Regulation Of Signaling Pathways Research Articles

Genome-wide identification, characterization, and expression analysis of BZR transcription factor family in Gerbera hybrida

BackgroundThe BZR family genes encode plant-specific transcription factors as pivotal regulators of plant BR signaling pathways, critically influencing plant growth and development.ResultsIn this study, we performed a genome-wide investigation of the BZR family gene in gerbera to identify the key components of the BR pathway that may function in petal growth. The identified BZR genes, named GhBEH1-7 (GhBEH1, GhBEH2, GhBEH3, GhBEH4, GhBEH5, GhBEH6, GhBEH7), are distributed across chromosomes 3, 5, 10, 11, 12, 14 and 15. These genes exhibit similar exon–intron structures and possess typical BZR family structures. Phylogenetic analysis clustered these genes into two distinct subgroups. Analysis of cis-acting elements revealed their involvement in hormone response, stress response, and growth regulation. Subcellular localization analysis indicated nuclear localization for GhBEH1 and GhBEH2, while the remaining five genes exhibited dual localization in the nucleus and cytoplasm. The transactivation assay indicated that GhBEH1 and GhBEH2 may function as transcriptional repressors, contrasting with the transcriptional activation observed for the other five genes. Notably, seven GhBEHs exhibit various expression patterns under different growth stages of ray florets and BR treatment conditions. Meanwhile GhBEH1 and GhBEH2 showed pronounced responsiveness to BR stimulation.ConclusionOur work explains genome-wide identification, characterization, and expression analysis of gerbera’s BZR transcription factor family. We hinted that these seven GhBEHs are involved in petal growth and development regulation. These findings provide a basis for further studies on the biological function of the BZR gene family in petal growth and a theoretical basis for future horticultural application in gerbera.

Transcriptomic and Phenotypic Responses of CucumberTrichome Density to Silver Nitrate and Sodium Thiosulfate Application

Cucumber (Cucumis sativus L.) is one of the most widely cultivated crops worldwide and is valued for its nutritional, economic, and ecological benefits. The regulation of defense mechanisms against herbivores, along with osmotic loss and environmental regulation, is greatly affected by trichomes in cucumbers. In this study, we attempted to characterize trichomes and examined fruit physiological and transcriptome profiles by RNA sequencing in cucumber breeding lines 6101-4 and 5634-1 at three stages of fruit development through foliar application with a combination of silver nitrate (AgNO3) and sodium thiosulfate (Na2S2O3) in comparison to non-treated controls. Notable increases in the number of trichomes and altered forms were observed for both inbred cultivars 6101-4 and 5634-1 against foliar application of chemical substances. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) involved in multiple pathways in cucumber trichome formation. The enrichment of differentially expressed transcripts showed that foliar application upregulated the expression of many stress-responsive and trichome-associated genes including plant hormone signal transduction, sesquiterpenoid and triterpenoid biosynthesis, and the mitogen-activated protein kinase (MAPK) signaling pathway. The dominant regulatory genes, such as allene oxide synthase (AOS) and MYB1R1 transcription factor, exhibited significant modulations in their expression in response to chemical application. The RNA-seq results were further confirmed by RT-PCR-based analysis, which revealed that after chemical application, the dominant regulatory genes, such as allene oxide synthase (AOS), PTB 19, MYB1R1, bHLH62-like, MADS-box transcription factor, and salicylic acid-binding protein 2-like, were differentially expressed, implying that these DEGs involved in multiple pathways are involved the positive regulation of the initiation and development of trichomes in C. sativus. A comparison of trichome biology and associated gene expression regulation in other plant species has shown that silver nitrate (AgNO3) and sodium thiosulfate (Na2S2O3) are also responsible for hormonal and signaling pathway regulation. This study improves our knowledge of the molecular mechanisms involved in C. sativus trichome development. It also emphasizes the possibility of utilizing chemical composition to modulate C. sativus trichome-related characteristics of C. sativus, leading to the improvement of plant defense mechanisms as well as environmental adaptation.

Computational Elucidation of a Monobody Targeting the Phosphatase Domain of SHP2

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated in various pathological conditions, including cancers and developmental disorders. Despite its importance, the molecular basis of SHP2’s regulatory mechanism remains poorly understood, hindering the development of effective targeted therapies. In this study, we utilized the high-specificity monobody Mb11 to investigate its interaction with the SHP2 phosphatase domain (PTP) using multiple replica molecular dynamics simulations. Our analyses elucidate the precise mechanisms through which Mb11 achieves selective recognition and stabilization of the SHP2-PTP domain, identifying key residues and interaction networks essential for its high binding specificity and regulatory dynamics. Furthermore, the study highlights the pivotal role of residue C459 in preserving the structural integrity and functional coherence of the complex, acting as a central node within the interaction network and underpinning its stability and efficiency. These findings have significantly advanced the understanding of the mechanisms underlying SHP2’s involvement in disease-related signaling and pathology while simultaneously paving the way for the rational design of targeted inhibitors, offering significant implications for therapeutic strategies in SHP2-associated diseases and contributing to the broader scope of precision medicine.

Prognostic implications and therapeutic response in GNAS-mutated colorectal adenocarcinoma: A retrospective cohort analysis.

244 Background: GNAS, a key regulator of the G-protein signaling pathway, is frequently mutated in colorectal adenocarcinomas and other malignancies. Despite its role in tumorigenesis, GNAS mutations remain understudied, with no established targeted therapies. Exploring the impact of GNAS alterations on therapeutic response and outcomes in colorectal cancer (CRC) is crucial for developing effective treatment strategies. Methods: We reviewed 531 CRC cases from our institutional Molecular Tumor Board database, identifying 8 patients with GNAS mutations. The prevalence ofGNASmutations in our cohort was 1.5%, which aligns with reported rates of 2-5% in various CRC cohorts. Comprehensive clinicopathologic data, including tumor histology, staging, treatment outcomes, and response rates, were analyzed. A detailed evaluation was conducted on stage IV patients to assess their response, progression-free survival (PFS), and overall survival (OS) in comparison to historical stage IV CRC benchmarks. Results: The cohort included 8 patients with a median age of 61 years (range: 33-73 years), with balanced gender representation (50% male, 50% female). The racial distribution was 50% Black or African American, 25% White, and 12.5% Asian or Pacific Islander. The majority of patients (62.5%) were diagnosed at stage IV, with primary tumor sites predominantly in the sigmoid colon and cecum. Among the 5 stage IV patients, while no patients achieved a complete or partial response, 3 exhibited stable disease, resulting in a 60% disease control rate (including stable disease). The median progression-free survival (mPFS) was 9 months, reflecting the duration of disease control before progression, while the median overall survival (mOS) was 15 months. These outcomes are notably lower than historical benchmarks for stage IV CRC, where response rates typically range from 40-50% with mOS of 20-24 months, highlighting the potentially adverse prognostic impact of GNAS mutations. Conclusions: Patients with GNAS-mutated colorectal adenocarcinoma appear to represent a unique subset with poorer therapeutic outcomes, even when achieving stable disease. The observed disease control in the absence of objective responses underscores the complexity of treating GNAS-mutated tumors and highlights the urgent need for targeted therapies tailored to this molecular subtype. Further research into the biological mechanisms underlying GNAS mutations and their impact on CRC treatment resistance is warranted to improve patient outcomes.

Integrative Analyses of Biomarkers and Pathways in Oxidative Stress-Related Genes for Gestational Diabetes Mellitus.

Oxidative stress (OS) plays a key role in the pathogenesis of gestational diabetes mellitus (GDM), but it was not well understood. We aimed to investigate the biomarkers and underlying mechanisms of OS-related genes in GDM. The GSE103552 and GSE70493 datasets of GDM were acquired from the Gene Expression Omnibus (GEO) database. Then, oxidative stress-related differentially expressed genes (OSDEGs) were screened between GDM and normal samples from these two datasets. Further analyses were conducted by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) for these OSDEGs. Subsequently, protein-protein interaction (PPI) network analyses of these OSDEGs were carried out to screen the hub genes. Eventually, we used single-sample Gene-set enrichment analysis (ssGSEA) to compare the immune cell infiltration between GDM and normal samples. We identified 26 OSDEGs. Enrichment analysis suggested that the OSDEGs enriched in OS and diabetes-related pathways. GSEA revealed that these OSDEGs enriched in sensory perception of taste and negative regulation of notch4 signaling pathways. Moreover, PPI analysis showed that 15 OSDEGs were the hub gene in GDM. A total of 14 hub genes were highly expressed in GDM and might be used as diagnosis biomarkers. Moreover, many potential agents might target 10 hub genes for GDM treatment. In addition, immune infiltrate analyses revealed that expression of 14 hub genes was positively correlated to immune infiltrates in GDM. OSDEGs are significant in GDM and may provide potential diagnostic biomarkers and treatment targets for GDM.

Dual role of cytosolic GSH in the ABA signaling pathway and plasma membrane ion channel regulation in guard cells of Vicia faba

Dual role of cytosolic GSH in the ABA signaling pathway and plasma membrane ion channel regulation in guard cells of Vicia faba

Comprehensive computational analysis of differentially expressed miRNAs and their influence on transcriptomic signatures in prostate cancer

Prostate cancer presents a major health issue, with its progression influenced by intricate molecular factors. Notably, the interplay between miRNAs and changes in transcriptomic patterns is not fully understood. Our study seeks to bridge this knowledge gap, employing computational techniques to explore how miRNAs and transcriptomic alterations jointly regulate the development of prostate cancer. The study involved retrieving miRNA expression data from the GEO database specific to prostate cancer. Identification of DEMs was conducted using the ‘limma’ package in R. Integration of these DEMs with mRNA interactions was done using the MiRTarBase database. Finally, a network depicting miRNA-mRNA interactions was constructed using Cytoscape software to analyze the regulatory network of prostate cancer. The study pinpointed seven pivotal differentially expressed microRNAs (DEmiRNAs) in prostate cancer: hsa-miR-185-5p, hsa-miR-153-3p, hsa-miR-198, hsa-miR-182-5p, hsa-miR-223-3p, hsa-miR-372-3p, and hsa-miR-188-5p. These miRNAs influence key genes, including FOXO3, NFAT3, PTEN, RHOA, VEGFA, SMAD7, and CDK2, playing significant roles in both tumor suppression and oncogenesis. The analysis revealed a complex network of miRNA-mRNA interactions, comprising 1849 nodes and 3604 edges. Functional Enrichment Analysis through ClueGO highlighted 74 GO terms associated with these mRNA targets. This analysis uncovered their substantial impact on critical biological processes and molecular functions, such as cyclin-dependent protein kinase activity, mitotic DNA damage checkpoint signalling, stress-activated MAPK cascade, regulation of extrinsic apoptotic signalling pathway, and positive regulation of cell adhesion. Our analysis of miRNAs and DEGs genes revealed an intriguing mix of established and potentially novel regulators in prostate cancer development. These findings both reinforce our current understanding of prostate cancer’s molecular landscape and point to unexplored pathways that could lead to novel therapeutic strategies. By mapping these regulatory relationships, our work contributes to the growing knowledge base needed for developing more targeted and effective treatments.

Delving Into lncRNA-Mediated Regulation of Autophagy-Associated Signaling Pathways in the Context of Breast Cancer.

Breast cancer is a multifaceted and prevalent malignancy, impacting a considerable proportion of women globally. Numerous signaling pathways intricately regulate cellular functions such as growth, proliferation, and survival. Among the various regulators, lncRNAs have emerged as significant players despite their inability to encode proteins. An expanding body of literature underscores the pivotal roles lncRNAs play in cancer biology, particularly in the context of breast cancer. Autophagy, the cellular process dedicated to the degradation and recycling of cellular components, is now recognized as a crucial factor in cancer initiation and progression. The interplay between lncRNAs, various signaling pathways, and autophagy in the pathophysiology of breast cancer remains an active area of investigation. Researchers have identified specific lncRNAs that are dysregulated in breast cancer patients, influencing the modulation of key signaling pathways. Using experimental methodologies and bioinformatics approaches, multiple lncRNAs have been elucidated, providing deeper insights into their contributions to breast cancer pathogenesis and metastatic processes. In summary, the pathophysiological landscape of breast cancer is characterized by the complex interactions involving lncRNA-mediated autophagy. This understanding paves the way for identifying novel therapeutic targets, prognostic markers, and diagnostic markers, ultimately contributing to improved treatment outcomes in breast cancer management.

A strategy for selective screening of dual-target bioactive compounds against hypertrophic scar through inhibiting angiotensin II type 1 receptor while stimulating type 2 receptor from Chinese herbs

BackgroundCutaneous hypertrophic scar is a fibro-proliferative hard-curing disease. Recent studies have proved that antagonists of angiotensin II type 1 receptor (AT1R) and agonists of type 2 receptor (AT2R) were able to relieve hypertrophic scar. Therefore, establishing new methods to pursue dual-target lead compounds from Chinese herbs is in much demand for treating scar.MethodsTo this end, we immobilized AT1R or AT2R onto the surface of silica gel from cell lysates through a specific covalent bond by bioorthogonal chemistry. The columns containing immobilized AT1R or AT2R were jointly utilized to pursue potential bioactive compounds simultaneously binding to AT1R and AT2R from the extract of Rhei Radix et Rhizoma. Their functions on AT1R and AT2R expressions were investigated by in vitro and in vivo experiments.ResultsAloe-emodin and emodin were identified as the potential bioactive compounds binding to both of the two receptors, thereby improving the appearance and pathomorphology of hypertrophic scar. They blocked the AT1R pathway to down-regulate the expression of transforming growth factor-β1 (TGF-β1) and stimulate matrix metalloproteinase-1 (MMP-1) expression. As such, the expression of collagen I/III reduced. Conversely, the bindings of the two compounds to AT2R reduced the production of nuclear factor-кB1 (NF-кB1), whereby the generation of interleukin-6 (IL-6) was blocked.ConclusionWe reasoned that aloe-emodin and emodin had the potential to become dual-target candidates against hypertrophic scar through the regulation of AT1R and AT2R signaling pathways. It showed considerable potential to become a universal strategy for pursuing multi-target bioactive compounds from Chinese herbs by the utilization of diverse immobilized receptors in a desired order.

An Insect Effector Mimics Its Host Immune Regulator to Undermine Plant Immunity.

Plants activate defense machinery when infested by herbivorous insects but avoid such costs in the absence of herbivory. However, the key signaling pathway regulators underlying such flexibility and the mechanisms that insects exploit these components to disarm plant defense systems remain elusive. Here, it is reported that immune repressor 14-3-3e in rice Oryza sativa (OsGF14e) regulates immune homeostasis. Infestation with brown planthopper (BPH) Nilaparvata lugens decreased OsGF14e expression; however, the level of downregulation is limited both by the short duration and the specific feeding location. OsGF14e interacts with Enhanced Disease Resistance 1-like (OsEDR1l), a Raf-like MAP kinase kinase kinase (MAPKKK), and repressed jasmonic acid, jasmonic acid-isoleucine, and H2O2 accumulation by enhancing OsEDR1l abundance and signaling ability. OsGF14e and OsEDR1l overexpression renders rice susceptible to BPH, whereas their knockout increases plant resistance but compromises rice growth and grain yield. Intriguingly, BPH 14-3-3e protein (Nl14) that shares high sequence homology and structural similarity with OsGF14e is identified from BPH saliva and egg-associated secretions. Mediated through BPH feeding and oviposition, Nl14, similar to OsGF14e, interacts with OsEDR1l and triggers the OsEDR1l signaling, thereby suppressing plant defenses and facilitating BPH infestation. Apparently, structural and functional mimicry makes it possible for this newly discovered BPH effector to exploit rice OsGF14e-EDR1l immune suppression module. The results reveal a novel mechanism deployed by herbivorous insects, in a manner similar to certain pathogen effectors, to evade host plant defenses by mimicking host immune regulators.

WTAP suppresses STAT3 via m6A methylation to regulate autophagy and inflammation in central nervous system injury.

Central nervous system (CNS) repair after injury is a challenging process limited by inflammation and neuronal apoptosis. This study identifies Wilms' tumor 1-associating protein (WTAP) as a pivotal regulator of neuronal protection and repair through m6A methylation of STAT3 mRNA. By employing spinal cord injury (SCI) as a representative model of CNS injury, transcriptomic analyses reveal WTAP as a key mediator of pathways related to neuronal autophagy and inflammation regulation. WTAP enhances neuronal autophagy by suppressing STAT3 expression and activity, which inhibits the NLRP3 inflammatory pathway. Functional studies demonstrate that WTAP knockdown exacerbates neuronal apoptosis, whereas overexpression improves cell viability, autophagy, and motor recovery. In vivo, WTAP promotes SCI repair via m6A-mediated suppression of STAT3 and regulation of the NLRP3 signaling pathway, highlighting its therapeutic potential for CNS injury repair.

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways.

Lately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways. Total RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level. These findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

SRT1720 Treatments Hepatic Ischemia Reperfusion Injury by Regulation of NF-κB Signaling Pathways and Reduce Cell Apoptosis: From Network Pharmacology to Experimental Validation.

Hepatic ischemia reperfusion injury (HIRI) is a common complication closely related to the prognosis of liver surgery, and effective treatment methods are still unavailable. SRT1720 has the characteristics of multifunction and multitarget which may cope with the multidirectional complex pathological process caused by HIRI. The present study aimed to explore the potential mechanism of SRT1720 in HIRI through a combination of network pharmacology, in vitro experiments and in vivo models. Differentially expressed genes (DEGs) were identified based on the GSE15480 and Genecards database. Enrichment analyses were then conducted. SRT1720-targeted genes were obtained through databases such as Chembl, TTD, GtoPdb, and so on. All target genes were standardized by the Uniprot database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified by STRING. Shared KEGG pathways were identified using a Venn diagram among SRT1720-targeted pathways and HIRI. Furthermore, experimental techniques such as cell apoptosis assay and western blotting were used to confirm the most significant biological processes and the key pathway between SRT1720-targeted and HIRI. This study identified 118 HIRI-related DEGs, 69 shared KEGG pathways of SRT1720 and HIRI. In addition, the findings revealed that SRT1720 significantly reduced liver ischemiareperfusion (I/R) injury. NF-κB signaling pathway and the expression of promoting apoptosis factors such as Bax and Caspase3 were inhibited, while antiapoptotic protein Bcl-2 was promoted in the SRT1720 group compared with the I/R group. The findings indicate that SRT1720 may inhibit the development of HIRI by inhibiting the NF-κB signaling pathway and reducing cell apoptosis, acting as a treatment for HIRI.

Ishophloroglucin A Isolated from Ishige okamurae Protects Glomerular Cells from Methylglyoxal-Induced Diacarbonyl Stress and Inhibits the Pathogenesis of Diabetic Nephropathy.

Ishige okamurae (I. okamuare), an edible brown alga, is rich in isophloroglucin A (IPA) phlorotannin compounds and is effective in preventing diseases, including diabetes. We evaluated its anti-glycation ability, intracellular reactive oxygen species scavenging activity, inhibitory effect on the accumulation of intracellular MGO/MGO-derived advanced glycation end products (AGE), and regulation of downstream signaling pathways related to the AGE-receptor for AGEs (RAGE) interaction. IPA (0.2, 1, and 5 μM) demonstrated anti-glycation ability by inhibiting the formation of glucose-fructose-BSA-derived AGEs by up to 54.63% compared to the untreated control, reducing the formation of irreversible cross-links between MGO-derived AGEs and collagen by 67.68% and the breaking down of existing cross-links by approximately 91% (p < 0.001). IPA protected cells from MGO-induced oxidative stress by inhibiting intracellular MGO accumulation (untreated cells: 1.62 μg/mL, MGO treated cells: 25.27 μg/mL, and IPA 5 μM: 11.23 μg/mL) (p < 0.001) and AGE generation and inhibited MGO-induced renal cell damage via the downregulation of MGO-induced RAGE protein expression (relative protein expression levels of MGO treated cells: 9.37 and IPA 5 μM:1.74) (p < 0.001). Overall, these results suggest that IPA has the potential to be utilized as a useful natural agent for the prevention and management of AGE-related diabetic nephropathy, owing to its strong anti-glycation activity.

Non-coding RNAs as mediators of epithelial - Mesenchymal transition (EMT) in metastatic colorectal cancers.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.

Mechanism of Hedyotis diffusa-Scutellaria barbata D. Don for treatment of primary liver cancer: analysis with network pharmacology, molecular docking and in vitro validation.

To investigate the active ingredients in Hedyotis diffusa-Scutellaria barbata D. Don and the main biological processes and signaling pathways mediating their inhibitory effect on primary hepatocellular carcinoma (HCC). The core intersecting genes of HCC and the two drugs were screened from TCMSP, Uniport, Genecards, and String databases using Cytoscape software, and GO and KEGG enrichment analyses of the intersecting genes were conducted. Molecular docking between the active ingredients of the drugs and the core genes was carried out using Pubcham, RCSB and Autoduckto to identify the active ingredients with the highest binding energy, whose inhibitory effect on HepG2 cells was verifies using CCK-8 assay, flow cytometry and Western blotting. TP53 and ESR1 were identified as the core genes of HCC and the two drugs. GO and KEGG analyses showed that the two genes were mainly involved in regulation of apoptotic signaling pathway, cell population proliferation, methane raft, and protein kinase activity, and participated in the signaling pathways of apoptosis, proteoglycans in cancer, PI3K Akt signaling pathway, and hepatitis B. Molecular docking studies showed that the active ingredients of the drugs could be docked with TP53 and ESR1 genes under natural conditions, and ursolic acid had the highest binding energy to ESR1 (-4.98 kcal/mol). The results of CCK-8 assay, flow cytometry and Western blotting all demonstrated significant inhibitory effect of ursolic acid on HepG2 cells. The inhibitory effect of Hedyotis diffusa-scutellariae barbatae on HCC is mediated by multiple active ingredients in the two drugs.

PIASy of orange-spotted grouper (Epinephelus coioides) negatively regulates RLRs-mediated innate antiviral immunity.

During viral infection, RIG-I-like receptors (RLRs) are cytoplasmic pattern recognition receptors that recognize and bind to viral RNA components, initiating the transcription of interferon-related genes, inflammatory cytokines and other factors, thereby triggering the cellular production of an antiviral innate immune response. The protein inhibitor of activated signal transducer and activator of transcription (STAT) (PIAS) protein family has become a hot research topic due to its extensive involvement in the regulation of cytokines, inflammatory factors and innate immune signaling pathways. In the present study, we investigated the role of fish PIASy in Singapore grouper iridovirus (SGIV) and red spotted grouper nervous necrosis virus (RGNNV) infections. The homologous sequence of orange-spotted grouper (Epinephelus coioides) PIASy gene (EcPIASy) was cloned and characterized, which encoded a 498-amino acid protein with 99.20% homology to Plectropomus leopardus. EcPIASy is expressed mainly in gills, blood, and liver. Subcellular localization showed that EcPIASy was uniformly distributed in the nucleus. Overexpression of EcPIASy promoted SGIV and RGNNV replication, and inhibited the expression of interferon related genes and pro-inflammatory factors induced by viruses. In addition, EcPIASy interacts with RLR signaling pathway-related genes EcMDA5, EcIRF3 and EcIRF7, whereas the interaction between EcPIASy and EcIRF3 does not depend on any specific structural domain of EcPIASy.. The results provide a better understanding of the relationship between PIASy and viral infection in fish.

Plasmodium falciparum raf kinase inhibitor is a lipid binding protein that interacts with and regulates the activity of PfCDPK1, an essential plant-like kinase required for red blood cell invasion.

Raf Kinase Inhibitor Protein (RKIP) is an important regulator of the MAPK signaling pathway in multicellular eukaryotes. Plasmodium falciparum RKIP (PfRKIP) is a putative phosphatidylethanolamine binding protein (PEBP) that shares limited similarity with Homo sapiens RKIP (HsRKIP). Interestingly, critical components of the MAPK pathway are not expressed in malaria parasites and the physiological function of PfRKIP remains unknown. PfRKIP is expressed throughout the asexual schizogony with maximum expression in late schizonts. Interestingly, PfRKIP and HsRKIP show pH-dependent differential interaction profiles with various lipids. At physiological pH, PfRKIP shows interaction with phosphatidic acid and lipids containing phosphorylated phosphatidylinositol group; however, HsRKIP shows no interaction under the same conditions. Mutation of conserved residues in the PEBP domain of PfRKIP decreases its interaction with PtdIns(3)P. Additionally, in silico docking and mutagenesis studies identified a unique IKK motif within the PEBP domain of PfRKIP that is important for its interaction with the lipids. Using ELISA, we demonstrate the interaction of PfRKIP with PfCDPK1. Importantly, we establish the interaction of PfRKIP and PfCDPK1 within the parasites using immunofluorescence assay and proximity biotinylation technique. Furthermore, our results suggest that PfRKIP regulates the kinase activity of PfCDPK1. In the presence of its substrate, PfCDPK1 hyper-phosphorylates PfRKIP which leads to its dissociation from PfCDPK1. Dissociation of PfRKIP allows PfCDPK1 to trans-phosphorylate its substrates. The molecular mechanism of interaction between PfRKIP and PfCDPK1 may be explored further to identify novel anti-malarial compounds.

Natural products and long non-coding RNAs in prostate cancer: insights into etiology and treatment resistance.

Globally, the incidence and death rates associated with cancer persist in rising, despite considerable advancements in cancer therapy. Although some malignancies are manageable by a mix of chemotherapy, surgery, radiation, and targeted therapy, most malignant tumors either exhibit poor responsiveness to early identification or endure post-treatment survival. The prognosis for prostate cancer (PCa) is unfavorable since it is a perilous and lethal malignancy. The capacity of phytochemical and nutraceutical chemicals to repress oncogenic lncRNAs and activate tumor suppressor lncRNAs has garnered significant attention as a possible strategy to diminish the development, proliferation, metastasis, and invasion of cancer cells. A potential technique to treat cancer and enhance the sensitivity of cancer cells to existing conventional therapies is the use of phytochemicals with anticancer characteristics. Functional studies indicate that lncRNAs modulate drug resistance, stemness, invasion, metastasis, angiogenesis, and proliferation via interactions with tumor suppressors and oncoproteins. Among them, numerous lncRNAs, such as HOTAIR, PlncRNA1, GAS5, MEG3, LincRNA-21, and POTEF-AS1, support the development of PCa through many molecular mechanisms, including modulation of tumor suppressors and regulation of various signal pathways like PI3K/Akt, Bax/Caspase 3, P53, MAPK cascade, and TGF-β1. Other lncRNAs, in particular, MALAT-1, CCAT2, DANCR, LncRNA-ATB, PlncRNA1, LincRNA-21, POTEF-AS1, ZEB1-AS1, SChLAP1, and H19, are key players in regulating the aforementioned processes. Natural substances have shown promising anticancer benefits against PCa by altering essential signaling pathways. The overexpression of some lncRNAs is associated with advanced TNM stage, metastasis, chemoresistance, and reduced survival. LncRNAs possess crucial clinical and transitional implications in PCa, as diagnostic and prognostic biomarkers, as well as medicinal targets. To impede the progression of PCa, it is beneficial to target aberrant long non-coding RNAs using antisense oligonucleotides or small interfering RNAs (siRNAs). This prevents them from transmitting harmful messages. In summary, several precision medicine approaches may be used to rectify dysfunctional lncRNA regulatory circuits, so improving early PCa detection and eventually facilitating the conquest of this lethal disease. Due to their presence in biological fluids and tissues, they may serve as novel biomarkers. Enhancing PCa treatments mitigates resistance to chemotherapy and radiation.

Combined treatment of HCC with CTLA-4 inhibitors and PD-1/PD-L1 inhibitors: mechanisms, progress and challenges

HCC seriously threatens human health, and the treatment methods are of crucial importance. The tumor microenvironment is critical to the origin and progression of HCC, and aberrant regulation of the immune checkpoint signaling pathway is a key method by which tumor cells avoid immune surveillance. Conventional single-treatment approaches for HCC have drawbacks. Inhibitors of PD-1/PD-L1 and CTLA-4, together known as the "golden combination," are the primary treatment for primary HCC. Compared with single treatment, it has a synergistic effect and benefits in boosting the immune response against the tumor and growing the number of recipients. However, it also has challenges. This study examines the state of combination treatment in HCC clinical trials as well as the current understanding of immune checkpoint inhibitors. By elaborating the cancer immune mechanism, it examines the mechanisms of action of the CTLA-4 and PD-1/PD-L1 immune checkpoints, and also the theoretical underpinnings and synergistic mechanism of combination treatment in HCC. Together with clinical study data, it assesses the effectiveness and potential of combination treatment for the cure of HCC, thoroughly examines the effects of conjunction treatment of CTLA-4 inhibitors and PD-1/PD-L1 inhibitors in the immunologic therapy of HCC, and anticipates the future of combination treatment, offering useful references for HCC immunotherapy.