are susceptible to environmental stress. The MdMYB gene family is one of the largest gene families in apples. It is widely involved in various resistance signaling pathways in apples and can interact with a variety of genes. Through anthocyanin synthesis, lignin synthesis, epidermal wax synthesis, Na + / H + pump regulation, hormone interaction, etc., the resistance of plants to abiotic and biotic stresses is improved. The MdMYB gene is regulated by multiple factors. It is regulated by epigenetic factors such as methylation and miRNA before transcription. At the transcriptional level, it is regulated by transcription factors such as MdHY5, MdWRKY11 and MdWRKY41. After translation, it is regulated by ubiquitin ligase, which is involved in MdSIZ, MdMEIL and other proteins. This paper reviews the physiological responses and signaling pathways of MdMYB-mediated apple stress resistance and the gene function regulation mechanism of MdMYB, in order to provide new ideas for the study of apple stress resistance.

Bovine oviductal organoids: a multi-omics approach to capture the cellular and extracellular molecular response of the oviduct to heat stress

BackgroundThe mammalian oviduct is a complex, fibromuscular organ known for its role in orchestrating a series of timely and dynamic changes to suitably support early embryogenesis. Climate change-induced heat stress (HS) is one of the largest single stressors compromising reproductive function in humans and farm animals via systemic changes in the redox status of the maternal environment, adversely affecting fertilization and early embryonic development. Oviductal organoids represent a unique 3-dimensional, biomimetic model to study the physiology of the oviduct and its subsequent impact on embryo development under various environmental conditions.ResultsOur study is the first to demonstrate an innovative approach to understanding the cascade of molecular changes sustained by bovine oviductal organoids under HS and the subsequent maternal signals harnessed within their secreted extracellular vesicles (EVs). Transcriptomic analysis of oviductal organoids exposed to HS revealed 2,570 differentially expressed genes (1,222 up‐ and 1,348 downregulated), while EV-coupled miRNome analysis disclosed 18 miRNAs with significant differential expression (12 up- and 6 downregulated) in EVs from thermally stressed organoids compared to EVs released from organoids cultured under thermoneutral conditions. Genes activated in oviductal organoids in response to thermal stress, include: COX1, ACTB, CST6, TPT1, and HSPB1, while miR-1246, miR-148a, miR21-5p, miR-451, and miR-92a represent the top highly abundant EV-coupled miRNAs released in response to HS. Pathway analysis of genes enriched in organoids exposed to thermal stress showed the enrichment of endocrine resistance, cellular senescence, and notch signaling pathways. Similarly, EV-coupled miRNAs released from thermally stressed organoids showed their potential regulation of genes involved in cellular senescence, p53 signaling, and TGF-beta signaling pathways.ConclusionsIn conclusion, the cellular and extracellular response of bovine oviductal organoids to in vitro HS conditions reveal the prospective impact of environmental HS on the physiology of the oviduct and the probable subsequent impacts on oocyte fertilization and early embryo development. Future studies elucidating the potential impact of HS-associated EVs from oviductal organoids on oocyte fertilization and preimplantation embryo development, would justify the use of an organoid model to optimally understand the oviduct-embryo communication under suboptimal environments.

Identification of Potential Mechanisms of Rk1 Combination with Rg5 in the Treatment of Type II Diabetes Mellitus by Integrating Network Pharmacology and Experimental Validation.

In this study, we aimed to explore the potential targets and functional mechanisms of Rk1 combined with Rg5 (Rk1+Rg5) against type II diabetes mellitus (T2DM). Network pharmacology and molecular docking were used to predict and verify the targets and signaling pathways of Rk1+Rg5 against T2DM. The results were further confirmed by a db/db mouse model and a model using PA-induced L6 cells. According to network pharmacology, a total of 250 core targets of Rk1+Rg5 towards T2DM were identified; the insulin resistance signaling pathways were enriched by KEGG. Results of molecular docking indicated good binding affinity of Rk1 and Rg5 to Akt1. In vivo and in vitro studies further showed that Rk1+Rg5 is an inhibitor of skeletal muscle insulin resistance. The results showed that Rk1+Rg5 significantly improved the hyperglycemic state of db/db mice, alleviated dyslipidemia, and promoted skeletal muscle glucose uptake. This phenomenon was closely related to the alleviation of the insulin resistance in skeletal muscles. Finally, the combination activated the Akt signaling pathway and promoted GLUT4 translocation to the cell membrane for glucose uptake. Altogether, our findings, for the first time, demonstrate that the combination of Rk1 and Rg5 could be beneficial for anti-T2DM, possibly involving ameliorated insulin resistance.