Cadmium (Cd) is a non-essential metal element for plant growth and development and can be easily absorbed by wheat roots and transported to the grain, thereby posing health risks to human. Therefore, exploring the effects of Cd on wheat root growth and development and key responsive genes are important. In this study, analysis of the root morphology of Aikang58 (AK58) seedlings under 0, 3 and 10 mg/L Cd treatments found that the total root length, total root surface area, and root average volume were significantly decreased while the total root tips were first increased and then decreased as the Cd treatment concentration increased. Subsequently, we analyzed root transcriptome data of AK58 and Chinese Spring (CS) seedlings under 0 and 1 mg/L Cd treatment for 15 days as well as Huixian Hong (HXH) and Xinmai 9 (XM9) at 0, 2, 6, 12, 24, 48, and 72 h post-Cd treatment with 0.2 mg/L, and found 177 key responsive genes. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that these genes were mainly related to amino acid metabolism, ABC transporters, and plant hormone signal transduction. Subsequently, we analyzed the expression of six key responsive genes using AK58 seedlings treated with different Cd concentrations. Interestingly, the expression of TraesCS2B02G394500 in the root showed a significant negative correlation with Cd concentrations. Further analysis of root morphology and ion content in different tissues found that this gene had a significant negative correlation with root development and was verified in five varieties with different genetic relationships with AK58. We found the protein encoded by TraesCS2B02G394500 was YSL12 by bioinformation analysis, which was involved in transmembrane transport of heavy metals. In conclusion, our results lay a theoretical foundation for analyzing the molecular mechanism of wheat in response to Cd.

Per- and polyfluoroalkyl substances (PFAS) are highly stable chemical contaminants of emerging concern for human and environmental health due to their non-natural chemistry, widespread use, and environmental persistence. Despite conventional metrology, mitigation strategies, and removal technologies, the complexity of this growing problem necessitates alternative approaches to tackle the immense challenges associated with complex environmental PFAS contamination. Recently, biology has emerged as an alternative approach to detect and mitigate PFAS and understand the molecular-level responses of living organisms to these compounds. However, little is understood of the impacts of PFAS on the environment, particularly impacts on microorganisms that play pivotal roles in nearly every ecosystem. Therefore, further study is needed to understand how microorganisms respond to different PFAS across growth phases.

Water deficit is a major environmental stress significantly affecting plant growth and productivity. This research examined the molecular and biochemical responses of Scrophularia striata, a traditional Iranian medicinal plant, to drought stress. It also evaluated whether the separate and combined application of salicylic acid (SA) and silicon (Si) could alleviate these negative effects. The present study was conducted in a greenhouse with a four-factor factorial completely randomized design (FCRD) experimental design with three replications. The treatments included combinations of drought stress level 50% of field capacity (FC50%), SA at two levels (0 and 100 mg L- 1), as well as Si at two levels (0 and 1 g L- 1). The evaluated biochemical parameters included β-carotene, α-tocopherol, and beta-amyrin (βA) content, as well as changes in the expression of genes involved in the terpenoid pathway. The mean comparison revealed that drought stress lowered the levels of β-carotene, α-tocopherol, and βA. This suggests that the adaptive metabolites changed in response to adverse environmental conditions. It reduced the expression of biosynthesis genes such as geranyl diphosphate synthas (GPPS), isopentenyl diphosphate isomerase (IPPI), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase (FPS), and beta-amyrin synthase (βAS). The use of SA heightened the expression of the isopentyl diphosphate isomerase gene. When salicylic acid (SA) and Si were employed together, they elevated the levels of β-carotene, α-tocopherol, and βA under FC50% drought stress conditions. The findings provide important insights into the transcriptional and metabolic reprograming of S.striata under drought stress. These results have significant implications for the development of drought-resilient of medicinal plants increasingly confronting climate changes stresses.

Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer's disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau-bearing mice. We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.

The molecular and functional changes in endothelial cells during disease progression such as cancer have been noted but the mechanism of their activation is still under-studied. Previously we discovered that tumor-derived Oncostatin M induced tumor-associated vascular phenotypes, and the activated endothelial cells in turn promoted tumor progression and metastasis of clear-cell renal cell carcinoma (ccRCC). However, the mechanism of Oncostatin M action remains unknown. Here, we reveal that Oncostatin M signaling triggers specific epigenetic reprogramming of endothelial cells through upregulation of lysine acetyltransferase 6B, leading to increased histone 3 lysine 14 acetylation (H3K14ac) in vitro and in vivo. H3K14ac-modified chromatins upregulate specific gene sets associated with hypoxic response, hyper-angiogenesis, inflammation, and mesenchymal transition. Targeting H3K14ac in endothelial cells by interfering with acetyltransferase 6B function or neutralizing Oncostatin M ameliorates the premalignant hyperplastic phenotypes in the autochthonous ccRCC mouse model and diminishes tumor growth and metastasis in the ccRCC xenograft model.

The mechanisms by which tumor-associated macrophages, key components of the glioblastoma (GBM) microenvironment, impair chemotherapy efficacy remain poorly understood. Resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, is associated with poor prognosis due to efficient DNA repair mechanisms. While low expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been linked to improved TMZ response, our previous findings suggest that N-methylpurine-DNA glycosylase (MPG) may also contribute to chemoresistance in GBM. Here, we report for the first time that conditioned medium from pro-inflammatory macrophages (CM-M1) enhances TMZ cytotoxicity by suppressing STAT3 phosphorylation, resulting in decreased MGMT and MPG expression in GBM cells. Proteomic profiling of CM-M1 revealed a unique, cytokine-rich secretome that may promote STAT1 activation, thereby inhibiting pSTAT3 and reducing DNA repair enzymes levels. Clinically, elevated MGMT and MPG protein levels were associated with increased pSTAT3 in our GBM patient cohort, and analysis of the TCGA database further showed that their combined overexpression correlates with significantly reduced progression-free survival. Gene silencing experiments confirmed the contribution of both enzymes to TMZ resistance, with dual knockdown producing a synergistic sensitizing effect. These findings uncover a novel mechanism of macrophage secretome-mediated chemoresistance and support the development of M1-based strategies to improve TMZ efficacy in GBM.

Trans-cinnamaldehyde (TCA), a natural compound isolated from the stem bark of Cinnamon cassia, has been recognized as a potential therapeutic agent for treating various diseases, including inflammatory conditions and diverse cancers. TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis selectively in cancer cells while sparing normal cells. However, resistance to TRAIL-mediated apoptosis is a significant limitation in cancer therapy. This study aimed to investigate whether TCA could enhance the sensitivity of colorectal cancer cells to TRAIL induced apoptosis and to elucidate the underlying molecular mechanisms involved in this synergistic effect. The study was designed to evaluate the antitumor effects of TCA and TRAIL, both individually and in combination, using colorectal cancer cell lines and in vivo models. Various colorectal cancer cell lines and normal cells were treated with TCA, TRAIL, or their combination. Cell viability assays were conducted to determine the synergistic effects. Western blotting was performed to analyze the expression of ER stress-related proteins. Knockdown of DR5 or CHOP was achieved using siRNA to evaluate its role in the combined anticancer effect. in vivo experiments were conducted to confirm the antitumor effects of the TCA and TRAIL combination. We observed that the combination of TCA and TRAIL exhibits synergistic antitumor effects both in vitro and in vivo. The anticancer effect was notably enhanced when TCA and TRAIL were used to treat various colorectal cancer cell lines, but not normal cells. Additionally, the levels of endoplasmic reticulum (ER) stress-related proteins, such as phosphorylated protein kinase RNA-like ER kinase (PERK), phosphorylation of the eukaryotic initiation factor 2 (eIF2α), and C/EBP homologous protein (CHOP), increased in a dose-dependent manner when treated with TCA. Significantly, TCA elevated DR5 expression levels through ER stress. Knockdown of CHOP reduced the combined effect of TCA and TRAIL. TCA enhances TRAIL-induced apoptosis in colorectal cancer cells by inducing ER stress and upregulating DR5 expression. These findings suggest that TCA is a promising agent for overcoming TRAIL resistance and improving its therapeutic efficacy in colorectal cancer treatment.

Rhabdomyosarcoma (RMS) is marked by a myogenesis differentiation blockade, and while the AKT/mTOR pathway is universally activated, its pharmacological inhibition has shown limited success. Here, we evaluate the activity of pan-AKT inhibitors Ipatasertib, ATP-competitive, and Miransertib, allosteric inhibitor, in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). Unlike Miransertib, Ipatasertib show significant antitumor activity against a subset of RMS. Besides AKT, the other target of Ipatasertib, but not of Miransertib, is PRKG1, a cGMP-dependent protein kinase that shares the ATP binding pocket with AKT. We investigate the role of PRKG1 in PRKG1-depleted RMS cells and in xenograft models by transcriptomic approaches. PRKG1 silencing in RMS cells reduces tumor formation in xenograft models and induces a differentiated myogenic transcriptome. RMS show higher PRKG1 expression compared to any other developmental cancer, akin to fetal skeletal muscle. Importantly, PRKG1 expression in RMS correlates with mesodermal transcriptional signature and enhanced sensitivity to Ipatasertib, regardless of the fusion oncogene status. The antitumor activity of Ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS.

L-2-hydroxyglutarate (L-2-HG) functions as a metabolite implicated in the progression of various tumors. HIF1A, a central regulator of the hypoxic response, is known to be regulated by several metabolites. This study aims to elucidate whether L-2-HG regulates the function of HIF1A through histone lactylation modification, thereby contributing to brain metastasis in renal cell carcinoma (RCC). A mouse model of RCC brain metastasis was constructed, and high-throughput metabolomics, transcriptomics, and proteomics sequencing analyses were conducted. Bioinformatics analysis revealed that L-2-HG enhanced HIF1A expression by promoting histone lactylation modification, which suppressed ferroptosis and facilitated RCC brain metastasis. In vitro cellular experiments were conducted, including cell treatment, transfection, chromatin immunoprecipitation (ChIP), malignant phenotype detection assays, Western blotting, and RT-qPCR. The results showed that L-2-HG increased the lactylation modification of HIF1A and enhanced the resistance of renal cancer cells to ferroptosis, thereby increasing cell proliferation, migration, and invasion. In vivo experiments using a nude mouse lung metastasis model demonstrated the mechanism through which L-2-HG promoted RCC brain metastasis.

Since its introduction in 2008, sorafenib has remained the standard first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Nevertheless, its clinical benefits are often compromised by the rapid emergence of drug resistance. This study explores the molecular mechanisms underlying sorafenib resistance, with particular emphasis on the involvement of connective tissue growth factor (CCN2/CTGF) in the regulation of c-Met signaling pathways.

One serious consequence of diabetes mellitus is diabetic retinopathy (DR), which impairs eyesight to the point of blindness. While glucocorticoid medications are commonly employed in the management of DR, their therapeutic efficacy requires enhancement. Due to the tight association between glucocorticoid-related genes and the onset and development of DR, a comprehensive examination of its root cause of activity may be able to overcome the drawbacks of existing treatment approaches.

Interleukin 1 beta (IL-1β) is upregulated following a tendon injury and in vitro studies have shown that it leads to numerous negative effects on tendon cell function and gene expression. IL-1β activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and we hypothesised that inhibiting NF-κB activation would mediate the negative effects of IL-1β on equine tendon cells in 3-dimensional (3D) cultures.

Neural tube defects (NTDs) are developmental malformations affecting 1300 newborns in the United States each year. Valproic acid (VA), a drug to treat seizures and mood disorders, can cause NTDs. Apoptosis is increased in the developing neural tubes (NTs) of embryos exposed to VA thereby identifying a possible mechanism for NTD formation. Numerous studies show that maternal immune stimulation (MIS) in the periconceptual period reduces birth defects including VA-induced NTDs. It is hypothesized that immunoregulatory cytokines may normalize the dysregulated apoptosis. This study examined maternal cytokine production and embryonic apoptotic gene expression following prebreeding stimulation with interferon-γ (IFN-γ) and gestational VA exposure.

Dental plaque biofilms, primarily formed by Streptococcus mutans, contribute significantly to oral diseases, necessitating effective anti-biofilm strategies. This study investigates the anti-biofilm potential of red pitahaya betacyanin fraction (BF) using transcriptomic analysis and an in vitro denture plaque model. Stringent differential gene expression analysis (p < 0.01, log2 fold change > ± 2) revealed that BF significantly downregulates genes involved in sucrose metabolism, energy production, and cell wall biosynthesis, impairing bacterial adhesion and biofilm integrity. Notably, the suppression of pfkB (phosphofructokinase) and fructose-specific PTS transporters revealed BF's ability to disrupt carbohydrate metabolism, while the downregulation of ciaR/ciaH two-component system impairs stress response and biofilm formation. Simultaneous upregulation of genes linked to glycolysis, arginine metabolism, and oxidative stress defence suggest an adaptive response to BF-induced stress. Gene ontology enrichment and protein-protein interaction analyses further confirmed that BF disrupts multiple bacterial pathways, including ATP synthesis, quorum sensing, and cell wall integrity. In an in vitro denture biofilm model, BF treatment resulted in a 79% reduction in plaque accumulation, demonstrating efficacy comparable to chlorhexidine while avoiding adverse effects such as staining. These findings underscore the potential of BF as a natural anti-biofilm agent with broad-spectrum inhibitory effects on S. mutans. Given its efficacy and safety profile, BF holds promise for incorporation into oral hygiene formulations as a novel therapeutic for biofilm-associated dental diseases.

Transmembrane protein 166 (TMEM166), an endoplasmic reticulum (ER)-resident membrane protein, exerts anticancer effects by inducing autophagy and apoptosis. Although tissues of various cancers downregulate its expression, the biological function of TMEM166 in hepatocellular carcinoma (HCC) remains unclear. Herein, we report that TMEM166 negatively regulates unfolded protein response (UPR) in HCC. TMEM166 was noted to interact with ACSL3 to maintain ACSL3 stability and facilitate lipid storage. TMEM166 deletion reduced ACSL3 expression and increased lipid utilisation in the mitochondria through fatty acid β-oxidation (FAO), ultimately boosting ATP production. Moreover, TMEM166-knockout (KO) cells demonstrated accelerated protein synthesis via the AMPK-mTOR axis. These effects induced sublethal ER stress and UPR activation in TMEM166-KO cells. Furthermore, TMEM166 KO promoted HCC cell proliferation and sorafenib resistance via UPR activity upregulation. We analysed the clinical significance of TMEM166-regulated UPR in human HCC cells and noted that TMEM166 expression was negatively correlated with the activities of UPR-related transcriptional factors such as ATF4, ATF6 and XBP1s in the cells. This study is the first to elucidate the relationship among TMEM166, ER stress, and HCC and may provide and indicate newer avenues for TMEM166-targeted gene therapy strategies for HCC treatment.

HERPUD1 is a protein of the endoplasmic reticulum (ER) that is sensitive to the unfolded protein response (UPR) induced during ER stress and has been linked to ER stress tolerance in cancer cells. Many tumors, including triple-negative breast cancer (TNBC), which lacks an effective treatment, display UPR activity as a malignancy trait. However, whether HERPUD1 provides an ER-dependent mechanistic link for tumorigenic agents and/or potential therapeutic targets remains unknown. To address these possibilities, we first analyzed HERPUD1 expression in breast cancer (BC) biopsies via immunohistochemistry and immunofluorescence, revealing significantly higher levels in BC, including luminal A and TNBC, compared to non-malignant tissue. In TNBC, in addition to epithelial cells, HERPUD1 associated with inflammatory infiltrates, highlighting its potential role in tumor progression. Palmitic acid (PA), a dietary saturated fatty acid, is an obesity-associated tumor risk factor that induces ER stress and activates UPR. Interestingly, MDA-MB-231 cells, but not other BC cell lines, specifically upregulate HERPUD1 together with XBP1s and ATF4, key UPR factors, in response to PA, whereas TG treatment elevated HERPUD1 across all tested cell lines. HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. HERPUD1 ablation also elevated UPR activation under TG. In contrast, PA-induced stress led to reduced UPR activation and lower IL-6 and IL-8 levels in the absence of HERPUD1 expression. We identified CK2 as a kinase that regulates HERPUD1 stability via Ser-59 phosphorylation. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.

Targeted therapies in cancer are limited by cells exhibiting drug tolerance. We aimed to target drug tolerance in order to delay the development of acquired resistance. In melanoma, tolerance to MAPK pathway inhibitors is associated with loss of SOX10 and an enhanced TEAD transcriptional program. We show that loss of SOX10 is sufficient to up-regulate TEAD targets with dependence on the co-activator, TAZ. Active TAZ is sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. We develop two covalent inhibitors, OPN-9643 and OPN-9652, designed to target the central palmitate binding pocket of TEADs. In SOX10-deficient cells, OPN-9643 and OPN-9652 reduce TEAD-dependent reporter activity and expression of TEAD targets, CTGF and CYR61. OPN-9643 and OPN-9652 treatment enhances the inhibitory effects of MAPK-targeted therapies in 2D and 3D growth assays in SOX10 knockout cells and reverses tolerance mediated by active TAZ. In vivo, OPN-9652 delays the onset of acquired resistance to BRAF inhibitors and MEK inhibitors from minimal residual disease. Thus, TAZ-TEAD activity plays an important role in melanoma drug tolerance and the development of acquired resistance.

This narrative review examines recent advances in understanding the epigenetic and transcriptional dynamics of the central-medial amygdala across different stages of ethanol use. It covers the various models and protocols of ethanol administration, emphasizing their strengths and limitations in helping understand ethanol-induced changes in brain and behaviour. The findings from protocols utilizing acute, chronic-intermittent ethanol (CIE) and chronic-continuous ethanol (CCE) exposure are summarized into a proposed mechanism of epigenetic dysregulation and neuroadaptation, spanning from initial ethanol exposure to withdrawal and its influence on gene expression and neuronal activity. This review also explores potential epigenetic targets for therapeutic intervention. Understanding the mechanisms that underlie histone remodelling during initial ethanol exposure, chronic exposure, and withdrawal has the potential to elucidate novel cessation strategies tailored to specific stages of alcohol use disorder (AUD).