Epidermal growth factor receptor inhibitors (EGFRIs) are used to treat certain cancers but frequently cause cutaneous inflammation that can hinder treatment. This is due in part to the effects of EGFRIs on pro-inflammatory signaling by interferon-γ (IFN-γ). However, the impact of EGFR ligands (i.e. EGF) on interferon signaling is unclear. The purpose of this study was to investigate the impact of EGF on IFN-γ transcriptional responses on a genome-wide scale in keratinocytes.

A new approach to siRNA delivery using high-density lipoprotein-like nanoparticles (HDL NPs) was investigated, incorporating oligoamine and cholesterol-derived cationic lipids (CLs) to associate siRNA with the carrier. Newly designed or commercially available compounds, including GL67 and 3-β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), were tested for siRNA binding, cytotoxicity, and siRNA cellular uptake. GL67 emerged as the most promising CL for siRNA delivery via HDL NPs. While it contributed to substantial siRNA uptake and cytosolic delivery in HepG2 cells, gene silencing remained limited, indicating a need for further optimization. Despite this, the study highlights the potential of positively charged cholesterol derivatives for siRNA delivery using HDL NPs. An analysis of the relationship between CL head group structure and HDL NPs' siRNA binding efficiency and cytotoxicity showed that factors such as oligoamine molecule conjugation site, linker type, amine group ethylation, and alkyl chain length between amine groups are crucial for optimizing CL design. Furthermore, the phospholipid environment surrounding CLs significantly influences HDL NPs' performance, particularly in siRNA cellular uptake. The study also revealed that intracellular siRNA trafficking varies by cell type, emphasizing the importance of customizing HDL NP formulations for specific cells. These insights are important for designing more effective HDL NPs for siRNA therapeutic delivery.

Endophyte can improve plant resistance to Pb stress, and long non-coding RNAs (lncRNAs) have been proved to play a vital role in response to environmental stress. However, there are few studies on the role of lncRNAs induced by endophyte in host plants under Pb stress. Therefore, we conducted high-throughput sequencing on root tissue of endophyte-infected and -uninfected rice seedlings under Pb stress, and analyzed the target genes of differentially expressed lncRNAs (DElncRNAs). The results showed that endophyte infection significantly increased plant height, above-ground fresh weight and dry weight, but significantly decreased root length and under-ground dry weight after 5 d of treatment. A total of 413 DElncRNAs (167 down-regulated and 246 up-regulated) were screened. Their target differentially expressed mRNAs (DEmRNAs) were significantly enriched in glutathione metabolism, plasma membrane and mineral elements transfer etc. DEmRNAs were most significantly enriched in glutathione metabolism, thereinto detected total glutathione, reduced and oxidized glutathione contents, glutathione S-transferase and glutathione reductase activities were significantly increased after 5 d of treatment. DElncRNAs and DEmRNAs were combined with miRNA database to construct ceRNA network. DEmRNAs in ceRNA network were mainly participated in carbohydrate metabolic process, peroxidase activity and phenylpropanoid biosynthesis. This study will help to understand the molecular mechanism elicited by endophytic infection within rice seedlings under Pb stress from the perspective of lncRNA.

Cadmium (Cd), a widespread and serious environmental pollutant, has recently garnered increasing scientific scrutiny due to its profound adverse effects. Although the evidence for Cd-induced reproductive toxicity is well established, it remains elusive on the intricate dose-response relationship and underlying molecular mechanisms, especially for transgenerational toxicity in animals. Here, we employed fruit fly (Drosophila melanogaster) as a model organism to examine the reproductive performance across five generations by parental exposure to varying concentrations of Cd (5, 50, and 500 μM). Firstly, our observations on the number of eggs laid, pupae formed, and adult flies emerged on the directly exposed generation (F0) confirmed a dose-dependent decline in fecundity. Transcriptome analysis revealed that, Cd-induced oxidative stress and ion transport disruption in the F0 generation could underlie synaptic dysfunction and impaired follicle cell development, impacting reproductive behavior and oocyte fertility. Employing dose-response analysis, Wnt signaling pathway and mTOR signaling pathway were identified as early molecular responses to Cd-induced toxicity. Secondly, sustained detrimental effects were observed for at least two to three generations after Cd removal. At the epigenetic level, Cd could perturb fecundity across generations by modulating Dnmt2 expression, a pivotal regulator of methylation processes. Moreover, despite phenotypic recovery in F4, persistent molecular changes indicate enduring toxicity, highlighting the need for vigilance against environmental Cd contamination and its long-term effects. Collectively, our findings enhance the understanding of Cd-induced reproductive toxicity and its transgenerational effects, and highlight the need to further improve the assessment of the multigenerational consequences of environmental Cd contamination.

Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke with high short-term mortality that can lead to cognitive and neurological impairment. Accurate and appropriate treatment strategies are urgently needed. Nimodipine (NDP) can not only improve blood circulation in SAH patients but also repair ischemic neuronal damage. microRNAs (miRNAs) are abundantly expressed in the brain and are involved in brain injury. Therefore, this study investigated the possible regulatory mechanisms of nimodipine on miRNAs in the process of cognitive dysfunction and neurological injury after SAH. The SAH rat model was established, miR-31-5p and hypoxia-inducible factor 1 subunit alpha inhibitor (HIF1AN) expressions were detected 48 h after modeling, and neurobehavioral function, neuronal apoptosis, activation of microglia, and inflammation were evaluated. Finally, the targeting relationship between miR-31-5p and HIF1AN was verified. The study findings explained that NDP treatment could effectively improve cognitive dysfunction, brain injury, neuronal injury, and neuroinflammation in SAH rats. SAH rats expressed down-regulated miR-31-5p and up-regulated HIF1AN. Overexpressing miR-31-5p or knocking down HIF1AN ameliorated cognitive dysfunction and brain damage in SHA rats. Mechanistically, nimodipine can promote miR-31-5p expression, and HIF1AN took part in the development of SAH as a downstream target gene of miR-31-5p. In conclusion, NDP ameliorates cognitive dysfunction and neurological damage in SHA rats by miR-31-5p/HIF1AN axis.

Pyruvate dehydrogenase B (PDHB) is an important component of the pyruvate dehydrogenase complex and is implicated in altering tumor metabolism and promoting malignancy. However, the specific impact of PDHB on hepatocellular carcinoma (HCC) metabolic reprogramming and its role in tumor progression remain to be elucidated. In our investigation, we have discerned a pronounced elevation in PDHB expression within HCC, intricately linked to delayed tumor staging, heightened tumor grading, and diminished prognostic outcomes. PDHB overexpression drives tumor growth and metastasis in vitro and in vivo. Mechanistically, PDHB mediates metabolic reprogramming by binding to the promoter regions of SLC2A1, GPI, and PKM2, promoting glycolysis-related gene transcription, contributes to HCC sorafenib resistance. In addition, Isoacteoside is a targeted inhibitor of PDHB and exert antitumor effects on HCC. In the mouse xenograft model, the combination of isoacteoside and sorafenib shows significantly better effects than sorafenib alone. In summary, our study validates PDHB as an oncogenic drug resistance-related gene capable of predicting HCC tumor progression. PDHB and Isoacteoside could be potential avenues for targeted and combination therapies in liver cancer.

The suppressors of cytokine signaling 2 (SOCS2) inhibits growth hormone receptor (GHR) signaling by negative feedback in the regulation of metabolism. In this study, we found that GHR upregulates SOCS2 expression, whereas KIT mutations, the key driver mutations of gastrointestinal stromal tumors (GISTs), inhibits SOCS2 expression in GISTs. Furthermore, SOCS2 associated and inhibited the activation of KIT mutations, but not wild-type KIT, in addition to its inhibition of GHR signaling, suggesting that KIT mutations may promote their activation by downregulation of SOCS2 expression. Accordingly, SOCS2 inhibited GIST cell survival and proliferation in vitro. In KITV558A/WT mice, knockout of SOCS2 expression increased the tumorigenesis of GISTs and decreased the life span of the mice. In addition, the presence of SOCS2 increased the inhibition of KIT signaling and GIST cell survival and proliferation by imatinib in vitro, and imatinib treatment further reduced tumor growth in KITV558A/WT mice compared with that in KITV558A/WT/SOCS2-/- mice, indicating the key role of SOCS2 in the sensitivity of GISTs to the targeted therapy. Taken together, our data revealed the key role of SOCS2 in the tumorigenesis of GISTs and the sensitivity of GISTs to the targeted therapy, providing a better basis for the improved treatment strategy.

Hyperglycemia is a hallmark of metabolic disorders, yet the precise mechanisms linking epigenetic regulation to glucose metabolism remain underexplored. Coactivator-associated arginine methyltransferase 1 (CARM1), a type I histone methyltransferase, promotes transcriptional activation through the methylation of histone H3 at arginine residues H3R17 and H3R26. Here, we identify a novel mechanism by which metformin, a widely prescribed antidiabetic drug, inhibits CARM1 activity. Using biochemical and biophysical assays, we show that metformin binds to the substrate-binding site of CARM1, reducing histone H3 methylation levels in CARM1-overexpressing hepatic cells and liver tissues from metformin-fed mice. This epigenetic modulation suppresses the expression of gluconeogenic enzymes (G6Pase, FBPase, and PCK1), thereby reversing CARM1-induced glycolytic suppression and regulating gluconeogenesis. Importantly, metformin does not alter CARM1 protein levels and its recruitment to gluconeogenic gene promoters but diminishes H3R17me2a marks at these loci. Our findings reveal a previously unrecognized epigenetic mechanism of metformin action, offering new therapeutic insights for hyperglycemia management.

In vitro culture impairs mitochondrial metabolism of IVP derived bovine embryos resulting in accumulation of reactive oxygen species. Recently, the antioxidant Mito-TEMPO has attracted attention due to its capability to accumulate within mitochondria. In order to investigate the potential of Mito-TEMPO to improve quality of IVP derived embryos, this study analyzed the developmental stage specific effect of Mito-TEMPO on developmental capacity, ROS balance, expression outline of antioxidative genes and cryo-resilience of blastocysts. In three subsequent experiments Mito-TEMPO (1 μM) was added either to the maturation medium (MTM), the culture medium (MTC) or to both the maturation medium and the culture medium (MTMC). Concerning cleavage- and blastocyst rates, no effect of Mito-TEMPO supplementation could be detected, although MTM and/or MTC groups revealed significantly (p < 0.05) lower levels of ROS. Expression outline of antioxidative genes under study was not affected in MTM group, whereas down-regulation of the proapoptotic gene BAX was observed in MTM as well as MTMC groups. Moreover, Mito-TEMPO significantly affected expression outline of genes with antioxidative functions within mitochondria (SOD2, GPX1, GSTA4) in MTC and/or MTMC groups and peroxisomes (CAT) in MTMC group. In contrast, expression of genes acting predominately outside mitochondria (NFE2L2 and PRDX1) was not affected. Of high impact, the present study revealed for the first time greatly improved reexpansion and hatching rates of bovine vitrified-warmed embryos as a consequence of supplementation of Mito-TEMPO to culture media. Collectively, the present study successfully proved that Mito-TEMPO alleviates negative effects of the in vitro culture environment in bovine pre-implantation embryos.

This study aimed to investigate the possible mechanism by which curcumin inhibits human prostate cancer (PCa) and castration-resistant prostate cancer (CRPC).

Type 3 iodothyronine deiodinase (Dio3) converts triiodothyronine (T3) to diiodothyronine, thereby reducing intracellular T3 levels. In this study, we investigated the potential roles of Dio3 in the differentiation of human pancreatic β cells, using β cells derived from human induced pluripotent stem cells (hiPSCs).

The platinum-based compounds are widely used in treating various types of cancer through their heavy metal component platinum. However, the development of chemoresistance often limits their clinical effectiveness. In this study, we report the roles of heavy metal response and its associated Hippo pathway in regulating platinum-based chemotherapy. Our data show that the MTF1-dependent heavy metal response induces cancer cell resistance to platinum-based compounds both in vitro and in vivo. This resistance is mitigated by Hippo pathway-mediated phosphorylation of MTF1. Moreover, pharmacological activation of the Hippo pathway sensitizes cancer cells to platinum-based compounds. Clinically, lung adenocarcinoma (LUAD) patients with high MTF1 activity exhibit poor overall survival rates, and Hippo pathway inactivation is positively correlated with elevated MTF1 transcriptional activity in platinum-treated LUAD patients. Collectively, our findings not only unveil a critical role of the Hippo-MTF1 pathway in regulating the response to platinum-based chemotherapy, but also suggest new strategies to enhance its efficacy by targeting the heavy metal response.

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

Previous research has shown that fluoranthene (Flu) exhibits dual uptake behavior in ryegrass. At low concentrations (1-10 mg/L), Flu uptake is higher, whereas at higher concentrations (20-40 mg/L), uptake appears to decrease. Furthermore, indole-3-acetic acid (IAA) content and antioxidant enzyme activity play distinct roles in this process. However, the molecular mechanisms underlying these behaviors remain unclear. To address this, we exposed ryegrass to different Flu concentrations (0, 5, and 20 mg/L) and conducted a combined transcriptomic and physiological analysis of the root system to elucidate the specific mechanisms of Flu uptake. Our results revealed that under 5 mg/L Flu treatment, ryegrass has a higher bioconcentration factor (BCF). The genes involved in IAA synthesis (TAA1, ALDH, and AAO1/2) were upregulated, which led to an increase in IAA content. Elevated IAA levels, in turn, promoted the expression of genes encoding H+-ATPase (ATP5A1, ATP5B, ATP5H, and ATP6E) and the ABC transporter protein (ABCB1), resulting in enhanced H+-ATPase activity, and facilitated the active transport of Flu. In contrast, the 20 mg/L Flu treatment resulted in a lower BCF. The downregulation of IAA synthesis genes (amiE and YUCCA) decreased IAA content. The downregulation of the H+-ATPase gene (ATP6C) and the ABC transporter protein gene (ABCG2), resulting in decreased H+-ATPase activity and inhibited Flu transport. Moreover, the promoted expression of redox-related genes (POD1, SOD1 and SOD2) further reduced Flu uptake. Elucidating the molecular mechanisms underlying Flu uptake in ryegrass may provide a theoretical foundation for developing strategies to regulate Flu accumulation in plants.

Progestogens and androgens have been found in many plants, but little is known about their physiological function. We used a previously established UPLC-ESI-MS/MS method to analyze progestogen and androgen profiles in fungal infections. Here we show that dehydroepiandrosterone (DHEA), a C19 steroid, specifically accumulates in shoots of Arabidopsis thaliana (L.) HEYNH. infected with Alternaria brassicicola (SCHWEIN.) WILTSHIRE. Elevated DHEA levels in plants seem not to be product of fungal sterol/steroid precursor activity, but an intrinsic plant response to the infection. DHEA was applied exogenously to analyze the effects of the androgen on development and gene expression in A. thaliana. Our findings reveal that DHEA treatment downregulates membrane-associated, salicylic acid and abscisic acid-regulated, as well as stress-responsive genes. Notably, DHEA does not inhibit the isoprenoid or post-lanosterol pathway of the ergosterol biosynthesis. Moreover, A. brassicicola was also treated with DHEA to analyze the growth, sterol pattern and membrane-integrity. Our data suggest that DHEA enhances the permeability of plant and fungal biomembranes. We propose that DHEA accumulation is a plant defense response which reduces fungal growth in plant tissues.

Reintroduction of tumor-suppressive microRNA-7-5p (miR-7) that is depleted in non-small cell lung cancer (NSCLC) represents a new therapeutic approach, whereas previous studies mainly used miR-7 mimics chemoengineered in vitro. Here we aim to establish the pharmacological actions and therapeutic potential of novel bioengineered RNA bearing a payload miR-7 (BioRNA/miR-7) molecule produced in vivo. First, through confocal imaging and immunoblot studies, we revealed that BioRNA/miR-7 altered NSCLC cell mitochondrial morphology accompanied by the downregulation of known target genes, epidermal growth factor receptor (EGFR), mitochondrial solute carrier family 25A37 (SLC25A37), and import inner membrane translocase subunit (TIM50). Second, through luciferase reporter and immunoblot studies, we validated mitochondrial acylglycerol kinase (AGK) as a new direct target for miR-7. Third, through real-time live-cell analyses, we revealed BioRNA/miR-7 to modulate mitochondrial respiration and glycolytic capacity. Fourth, live-cell and endpoint viability studies demonstrated that the combination of BioRNA/miR-7 with pemetrexed (PEM) elicited a strong synergistic effect to inhibit NSCLC cell growth, associated with an increased intracellular PEM accumulation, as quantified by a liquid chromatography tandem mass spectrometry method. Finally, through in vivo therapy study using NSCLC patient-derived xenograft mouse model, we demonstrated the efficacy and tolerability of BioRNA/miR-7 monotherapy and combination therapy with PEM to control tumor progression. Our collective works establish a role for miR-7 in NSCLC metabolism and PEM disposition and support our novel, in vivo produced BioRNA/miR-7-5p for molecular pharmacological research. Our findings further illustrate the potential of BioRNA/miR-7 plus PEM combination as a potential treatment to combat NSCLC tumor progression. SIGNIFICANCE STATEMENT: MiR-7 is a tumor-suppressive microRNA depleted in non-small cell lung cancer (NSCLC), and in vitro chemoengineered miR-7 mimics were shown to inhibit tumor growth in NSCLC cell-derived xenograft mice. Here, a novel in vivo bioengineered miR-7 molecule, namely BioRNA/miR-7, was used to effectively control target gene expression and NSCLC cell metabolism. Furthermore, BioRNA/miR-7 was demonstrated to remarkably improve pemetrexed antitumor activity in NSCLC patient-derived tumor mice, supporting the role of miR-7 in NSCLC metabolism and potential for BioRNA/miR-7 to improve NSCLC therapy.

Glioblastoma (GBM) tumors exhibit extensive genomic, epigenomic, and transcriptional diversity, with significant intratumoral heterogeneity, complicating standard treatment approaches involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed an integrative multi-omics approach, including targeted proteomics, transcriptomics, genomics, and DNA methylation profiling, to investigate the response of a representative panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation and RT and TMZ treatments. Differentiated CSC progenies retained the expression of key stemness genes and survival pathways, while activating the BMP-Smad signaling pathway and upregulating extracellular matrix components. This was associated with increased resistance to TMZ, though not to RT, across all models. We identified TP53 status as a critical determinant of transcriptional response to both RT and TMZ, which was also modulated by the differentiation state and treatment modality in wildtype (wt) p53 GBM cells. Both mutant and wt p53 models exhibited significant activation of the DNA-damage associated interferon (IFN) response in CSCs and differentiated cells, implicating this pathway in the GBM response to therapy. We observed that activation of NF-κB was positively correlated with the levels of O-6-methylguanine-DNA methyltransferase (MGMT) protein, a direct DNA repair enzyme leading to TMZ resistance, regardless of MGMT promoter methylation status, further supporting the clinical potential for inhibition of NF-kB signaling in GBM treatment. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor clinical outcomes. Hence cost-effective drugs with fewer side effects as a standard supportive therapy might yield substantial advantages in efficacy and safety. Kadukkai maathirai (KM) is being used as a supplement in hepatocellular carcinoma. We evaluated whether KM has any preventive action on cancer progression in diethyl nitrosamine (DEN) - induced HCC in rats.

Plant cell expansion is regulated by hormones and driven by turgor pressure, which stretches the cell wall and can potentially cause wall damage or rupture. How plant cells avoid cell wall rupture during hormone-induced rapid cell expansion remains poorly understood. Here, we show that the wall-sensing receptor kinase FERONIA (FER) plays an essential role in maintaining cell wall integrity during brassinosteroid (BR)-induced cell elongation. Compared with the wild type, the BR-treated fer mutants display an increased initial acceleration of cell elongation, increased cell wall damage and rupture, reduced production of reactive oxygen species (ROS), and enhanced cell wall acidification. Long-term treatments of fer with high concentrations of BR cause stress responses and reduce growth, whereas osmolytes, reducing turgor, alleviate the defects. These results show that BR-induced cell elongation causes damage to cell walls and the release of cell wall fragments that activate FER, which promotes ROS production, attenuates apoplastic acidification, and slows cell elongation, thereby preventing further cell wall damage and rupture. Furthermore, we show that BR signaling promotes FER accumulation at the plasma membrane (PM). When the BR level is low, the GSK3-like kinase BIN2 phosphorylates FER to reduce FER accumulation and translocation from the endoplasmic reticulum to PM. BR-induced inactivation of BIN2 leads to dephosphorylation and PM accumulation of FER. Thus, BR signaling enhances FER-mediated cell wall integrity surveillance while promoting cell expansion, whereas FER acts as a brake to maintain a safe cell elongation rate. Collectively, our study reveals a vital signaling circuit that coordinates hormone signaling with mechanical sensing to prevent cell rupture during hormone-induced cell expansion.

One of the primary challenges that the expanding population faces is water scarcity. Thus, a global imperative has been established to safeguard extant water resources and optimize their utility through sustainable practices and efficient management. In the present investigation, Azolla pinnata, a pteridophyte (fern), was employed to phytoremediate Cr (VI) from chromium-polluted water. The potential of this treated water for agricultural purposes was verified through the use of Vicia faba plants.