Acute myocardial infarction (AMI) is a leading cause of heart failure, often accompanied by myocardial fibrosis (MF), characterized by excessive extracellular matrix accumulation. Endothelial-to-mesenchymal transition (EndMT) plays a key role in MF progression post-AMI. Neuregulin-1 (NRG-1), a growth factor with cardioprotective properties, has emerged as a potential therapeutic target. Tongxinluo (TXL), a traditional Chinese medicine, mitigates MF by upregulating NRG-1. This study elucidates the mechanisms underlying the protective effects of NRG-1 and TXL against MF following AMI. Left anterior descending artery ligation established a model for mice with AMI. Adeno-associated virus was used to modulate NRG-1 expression in the myocardium. Echocardiography assessed cardiac function, and histological staining was used to evaluate MF. Expression levels of markers for myofibroblasts (α-SMA, FSP-1) and endothelial cells (CD31, VE-cadherin) were analysed to investigate EndMT. The involvement of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in NRG-1's protective mechanism was validated using biochemical methods. Tongxinluo was administered to mice with AMI via gavage for 4 weeks, and its effects on cardiac function, MF and EndMT were assessed. Overexpression of NRG-1 in mice with AMI ameliorated cardiac dysfunction and reduced interstitial and perivascular fibrosis, whereas NRG-1 deficiency exacerbated these effects. NRG-1 protected against EndMT, as evidenced by changes in myofibroblast and endothelial cell markers. The PI3K/AKT signalling pathway was involved in NRG-1's protective mechanism against MF. The administration of TXL to mice with AMI improved cardiac function and reduced MF by activating NRG-1. Furthermore, TXL inhibited EndMT post-AMI through the NRG-1/PI3K/AKT pathway. NRG-1 and TXL protect against MF post-AMI by mitigating EndMT through the PI3K/AKT pathway. These findings suggest that targeting NRG-1 or using TXL may be promising therapeutic strategies for MF following AMI.

This study investigates the role of membrane-associated protein 17 (MAP17) and the Akt signaling pathway in the progression of papillary thyroid carcinoma (PTC).

We previously demonstrated that the midnolin gene (MIDN) is a risk factor for Parkinson's disease (PD) in Yamagata and British cohorts, and that neurite outgrowth is abolished by MIDN knockout in PC12 cells. Therefore, drugs that upregulate MIDN may have neurotrophic effects. In this study, acetylcholine increased MIDN promoter activity and gene expression in a concentration-dependent manner in SH-SY5Y cells. These effects were suppressed by atropine and a Gq inhibitor, YM254890, indicating that muscarinic receptor/Gq signaling is required for the induction of MIDN by acetylcholine. Our findings suggest that drugs that upregulate MIDN may have therapeutic potential for PD.

Maternal exposure to particulate air pollution increases the incidence and severity of asthma in offspring, yet the mechanisms for this are unclear. Known susceptibility loci are a minor component of this effect. We interrogate a mouse allergic airway disease model to assess epigenetic associations between maternal air pollution exposure and asthma responses in offspring. Maternal air pollution exposure increased allergic airway disease severity in adult offspring associated with a suppressed transcriptomic response. Control progeny showed differential expression of 2842 genes across several important pathways, whilst air pollutant progeny showed an 80% reduction in differentially expressed genes and abrogation of many pathway associations. Whole genome CpG methylome analysis following allergen challenge detected differential methylation regions across the genome. Differentially methylated regions were markedly reduced in air pollutant offspring, and this was most evident in intronic regions and some transposable element classes. This study shows that asthma in adult offspring of PM2.5 exposed mothers had a markedly repressed transcriptomic response, a proportion of which was associated with identifiable changes in the lung's methylome. The results point to an epigenetic contribution to the severity of asthma in offspring of mothers exposed to particulate air pollution.

G-quadruplex (G4) is a guanine-rich secondary structure found in DNA and RNA involved in various biological roles. Recently, a non-canonical RNA G-quadruplex (rG4), known as poly(UG) (pUG) fold, was discovered in Caenorhabditis elegans. This unique structure was found to induce RNA interference (RNAi) upon recruitment of RNA-dependent RNA polymerase (RdRP), resulting in trans-generational gene silencing. Herein, we develop a novel L-RNA aptamer, L-apt3.1, that binds to the pUG fold. We uncover that L-apt3.1 consists of a parallel rG4 structural motif, and mutagenesis analysis illustrates that the rG4 motif in L-apt3.1 is essential for pUG fold recognition. We show that L-apt3.1 interacts strongly with pUG fold, and notably, it is the first reported aptamer that can bind to pUG fold in vitro. We also demonstrate that L-apt3.1 possesses great biostability in cellular environments and negligible toxicity in vivo. Furthermore, we report that L-apt3.1 can interact with pUG fold in vivo, and with a comparable performance to the G4 ligand, N-methyl mesoporphyrin, in inhibiting gene silencing in C. elegans. Overall, we demonstrate the development of pUG fold-targeting L-RNA aptamer for the first time, and show that this new aptamer tool can be applied to control pUG fold-mediated gene expression in vivo.

Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER + breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.

Despite being one of the primary and most effective treatments for advanced stages of lung cancer, chemotherapy drugs like carboplatin have limitations due to their adverse side effects and the development of drug resistance in lung cancer cells. However, recent studies have shown promising results in using small interfering RNAs (siRNAs) as a therapeutic agent for cancer treatment. Hence, this study aimed to investigate the potential of combining siRNA-DLGAP1-AS2 with carboplatin in human lung cancer cell lines. The viability of the cells was assessed using the MTT assay, and apoptosis induction was examined through Annexin V/Pi staining. Additionally, the effect of the combination on cell cycle arrest and colony formation of lung cancer cells was studied. Furthermore, the expression of Bax, Bcl-2, MMP-2, MMP-9, GCLC, and CD44 was evaluated. Our functional analysis revealed that inhibiting the expression of DLGAP1-AS2 increased the sensitivity of lung cancer cells to carboplatin. Moreover, our study demonstrated that the combination of DLGAP1-AS2 inhibition through siRNA-DLGAP1-AS2 transfection and carboplatin treatment had a tumor-suppressive function, inhibiting the progression and proliferation of A549 lung cancer cells. Therefore, it can be concluded that targeting DLGAP1-AS2 using specific siRNA in combination with carboplatin chemotherapy holds promise as a valuable therapeutic approach for lung cancer.

Cyclic diguanylate (c-di-GMP) is a central biofilm regulator in Pseudomonas aeruginosa, where increased intracellular levels promote biofilm formation and antibiotic tolerance. Targeting the c-di-GMP network may be a promising anti-biofilm approach, but most strategies studied so far aimed at eliminating surface-attached biofilms, while in vivo P. aeruginosa biofilms often occur as suspended aggregates. Here, the expression profile of c-di-GMP metabolism-related genes was analysed among 32 P. aeruginosa strains grown as aggregates in synthetic cystic fibrosis sputum. The diguanylate cyclase SiaD proved essential for auto-aggregation under in vivo-like conditions. Virtual screening predicted a high binding affinity of echinacoside towards the active site of SiaD. Echinacoside reduced c-di-GMP levels and aggregate sizes and potentiated tobramycin activity against aggregates in >80% of strains tested. This synergism was also observed in P. aeruginosa-infected 3-D alveolar epithelial cells and murine lungs, demonstrating echinacoside's potential as an adjunctive therapy for recalcitrant P. aeruginosa infections.

Heat stress (HS) poses a substantial challenge in the poultry sector, resulting in considerable economic losses as it negatively impacts the well-being and productivity of chickens. Dried plum (DP) is a rich source of minerals, vitamins, antioxidants, and phenolic compounds. Studies have indicated that DP offers various health advantages, including preserving the body's redox system, immune function, and calcium balance. In our previous study, DP supplementation improved overall growth performance and intestinal health metrics in heat-stressed broilers. Considering the beneficial effects of DP on health, we hypothesized that adding DP to the diet would mitigate the harmful impacts of heat stress in the liver of broiler chickens. Day-old unsexed broiler chicks (n = 72) were raised under standard conditions and randomly assigned to three treatment groups (n = 24/group): 1) Control, 2) heat stress with basal diet (HS), and 3) heat stress with supplement (DP). During the finisher stage, the DP group received feed containing 2.5% DP during treatment, while the other groups were given a standard finisher diet. After 21 d, birds in the HS and DP groups were subjected to cyclic heat stress conditions for 3 wk. The heat stress conditions involved exposing the birds to a temperature of 33-35°C for 8 h during the daytime. In contrast, the birds in the Control group were raised under normal conditions with temperatures ranging from 22-24°C. DP supplementation significantly increased (P < 0.05) heat shock factor 1 (HSF1) expression in the liver compared to the Control group. DP supplementation significantly increased (P < 0.05) thioredoxin (TXN), peroxiredoxin (PRDX), insulin-like growth factor 1 (IGF1), and methyl-CpG binding domain (MBD4) expression in the DP group compared to the HS group. Fructose-1,6-bisphosphatase 1 (FPB1) expression was significantly decreased (P < 0.05) in the DP group compared to the HS group. Solute Carrier Family 3 Member 1 (SLC3A1), DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3 alpha (DNMT3A), ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), ten-eleven translocation methylcytosine dioxygenase (Tet3), and thymine DNA glycosylase (TDG) expression were significantly increased (P < 0.05) in the DP group compared to the other treatment groups. In conclusion, post-hatch DP supplementation lessened the negative effects of HS on broiler chickens by upregulating genes related to heat shock, antioxidants, growth, nutrient transporters, and epigenetics in the liver.

Background: The purpose of this study was to investigate the role of the early growth response gene 1 (EGR1) in inducing senescence in lung cancer cells by Qidongning Formula (QDF). Methods: Cell-Counting-Kit-8 was used to study the effect of QDF on A549 and NCI-H1975 cells proliferation. Senescence-associated β-galactosidase (SA-β-GAL) staining was used to examine the effect of QDF on cellular senescence. RT-qPCR analyses and Western blot were used to monitor the expression of EGR1 and the senescence-associated proteins p21 and p53. A rescue assay using an EGR1-overexpressing vector to explore whether EGR1 is a key target gene of QDF-induced lung cancer senescence. Bioinformatics analyses were used to identify the regulatory network involved in the process of QDF-induced senescence in lung cancer cells, downstream of EGR1 activation. Results: QDF could inhibit the proliferation of lung cancer cells in a concentration- and time-dependent manner. SA-β-GAL assay showed that QDF can induce lung cancer cells senescence, an increase in QDF concentration led to a significant increase in the number of cells that stained positive in the SA-β-GAL assay in the group exposed to a higher concentration of QDF. Western blot and RT-qPCR analyses indicated that the expression levels of the p53 and p21 proteins in A549 and H1975 cells increased significantly after QDF intervention. Additionally, EGR1-overexpressing can enhance QDF-induced senescence in lung cancer cells. Bioinformatics analyses revealed the EGR1 target genes implicated in QDF-induced senescence in A549 cells, including 21 senescence-related genes. Conclusion: The present study suggests QDF induces cellular senescence through activation of EGR1 in lung cancer cells and provides an insight for understanding the antitumor mechanisms of this Chinese traditional medicine.

Lipids play crucial roles in plant-microbe interactions, functioning as structural components, signaling molecules, and microbe-associated molecular patterns (MAMPs). However, the mechanisms underlying lipid perception and signaling in plants remain largely unknown. Here, we investigate the immune responses activated in barley (Hordeum vulgare) by lipid extracts from the beneficial root endophytic fungus Serendipita indica and compare them to responses elicited by chitohexaose and the fungal sterol ergosterol. We demonstrate that S. indica lipid extract induces hallmarks of pattern-triggered immunity (PTI) in barley. Ergosterol emerged as the primary immunogenic component and was detected in the apoplastic fluid of S. indica-colonized barley roots. Notably, S. indica colonization suppresses the ergosterol-induced burst of reactive oxygen species (ROS) in barley. By employing a multi-omics approach, which integrates transcriptomics, phosphoproteomics, and metabolomics, we provide evidence for the phosphorylation of phosphatidylinositol phosphate (PIP) metabolic enzymes and activation of diterpene biosynthesis upon exposure to fungal lipids. Furthermore, we show that phosphatidic acid (PA) enhances lipid-mediated apoplastic ROS production in barley. These findings indicate that plant lipids facilitate immune responses to fungal lipids in barley, providing new insights into lipid-based signaling mechanisms in plant-microbe interactions.

Glioblastoma (GBM) patients frequently develop resistance to temozolomide (TMZ), the standard chemotherapy. While targeting cancer metabolism shows promise, the relationship between metabolic perturbation and drug resistance remains poorly understood.

The microalga Aphanizomenon flos-aquae (AFA) has garnered attention for its potential therapeutic benefits in various health conditions, primarily through its use in nutraceutical formulations. While biological effects of AFA have been extensively studied in preclinical models, including murine systems, its nutrigenomic and epigenetic impacts remain underexplored. This study investigates the potential epigenetic mechanisms of AFA, focusing on its ability to modulate DNA methylation, a key regulatory process in gene expression. Specifically, we examined the influence of AFA on the methylation status of genes encoding pro-inflammatory interleukins, as these cytokines play a crucial role in immune response modulation and inflammation. Given the known impact of AFA on inflammatory markers, we aimed to determine whether the effects of AFA involve direct or indirect modulation of DNA methylation patterns in genes associated with inflammation. Our findings, presented here for the first time, reveal the capacity of AFA to influence DNA methylation, with implications for its role in cellular regulatory processes. These results warrant further investigation into precise mechanisms of action of AFA and its potential in clinical applications targeting inflammation-related pathways.

Salt stress has become a major threat to peanut yield and quality, and salt stress is particularly detrimental to seedling growth. Combined analysis of the physiology and transcriptomics of salt-tolerant variety (NH5) and salt-sensitive variety (FH23) under 200 mM NaCl stress was conducted to identify the key factors influencing the differences in salt tolerance and to investigate the potential regulatory mechanisms and hub genes associated with salt tolerance in peanuts.

Lenvatinib has been employed in the treatment of advanced liver cancer; however, its clinical application is significantly impeded by frequent drug resistance. Recent studies have revealed that lenvatinib treatment triggers ferroptosis in liver cancer cells, providing a novel approach to addressing lenvatinib resistance. In this study, we initially validated the induction of ferroptosis by lenvatinib in liver cancer cells. Remarkably, protocadherin 17 (PCDH17), an adhesion-related protein, was found to be down-regulated in liver cancer, and overexpression of PCDH17 could induce ferroptosis in liver cancer cells. Importantly, silencing PCDH17 inhibited the impact of lenvatinib on liver cancer cell ferroptosis, while overexpression of PCDH17 had the opposite effect. These findings were further confirmed using a xenograft tumor model in BALB/c nude mice. Additionally, lenvatinib-resistant (LR) liver cancer cells were generated for additional validation purposes. It was observed that LR-liver cancer cells lost their susceptibility to ferroptosis induction by lenvatinib; however, overexpression of PCDH17 reactivated their sensitivity to ferroptosis. Corresponding results were also verified in BALB/c nude mice models. In conclusion, these results suggest that as a novel regulator of ferroptosis, PCDH17 can alleviate lenvatinib resistance and potentially enhance the therapeutic efficacy of lenvatinib in treating liver cancer.

Zinc (Zn) is an essential trace element involved in a wide variety of cellular processes and is vital for optimal liver function. Our objective was to elucidate the potential therapeutic role of Zn in hepatocellular carcinoma (HCC), the third leading cause of cancer-related death and the first cause of death in patients with cirrhosis.

Post-translational modification by the small ubiquitin-like modifier (SUMO) is essential for cellular differentiation and homeostasis. Here, we investigate the role of SUMOylation in adipose tissue development using TAK-981, a pharmacological inhibitor of SUMOylation. Administration of TAK-981 to mice resulted in significant defect in weight gain and adipocyte atrophy in perigonadal white adipose tissue (gWAT) depots. Gene expression analyses revealed a marked downregulation of adipogenic genes, including Pparg, Cebpa, and Fasn. Our data thus indicate that TAK-981 treatment impaired adipogenesis in gWAT, consistent with prior findings that SUMOylation supports transcriptional regulation of adipogenesis and lipid metabolism. We also found significant infiltration of immune cells and efferocytosis in gWAT. Our results thus indicate that SUMOylation inhibition using a small molecule phenocopies genetic hypoSUMOylation models, highlighting its critical role in maintaining adipocyte functionality and immune environment. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our results underscore the importance of considering the potential unintended effects of SUMOylation inhibition on adipose tissue in patients.

Nicotinamide adenine dinucleotide kinase (NADK) is essential to the generation of nicotinamide adenine dinucleotide phosphate (NADP(H)), an important metabolic coupling factor involved in glucose-stimulated insulin secretion. In the present study, we showed that the expression of Nadk and Nadk2 transcripts and NADP(H) content were lower in islets of 80-week-old (aged) mice than those of 8-week-old (young) mice. This was associated with diminished oral glucose tolerance of old mice and the glucose-stimulated insulin secretion (GSIS) response of islets. Knockdown (KD) of Nadk or Nadk2 gene expression in NIT-1 cells impaired glucose-stimulated insulin secretion. Metabolomic analysis revealed that Nadk KD specifically affected purine metabolism in glucose-stimulated cells. The levels of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were higher in KD cells than in the non-targeting control (NTC) cells. Phosphorylation of AMP-activated protein kinase (AMPK) was elevated in glucose-treated KD cells compared to that of NTC cells. Increased AICAR level and AMPKα phosphorylation were observed in the glucose-stimulated islets of the aged mice. Genetic and pharmacological inhibition of AMPK promoted glucose-stimulated insulin release by KD cells and the aged mouse islets. It is likely that NADK is modulatory to AMPK activation in pancreatic β-cells and to their GSIS response. Enhanced AICAR formation in KD cells was accompanied by significantly increased conversion from inosine monophosphate (IMP) in a tetrahydrofolate (THF)-dependent manner. Folate supplementation augmented the GSIS response of KD cells and aged mouse islets. Taken together, these findings suggest that the aging-associated decline in NADK expression may underlie the reduced insulin secretory capacity of pancreatic β-cells.

MicroRNAs (miRNAs) regulate biological processes by inhibiting translation and causing mRNA degradation. In this study, we identified the miRNAs involved in the development and progression of lupus nephritis (LNs) and verified their roles.

Head and neck cancer (HNC) is a genetically complex cancer type having treatment difficulties due to affecting multiple organs in complex anatomical sites. Radiotherapy resistance, chemotoxicity, post-surgery disability makes HNC treatment more complicated. Therefore, there is need to developed new treatment approaches. Nanoparticle-based therapies especially cerium oxide nanoparticles with its anti-cancer features, high catalytic activity, anti- or pro-oxidant and radio-protective properties give a boon for HNC treatment. In the current study, two dextran-coated cerium oxide nanoparticles (Dex-CeNPs) namely SD1 and SD2 were synthesized and characterized by using two types of dextran (D1 and D2) having distinct molecular weights and branching characteristics to understand their potential as a new HNC treatment strategy while evaluating the role of dextran type. The effectivity of the SD1 and SD2 on the HNC cell lines (A253, SCC-25, FaDu) were investigated by analyzing their cytotoxicity, genotoxicity, reactive oxygen species (ROS) generation properties. Low IC50 value, high ROS generation and stability profiling of SD2 compared to SD1 indicates the distinct function of dextran type on Dex-CeNPs effectivity on HNC. To better elucidate the effectivity of SD2, flow cytometry analysis and pro-apoptotic (TP53, CASP3, BAX) and anti-apoptotic (Bcl-2) gene expression profiling were investigated in detail. The findings indicate that SD2 exhibits an influence on head and neck cancer cells via the apoptotic pathway. Our research sets the framework for the development of Dex-CeNPs as remarkable nanotherapeutic candidates for treatment of head and neck cancer.