cGMP-PKG Signaling Research Articles

PTTG1 promotes M2 macrophage polarization via the cGMP-PKG signaling pathway and facilitates EMT progression in human epithelial ovarian cancer cells

Epithelial Ovarian Cancer (EOC) is complex and heterogeneous, making accurate prognosis and treatment prediction difficult. New therapeutic targets and their mechanisms are urgently needed. This study explored the role of PTTG1 in ovarian cancer via the cGMP-PKG signaling pathway, focusing on its effects on M2 macrophage polarization and EMT progression in EOC cells. Using the GSE135886 database, we performed differential gene expression, pathway enrichment, and immune infiltration analyses to identify key targets influencing EMT and macrophage polarization. We then constructed PTTG1 knockdown and overexpression cell lines to assess the impact of PTTG1 on cell proliferation, migration, invasion, EMT, and macrophage polarization in vitro. Analysis revealed that differentially expressed genes were enriched in the cGMP-PKG pathway and correlated with M2 macrophages. PTTG1 overexpression in A2780 and SK-OV-3 ovarian cancer cells promoted proliferation, invasion, and migration, while enhancing sGC, PKG1, and PKG2 expression to activate the cGMP-PKG pathway and induce M2 macrophage polarization. PTTG1 knockdown produced opposite results, reinforcing our conclusions. This study uncovers a novel mechanism of PTTG1 in ovarian cancer development and suggests it as a potential therapeutic target.

Identification of Alzheimer’s disease susceptibility genes by the integration of genomics and transcriptomics

ABSTRACT Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease. With the deepening of clinical and genomic research, a series of biomarkers and risk factors related to AD have been identified. However, the exact molecular mechanism of AD is not completely understood. Methods By combining expression quantitative trait loci (eQTLs) analysis with the results of genome-wide association studies (GWAS), the candidate genes (CG) related to AD were screened out accurately. We identified that intersection genes of differentially expressed genes (DEGs) and CG are the key genes. Then, GO, KEGG, and GSEA were utilized for functional enrichment analysis. Finally, we predicted AD responses to immunotherapy by the single sample gene set enrichment analysis (ssGSEA). Results A total of 253 DEGs were identified. The three key genes (VASP, SURF2, and TARBP1) were identified by taking the intersection of DEGs and CG. Through Mendelian randomization (MR) analysis, it was found that the risk of AD was significantly increased when VASP expression increased (OR = 0.1.046), while the risk of AD was significantly decreased when SURF2 (OR = 0.897) and TARBP1(OR = 0.920) expression increased. Subsequently, the functional analysis indicated that the core genes were mainly enriched in Leukocyte Transendothelial Migration, cGMP-PKG signaling pathway, and Rap1 signaling pathway. Through ssGSEA analysis showed that all three core genes were significantly related to M2 macrophages. Conclusions Three core genes were screened by integrating eQTLs data, GWAS data and transfer group data, and the potential mechanism of diagnosis and treatment of AD was revealed.

A study on the microbiome within oropharyngeal cancer tissues

Oropharyngeal cancer (OPC), a prevalent head and neck malignancy, is witnessing a rise in incidence and mortality rates annually. Our study aimed to understand the microbial composition within OPC tissue, utilizing the 2bRAD-M technique to analyze microbiome characteristics of tissue samples from 46 OPC patients and 31 with tonsillitis, followed by bioinformatics analysis. We identified higher relative abundances of Selenomonas sputigena, Nocardia farcinica, and other species in the OPC group compared to the tonsillitis group. KEGG functional prediction revealed enrichment in bile secretion, type II polyketide backbone biosynthesis, staurosporine biosynthesis, and cGMP-PKG signaling pathways. HPV-positive OPC patients showed greater abundances of Pseudomonas and other species, with differential gene enrichment in “ATP-binding cassette” and “ACSL” processes. These microbial disparities may offer potential biomarkers for OPC prediction and insight into its progression, informing treatment strategies for HPV-positive and HPV-negative patients.

Systematic Ocular Phenotyping of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies.

This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

Deciphering the Role of Putative Novel miRNAs Encoded From the Newly Found Genomic Regions of T2T-CHM13 in the Progression of Collecting Duct Renal Cell Carcinoma.

Collecting duct renal cell carcinoma (cdRCC) is a rare and aggressive renal cancer subtype. The molecular mechanisms underlying cdRCC remain poorly understood, which presents a significant challenge for the development of effective treatment strategies. Advances in genome sequencing, particularly the discovery of new genomic regions in the T2T-CHM13 reference genome, have provided an opportunity to expand our understanding of this disease. Our study specifically aims to investigate the role of miRNAs encoded by these regions, proposing them as potential epigenetic regulators in the pathogenesis of cdRCC. We used bioinformatic pipelines and small RNA-seq data analysis to predict novel miRNAs from the newly discovered genomic regions of T2T-CHM13. RNA-seq analysis of cdRCC tumors was performed to identify differentially expressed genes, and target prediction tools were used to find miRNA-mRNA interactions. Functional enrichment analyses were conducted to characterize the biological pathways affected. Using computational approaches, we predicted 156 novel miRNAs from T2T-CHM13's newly resolved sequences. RNA-seq and miRNA-mRNA interaction analyses identified 345 downregulated genes targeted by novel miRNAs and 395 downregulated genes targeted by known miRNAs. A comprehensive functional enrichment analysis of these perturbed genes revealed distinctive pathways, including cGMP-PKG signaling, calcium signaling, adipocytokine signaling, PPAR signaling, and apelin signaling, all of which are implicated in tumorigenesis. Furthermore, Gene Ontology analysis linked miRNA-targeted genes to disrupted cell-cell junctions and adhesion, providing a mechanistic explanation for aggressive invasion and metastasis in cdRCC. Additionally, a significant number of the target genes involved in metabolic and ion transport pathways were perturbed, explaining metabolic alterations in the cancer cells. We also identified 15 tumor suppressor genes downregulated by novel miRNAs, 6 of which were uniquely targeted, highlighting the potential of these miRNAs as cdRCC-specific biomarkers. In conclusion, our study offers valuable insights into cdRCC biology from an epigenetic perspective, laying the groundwork for future research aimed at developing targeted therapies.

Identification and Functional Validation of ACSL1 and FABP3 as Muscle-Related Genes Screened by Transcriptomics in Crossbred Duroc × Berkshire × Diannan Small-Eared Pigs

Background: Crossbreeding strategies that combine the growth performance of Western pig breeds with the meat quality traits of Chinese indigenous breeds have garnered considerable interest. Duroc pigs are known for their high growth efficiency but have relatively low intramuscular fat (IMF) content. In contrast, native breeds like the Diannan Small-Eared pig exhibit superior pork quality with higher IMF levels. This study aimed to compare the muscle growth characteristics and molecular mechanisms between Duroc × Landrace × Yorkshire (DLY) and Duroc × Berkshire × Diannan Small-Eared (DBD) pigs. Methods: The longissimus dorsi tissue of 210-day-old DLY and DBD pigs was collected for analysis. HE staining assessed muscle fiber characteristics, IMF content was measured, and ELISA quantified muscle-derived growth and development-related factors. Transcriptome sequencing was conducted, followed by differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) analyses. Functional validation of key genes was performed in C2C12 cells. Results: DBD pigs exhibited significantly larger muscle fiber diameter and higher IMF content compared to DLY pigs. IGF1 and GH levels were elevated in DBD pigs. Transcriptome analysis identified 185 upregulated and 102 downregulated genes, with enrichment in pathways including PI3K-Akt, MAPK, FoxO, and cGMP-PKG signaling. ACSL1 and FABP3 were functionally validated, showing promotion of differentiation and inhibition of proliferation in C2C12 cells. Conclusions: DBD pigs exhibit superior muscle growth traits and higher IMF content compared to DLY pigs. ACSL1 and FABP3 may serve as key regulators of muscle development in pigs.

MEF2A, MEF2C, and MEF2D as potential biomarkers of pancreatic cancer?

BackgroundThe myocyte enhancer factor-2 (MEF2) family genes were involved in the carcinogenesis and prognosis of multiple human tumors. The impact of MEF2s on the occurrences, progression, and clinical outcome of pancreatic cancer (PAAD) remains unknown.MethodsThis study used the CCLE, HPA, EMBL-EBI, and GEPIA2 databases to study MEF2s expression in PAAD patients. We also investigated the relationship between MEF2s expression and methylation through the DiseaseMeth database, and used MEXPRESS to verify the association. Then we utilized the Kaplan–Meier Plotter and GEPIA2 databases to evaluate the prognostic value of MEF2s in PAAD. The cBioPortal database was used to explore the alteration features of MEF2s in PAAD. We then investigated the association between MEF2s expression, immune cells infiltration, and immune infiltration markers using the TIMER database. Finally, Metascape, STRING, and Cytoscape tools were used for functional enrichment analysis.ResultsMEF2A, MEF2C, and MEF2D were found to be highly expressed in PAAD patients’ tissues compared to normal tissues, whereas MEF2B expression did not show significant differential expression. In addition, the protein expression of MEF2A, MEF2C, and MEF2D was higher in PAAD tissues. Negative correlations were observed between the expression level of MEF2A, MEF2C, and MEF2D and the methylation levels in multiple sites. High expression of MEF2A was related to poor overall survival (p = 0.0071) and relapse-free survival (RFS) (p = 0.0089) of PAAD. High expression of MEF2C was associated with worse RFS of PAAD (p = 0.043). MEF2A was a Truncating mutation, and it was shown that the “G27Wfs*8” mutation point was distributed in the SRF-TF domain. Both MEF2C and MEF2D were a Missense mutation. MEF2A, MEF2C, and MEF2D expression was positively corresponded with five immune cells infiltration (CD8 + T cells, B-cells, neutrophils, macrophages, and dendritic cells), especially for CD8 + T cells and macrophages. Among the 20 pathways, hsa05140 (Leishmania infection), hsa04022 (cGMP-PKG signaling pathway), hsa05145 (Toxoplasmosis), hsa04371 (Apelin signaling pathway), and hsa04064 (NF-kappa B signaling pathway), were closely connected with the occurrence and development of PAAD.ConclusionsOur results indicated that the overexpression of MEF2A, MEF2C, and MEF2D in patients with PAAD. MEF2A could be used as a prognostic biomarker for PAAD, MEF2C might be a potential oncogene for PAAD, and MEF2D had potential biological significance.

Screening and identification analysis of core markers for leukemia and cervical cancer: Calmodulin 3 as a core target.

Leukemia is a type of malignant tumor affecting hematopoietic system. Cervical cancer is a malignant tumor of female reproductive tract. The relationship between Calmodulin 3 (CALM3) and leukemia, cervical cancer remains unclear. Leukemia dataset GSE26294 and cervical cancer dataset GSE173097 profiles were downloaded from gene expression omnibus. Principal component analysis, differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, gene set enrichment analysis, immune infiltration analysis, protein-protein interaction network construction and analysis, survival analysis were performed. Gene expression heatmaps were plotted. Comparative Toxicogenomics Database (CTD) was used to find diseases most related to core genes. 77 DEGs were identified. According to gene ontology, in biological process category, they were mainly enriched in cell proliferation, immune response, and apoptotic process. In cellular component category, they were mainly enriched in nucleus and Golgi apparatus. In molecular function category, they were mainly enriched in DNA binding, protein binding, transcription factor activity. In Kyoto encyclopedia of gene and genome analysis, they were mainly enriched in cell adhesion molecules, Wnt signaling pathway, cAMP signaling pathway, cGMP-PKG signaling pathway, and basal cell carcinoma. The soft-threshold power in WGCNA was set to 1, generating 6 modules. Finally identifying 3 core genes (CALM3, secreted frizzled-related protein 4, plasminogen). CTD analysis revealed that core genes were related to leukemia, coagulation disorders, vaginal tumors, cervical tumors, autoimmune diseases, and inflammation. CALM3 is lowly expressed in leukemia samples and highly expressed in cervical cancer samples.

The role of APOA1-AS in colorectal cancer: Investigating its association with malignant biological behaviors.

The role of APOA1-AS in colorectal cancer: Investigating its association with malignant biological behaviors.

Multi-omics uncover acute stress vulnerability through gut-hypothalamic communication in ducks.

1. The avian gut hosts a complex and dynamic microbial ecosystem, which is essential for regulating host organ function. However, the relationship between the gut microbiota and the hypothalamic axis in acute stress vulnerability in ducks remains unclear.2. This study investigated how the gut microbiota affects microbial metabolism and the host stress response by comparing hypothalamic neurotransmitter availability, microbial composition and co-metabolites generated by both the microbiota and hypothalamus in ducks exhibiting the lowest active avoidance (LAA) and highest active avoidance (HAA) behaviour.3. The HAA group experienced a significant increase in the availability of arginine, histidine, glutamine, norepinephrine, L-tyrosine and melatonin during acute stress in the hypothalamus, compared to that in the LAA group. The 16S rRNA sequencing revealed significant differences in the gut microbiota composition based on acute stress vulnerabilities.4. Both caecal and hypothalamic metabolomic analyses identified 71 metabolites altered in caecal content and 95 in the hypothalamus. There was significant enrichment in pathways such as the cGMP-PKG signalling, dopaminergic synapse and endocrine resistance.5. Correlation analyses demonstrated that certain co-metabolites, including 1,3-dicyclohexylurea, 1-deoxyvaleric acid, 2-amino-2-methyl-1,3-propanediol, 3-chloroaniline, methenamine, N4-acetylcytidine-triphosphate and traumatin, may play a role in the gut microbiota-hypothalamic axis.6. The results suggested that the gut microbiome influenced acute stress responses. This provided a basis for understanding gut-hypothalamic communication and its impact on behaviour in ducks.

Mechanism of action of aloperine in the treatment of pulmonary arterial hypertension based on network pharmacology and molecular docking methods.

Pulmonary arterial hypertension is asevere pulmonary vascular disease, marked by high mortality and substantial treatment costs, underscoring the urgent need for the exploration of traditional Chinese medicine as apotential therapeutic strategy for pulmonary hypertension. This study aimed to investigate the underlying mechanisms of aloperine in treating PAH through network pharmacology and molecular docking approaches. The Swiss Target Prediction database was employed to predict molecular targets of aloperine, while Cytoscape was used to construct the "active component-target" network. Disease-associated targets were identified through the GeneCards and OMIM databases and cross-referenced with drug targets to determine effective targets of aloperine for PAH treatment. Analysis of protein-protein interaction (PPI) was conducted using the STRING database. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out via the Metascape platform. Following screening, 42molecular targets of aloperine, 1264 disease-related targets, and 23effective targets of aloperine in treating PAH were identified. The PPI analysis revealed that aloperine targets SLC6A2, ADRA1B, CYP2D6, CCR5, and JAK2, all of which play atherapeutic role in PAH. The GO and KEGG pathway analyses identified relevant biological functions, such as membrane raft organization, Gprotein-coupled amine receptor activity, and regulation of tube diameter, as well as ten pathways including neuroactive ligand-receptor interaction, the cGMP-PKG signaling pathway, calcium signaling, and vascular smooth muscle contraction. Molecular docking results confirmed the interaction between aloperine and its key targets, with ahigh docking affinity observed between aloperine and the core target ADRA1A. Network pharmacology analysis demonstrated that aloperine exerts its therapeutic effects in PAH primarily through multi-target and multi-pathway mechanisms, providing anovel direction and foundation for PAH treatment.

VASP Knockdown Ameliorates Lipopolysaccharide-Induced Acute Lung Injury with Inhibition of M1 Macrophage Polarization Through the cGMP-PKG Signaling Pathway.

Alveolar macrophage (AM) polarization plays a pivotal role in the inflammatory response during acute lung injury (ALI). As reported previously, vasodilator-stimulated phosphoprotein (VASP) may function as an anti-inflammatory agent in hepatic tissues. However, the specific role of VASP in ALI-induced macrophage polarization remains unclear. To elucidate the role of VASP in ALI, we established a lipopolysaccharide (LPS)-induced M1 polarization model of MH-S cells. RNA sequencing was performed to identify differentially expressed genes during macrophage polarization. The results revealed significant upregulation of the VASP gene. Subsequently, VASP gene knockdown in the lungs was achieved by intratracheal delivery of VASP-AAV6, and the resulting ALI symptoms and macrophage polarization were assessed. The VASP gene was also knocked down in MH-S cells; these cells were then stimulated with LPS for 24h, and polarization-related markers of macrophages were analyzed. Finally, to validate the involvement of the PKG-VASP signaling pathway, experiments were conducted with a PKG agonist (8-Br-cGMP) and inhibitor (KT5823), and the effects of modulating the PKG-VASP pathway on macrophage polarization were investigated. VASP knockdown notably ameliorated ALI symptoms in these mice with LPS-induced ALI. Additionally, in vitro experiments showed that the PKG-VASP signaling pathway plays a pivotal role in macrophage polarization. VASP knockdown protected mice from LPS-induced ALI by inhibiting M1 polarization, and its protective effects were partially mediated by the cGMP-PKG signaling pathway.

SPATIAL BRAIN PROTEOMIC ANALYSIS IN A CLOZAPINE-TREATED SCHIZOPHRENIA-LIKE MOUSE MODEL

Abstract Background Schizophrenia is a complex psychiatric disorder characterized by a spectrum of cognitive, emotional, and behavioral symptoms. Despite substantial research efforts and the accumulation of evidence, the definitive molecular mechanisms underlying schizophrenia remain elusive, with up to 30% of patients exhibiting treatment-resistance. Clozapine (CLZ), an atypical antipsychotic, has demonstrated remarkable effectiveness in the treatment on treatment-resistant schizophrenia, especially in cases where other antipsychotics have been ineffective. Elucidating the molecular mechanisms of clozapine can contribute to the development of effective treatment strategies; however, the impact on the expression of brain molecules involved in its pharmacological actions is not fully understood. Aims &amp; Objectives This study aims to investigate spatial alterations in the brain proteome of a schizophrenia-like mouse model administered phencyclidine (PCP) or subsequently treated with CLZ, and to obtain insights into the neurobiological pathways that underlie the therapeutic effects of CLZ. Methods PCP (10 mg/kg, s.c.) or saline (10 mL/kg, s.c.) was injected once a day for 14 consecutive days to the 6- week-old male ICR strain mice. After PCP or saline administration, CLZ (10 mg/kg or 30 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) was treated once a day for 7 consecutive days. Twenty-four hours after the last administration, the prefrontal cortex (PFC), nucleus accumbens (NAc), striatum (STR), hippocampus (HIP), and amygdala (AMY) were collected and subjected to proteomic analysis. Protein extraction, purification, and digestion from the brain samples were carried out, followed by nanoflow liquid chromatography-tandem mass spectrometry for comprehensive proteome profiling. Results We performed pathway analysis on differentially expressed proteins (DEPs) and confirmed their biological significance. As a result, DEPs related to the interaction of the two factors (PCP and CLZ) were associated with various pathways, including glutamatergic synapses in the PFC, retrograde endocannabinoid signaling in the STR, Alzheimer's disease in the HIP, oxidative phosphorylation in the AMY. Several pathways were common to multiple brain regions; retrograde endocannabinoid signaling in the PFC, STR, and AMY, synaptic vesicle cycle in the PFC, STR, and HIP, Parkinson's disease in the PFC and STR, cGMP-PKG signaling pathway in the PFC and AMY, and glycolysis/gluconeogenesis in the HIP and AMY. Discussion &amp; Conclusion Our study has provided a multitude of insights into the spatial profiles of protein expression within the multiple brain regions of interest following administration of PCP or CLZ. Interestingly, a common molecular pathway related to the synaptic vesicle cycle has been identified in the PFC, STR, and HIP, which are involved in behavioral phenotypes, such as cognitive impairments and emotional disturbances. Elucidating the functional roles of DEPs associated with common or specific pathways across various brain regions may contribute to the development of novel treatment strategies for treatment-resistant schizophrenia.

Toxicological landscape of Fuzi: a comprehensive study on the spatial distribution of toxicants and regional neurotoxicity variability in zebrafish.

Fuzi, a Chinese herb widely used in clinical settings, exhibits varying levels of toxicity depending on its geographical origin. Diester-type alkaloids are the primary contributors to the toxicity of Fuzi. This study aims to investigate regional differences and underlying mechanisms of Fuzi-induced neurotoxicity across China. Matrix-assisted laser desorption/Ionization mass spectrometry imaging (MALDI-MSI) method was employed to map the spatial distribution of six key diester-type alkaloids from Fuzi samples originating from five major regions. The results showed that the diester-type alkaloids were primarily distributed in the cuticle of Anguo- and Ludian-Fuzi, in the cuticle, cork, and pith of Butuo-Fuzi, in the phloem and pith tissues of Chenggu-Fuzi, and in the cuticle, cork, inner phloem, and pith of Jiangyou-Fuzi. When zebrafish were exposed to a Fuzi decoction for 24h, it was observed that Jiangyou-Fuzi induced the most significant neurobehavioral abnormalities, lipid peroxidation damage, and aberrant neurotransmitters release. RNA sequencing analysis further indicated that the amino acid metabolism, ErbB, cGMP-PKG, and p53 signaling pathways-regulated by changes in the expression of Glub, Mao, GAB1, PRKG1B, PSEN2, and BAXα genes were disrupted to varying extents by Fuzi from different origins. In summary, the regional variability in the neurotoxicity of Fuzi can be attributed to differences in the distribution of its active compounds and underlying mechanisms. Among the samples tested, Jiangyou-Fuzi exhibited the highest neurotoxicity, followed by Anguo-, Chenggu-, Ludian-, and Butuo-Fuzi.

Transcranial alternating current stimulation inhibits ferroptosis and promotes functional recovery in spinal cord injury via the cGMP-PKG signalling pathway.

Transcranial alternating current stimulation inhibits ferroptosis and promotes functional recovery in spinal cord injury via the cGMP-PKG signalling pathway.

Comparative Efficacy of β-Carotene and Losartan Against Isoproterenol-Induced Cardiac Fibrosis: An Experimental and Computational Studies

Objective β-carotene, a vitamin A precursor is reported to inhibit molecular pathways cardinal to pathogenesis of fibrotic tissue alterations and in this study, the effectiveness of 14 days oral administration of β-carotene (10, 20, and 40 mg/kg/day) in the cardiac fibrosis (CF) in rats was studied and explored the mechanisms through network pharmacology. Methods CF was induced by isoproterenol (ISO) 6 mg/kg/SC from day 1 to day 7. Losartan (LOS) 10 mg/kg/day/p.o. served as the standard. Both β-carotene and LOS were administered from day 1 to 14. On the 15th day, ECG and blood pressure (systolic, diastolic and mean) were recorded in the anesthetized rats followed by their euthanasia. The extent of cardiac fibrosis in the isolated hearts was determined using heart coefficient, tissue levels of hydroxyproline, histological examination. The oxidative stress in cardiac tissue was estimated, as GSH, SOD, catalase, MDA and NO. β-carotene targeted proteins pathway, process, and functional enrichment analysis were explored through network pharmacology. Results β-carotene dose-dependently mitigated the biochemical and histological changes induced by ISO in heart tissues. In ECG, it restored ST height, QT, and QRS intervals. Additionally, it normalized systolic, diastolic, and mean arterial pressures. The reduction in heart coefficient suggests β-carotene’s potential to inhibit collagen deposition in heart tissue. β-carotene normalized oxidative stress markers, and hydroxyproline levels. All other biochemical parameters were restored to normal levels with β-carotene treatment. β-carotene 40 mg/kg dose showed comparable effect to that of LOS 10 mg/kg. β-carotene modulated IL-17, TNF, NF-kappa B, HIF-1, Sphingolipid, Relaxin, Adipocytokine, cAMP, Toll-like receptor, MAPK, PI3K-Akt, cGMP-PKG, VEGF, Ras, and PPAR signaling pathways. Conclusions β-carotene dose-dependently protects against ISO-induced CF in rats, with 40 mg/kg as an effective antifibrotic dose.

Celastrol Ameliorates Hypoxia-Induced Pulmonary Hypertension by Regulation of the PDE5-cGMP-PKG Signaling Pathway.

Pulmonary hypertension (PH) is a severe pulmonary vascular disease characterized by poor clinical outcomes and limited therapeutic options. Celastrol (CEL), a natural product derived from Tripterygium wilfordii Hook F, has shown therapeutic potential in PH models, although its mechanisms are not fully understood. This study aims to investigate the role of CEL in PH and explore its potential underlying mechanisms. This study investigates the role of CEL in PH and explores its underlying mechanisms. We evaluated the effects of CEL in a chronic hypoxia-induced PH rat model and hypoxia-stimulated human pulmonary arterial smooth muscle cells (HPASMCs). Bioinformatics and network pharmacology were employed to identify potential targets and pathways, which were then validated through mechanistic and functional analyses. CEL significantly reduced right ventricular systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH rats. It also decreased proliferating cell nuclear antigen expression and promoted apoptosis in pulmonary arterioles. Our findings suggest that CEL's therapeutic effects are mediated through the modulation of phosphodiesterase 5 (PDE5) and the activation of the cGMP-PKG signaling pathway. In HPASMCs, CEL treatment mirrored the invivo results, and PDE5 overexpression negated CEL's antiproliferative, antimigratory, and pro-apoptotic effects. CEL ameliorates pulmonary vascular remodeling and right ventricular dysfunction in PH, potentially through the PDE5-cGMP-PKG signaling pathway. These findings position CEL as a promising candidate for PH therapy.

Vericiguat improves cardiac remodelling and function in rats with doxorubicin-induced cardiomyopathy.

Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has been demonstrated effective in improving prognosis of patients with heart failure with reduced ejection fraction. However, there are limited data concerning the effect of vericiguat in patients with doxorubicin (DOX)-induced cardiomyopathy (DIC). In this study, we investigated the effects of vericiguat on cardiac structure and function in rats with DIC as well as their potential mechanisms of action. DIC rats were established by intraperitoneal injection of DOX (1mg/kg) twice a week for 6weeks, followed by intragastric administration of vericiguat 1mg/kg/day or an equal volume of normal saline for 8weeks. Cardiac histology and function, circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP), nitric oxide (NO), and oxidative indices, as well as myocardial cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling, oxidative and apoptosis-associated protein were measured. Compared with the control group, rats treated with DOX exhibited significantly increased heart size, reduced systolic function and elevated plasma levels of NT-proBNP. Histological findings revealed myocardial cell atrophy, fibrosis and apoptosis. Vericiguat treatment effectively reversed DOX-induced cardiac remodelling and improved systolic function. Mechanistically, Vericiguat attenuated the inhibitory effects of DOX on the myocardial cGMP-PKG axis and nuclear factor erythroid 2-related factor 2 (Nrf2) protein, thereby alleviating oxidative stress and apoptosis. Vericiguat improved cardiac remodelling and contractile function in rats with DIC through upregulation of cGMP-PKG signalling and inhibition of oxidative stress and myocardial apoptosis.

Supramolecular Combination Chemotherapy: Directly Inducing Immunogenic Cell Death To Inhibit Tumor Metastasis via Host-Guest Interactions.

Tumor metastasis is a difficult clinical problem to solve due to tumor heterogeneity and the emergence of antiapoptotic clones driven by tumor evolution. Clinical combination chemotherapy remains a standard treatment for solid metastasis tumors but with worse treatment efficiency. It is worth exploring a high-efficiency and low-side-effect therapeutic method to solve solid metastases. Herein, we fabricate a supramolecular combination chemotherapeutic system based on host-guest interactions using a cucurbit[8]uril complex (CB[8]-lobaplatin-oxaliplatin, CLO). We explored whether CLO can induce colorectal cancer cell death by activating immunogenic cell death (ICD) to inhibit cancer cell migration in a safe and effective manner. CLO inhibits the viability of human colorectal cancer cells (HCT116) at only 10 μM and alleviates the cytotoxicity induced by lobaplatin-oxaliplatin (LO) in normal colorectal cells (NCM460). Interestingly, CLO can trigger ICD in colorectal tumor cells, and our results verified the upregulations of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) release and cell surface calreticulin (CRT) exposure. Besides, we found that CLO can inhibit tumor migration both in vivo and in vitro, and bio-AFM characterization of tumor cellular surface also confirmed this phenomenon. To further investigate the underlying mechanisms of the antitumor effects of CLO, quantitative proteomics was employed, and the results indicated that the citrate cycle (TCA cycle), protein processing in the endoplasmic reticulum, cGMP-PKG signaling pathway, p53 signaling pathway, chemical carcinogenesis, and necroptosis signaling pathway might contribute to CLO-induced antitumor effects. Collectively, our study suggests that the supramolecular combination chemotherapeutic system based on CB[8] host-guest complex can activate ICD to inhibit metastasis in antitumor strategy and exhibits a remarkable potential for supramolecular immunotherapy.

Investigating the Therapeutic Mechanisms of Total Saikosaponins in Alzheimer's Disease: A Metabolomic and Proteomic Approach.

Alzheimer's disease (AD) is the leading cause of dementia among the elderly, yet effective treatments remain elusive. Total saikosaponins (TSS), the primary bioactive components in Bupleurum chinense, have shown promising therapeutic effects against AD in previous studies. Methods: To delve deeper into the mechanisms underlying the therapeutic role of TSS in AD, we investigated its neuroprotective effects and associated molecular mechanisms in APP/PS1 mice. Further, we employed metabolomic and proteomic analyses, with a focus on the potential protein-level changes induced by TSS, particularly those related to metabolite accumulation in the brain. Results: Our results showed that lysophosphatidylcholine, adenosine, and sphingomyelin in plasma might serve as potential biomarkers. Compared to the control group, AD mice exhibited significantly increased expression of proteins related to neuroinflammatory pathways, whereas proteins involved in cAMP signaling, cGMP-PKG signaling, and synaptic plasticity pathways were significantly downregulated. Notably, these signaling pathways were partially reversed in APP/PS1 mice following TSS administration. Behavioral tests demonstrated that TSS effectively improved the learning and memory functions of mice. Conclusions: Our findings suggest that TSS ameliorate cognitive decline through regulating neuroinflammatory pathways, cAMP and cGMP signaling, and synaptic plasticity pathways, providing insights into its therapeutic potential in AD.