Using gene silence and heterologously overexpression, hydrogen sulfide synthesis-related genes l-cysteine desulfhydrase and d-cysteine desulfhydrase have been shown to enhance salt tolerance in tomato seedlings. Hydrogen sulfide (H2S) plays an important role in alleviating abiotic stress. L-Cysteine desulfhydrase (LCD) and D-cysteine desulfhydrase (DCD) are two important H2S synthesis enzymes. Until now, whether and how SlDCD and SlLCD increase salt tolerance in plant are still unknown. Here, we explored the effects of SlDCD and SlLCD on salt tolerance in tomato seedlings by silencing SlDCD and SlLCD and heterologously overexpressing SlDCD and SlLCD. In tomato seedlings, exogenous sodium hydrosulfide (NaHS, a H2S donor) increased salt tolerance while decreasing H2S synthesis-related enzyme activity, endogenous H2S levels, and H2S synthesis-related gene expression. Silencing SlDCD and SlLCD inhibited tomato seedling growth under salt stress, increased relative conductivity, MDA, H2O2, O2-, Pro, and carotenoid content, Ci and NPQ. In contrast, it decreased the activity of antioxidant enzymes (POD, SOD, CAT and APX) and the expression of related genes (POD, SOD, CAT and APX), chlorophyll content, photosynthetic parameters (Pn, Gs and Tr) and fluorescence parameters (Fv/Fm, φPSII and qP), while exogenous NaHS considerably mitigated the adverse impacts of salt stress in SlDCD and SlLCD silenced-tomato seedlings. Overexpression of SlDCD and SlLCD in Arabidopsis significantly enhanced plant salt tolerance. Taken together, our results indicate that SlDCD and SlLCD could enhance the antioxidant activity and photosynthesis capacity under salt stress, which results improving salt tolerance in tomato seedlings.

To investigate the apoptotic and anti-angiogenic effects of metformin in human MCF7 breast cancer cells.

The immunomodulatory function of estrogen within the ovary remains a subject of ongoing debate, and the neonatal ovarian immune microenvironment, particularly its modulation by estrogen, has not been comprehensively characterized. In this study, the effects of 17β-estradiol (E 2), a key regulator of immune function, were investigated using single-cell transcriptomic profiling of C57BL/6J neonatal mouse ovaries after E 2 treatment. Results revealed dynamic alterations in the proportion of immune cell types after E 2 treatment, accompanied by changes in cytokine and chemokine expression. Detailed analyses of gene expression, cell states, and developmental trajectories across distinct cell types indicated that E 2 treatment influenced cell differentiation and development. Notably, E 2 treatment reduced the abundance of macrophages and promoted a phenotypic transition from M1 to M2 macrophages. These findings demonstrate that the neonatal mouse ovarian immune microenvironment is sensitive to estrogenic modulation, which governs both the distribution and functional specialization of resident immune cells, offering novel mechanistic insights into the immunomodulatory roles of estrogen across various immune cell types.

JS-K is a precursor drug of nitric oxide (NO) and inhibits tumor growth through various mechanisms. Ferroptosis, a form of cell death closely related to lipid peroxidation, is increasingly being recognized for its role in cancer biology. However, the relevance of ferroptosis in the anti-tumor effects of JS-K is yet to be defined. The cytotoxic effects of erastin and JS-K were evaluated in various renal cell carcinoma (RCC) cell lines and normal human renal epithelial cells. Cell viability and the intracellular levels of ferrous ions, glutathione (GSH), lipid peroxides, and malondialdehyde (MDA) were measured using standard in vitro assays. The expression levels of specific proteins were analyzed by western blotting. Subcutaneous xenografts of RCC were established in a nude mouse model, and the anti-tumor effects of JS-K were assessed by histological and immunohistochemical methods. Erastin selectively inhibited the growth of RCC cells without affecting normal renal cells. In addition, JS-K induced ferroptosis in RCC cells by reducing cellular GSH levels, increasing lipid peroxidation, and elevating ferrous ion levels, and the effects of JS-K were neutralized by N-acetylcysteine (NAC). At the molecular level, JS-K downregulated GSTP1 by blocking the transcription factor c-Myc. Finally, JS-K inhibited tumor growth in a mouse model by inducing ferroptosis. JS-K induces ferroptosis in RCC cells by depleting glutathione through the inhibition of the c-Myc-GSTP1 axis.

Syndecan-4 (SDC4), a key member of the sulfated heparan sulfate proteoglycan (SDC) family, plays an important role in cell signaling. However, its function and regulatory mechanisms in tumors remain poorly understood. In this study, bioinformatic analysis revealed that SDC4 is significantly overexpressed in 16 types of tumors and positively correlated with poor prognosis in four types of these diseases. Knockdown of SDC4 inhibited tumor cell migration. Further analysis showed six transcription factors, including NF-κB, which potentially regulate SDC4 transcription. The UCSC Genome Browser database showed NF-κB binding peaks covered the SDC4 promoter in TNFα-stimulated tumor cells. ChIP-qPCR assay confirmed that TNFα treatment led to NF-κB binding at the SDC4 promoter, a genomic region also enriched for the active transcription mark H3K27Ac. qRT-PCR results demonstrated that TNFα treatment upregulated SDC4 in tumor cells. Immunofluorescence assay or qRT-PCR showed that the NF-κB inhibitor Bay11-7082 blocked TNFα-induced nuclear translocation of NF-κB, while both qRT-PCR and Western blot analyses showed Bay11-7082 could inhibit TNFα-induced upregulation of SDC4 at both mRNA and protein levels. Furthermore, SDC4 expression was positively correlated with NF-κB subunit RelA expression across 22 tumor types. In conclusion, this study identifies SDC4 as an oncogenic target gene of NF-κB, providing new insights for the development of anti-tumor therapies targeting the NF-κB pathway.

Mammary gland development and lactation in dairy sheep are regulated by hormones and autophagy; however, the role of estrogen-mediated autophagy remains unclear. This study determined that estrogen enhances autophagy, promotes CXCR4 and CXCL12 gene expression, and increases the number of autolysosomes in sheep mammary epithelial cells. Co-treatment with a CXCR4 overexpression vector and the small-molecule alternative of CXCL12, NUCC-390, significantly upregulated ATG5 and LC3 gene expression, increased the abundance of the autophagy-associated protein ATG5 and the LC3II/I ratio, and increased the consumption of the autophagy substrate P62. These results suggest that CXCR4 and CXCL12 signaling promotes autophagy in mammary epithelial cells. Conversely, co-treatment with a CXCR4-specific blocker and estrogen inhibited autophagic changes in ATG5, P62, and LC3 levels, reducing the number of autophagosomes and autolysosomes. Overall, this study demonstrated that estrogen promotes autophagy in sheep mammary epithelial cells through the CXCL12/CXCR4 signaling axis, revealing the underlying mechanisms behind estrogen-mediated autophagy.

Conventional expression studies quantify messenger RNA (mRNA) transcript levels gene-by-gene. We recently showed that protein expression is modulated at a global scale by amino acid availability, suggesting that mRNA expression levels might be equivalently affected. Through re-analysis of public transcriptomic datasets, it was confirmed that nucleobase supply interacts with the specific demands of mRNA A + U:C + G sequence composition to shape a global profile of expression, which can be quantified as a gradient of average expression change by average composition change. In mammals, each separate organ and cell-type displays a distinct baseline profile of global expression. These profiles can shift dynamically across the circadian day and the menstrual cycle. They are also significantly distorted by viral infection, multiple complex genetic disorders (including Alzheimer's disease, schizophrenia, and autoimmune disorders), and after treatment with 115 of the 597 chemical entities analysed. These included known toxins and nucleobase analogues, but also many commonly prescribed medications such as antibiotics and proton pump inhibitors, thus revealing a new mechanism of drug action and side-effect. As well as key roles in disease susceptibility, mRNAs with extreme compositions are significantly over-represented in gene ontologies such as transcription and cell division, making these processes particularly sensitive to swings in global expression. This may permit efficient, en bloc transcriptional reprogramming of cell state through simple adjustment of nucleobase proportion and supply. It is also proposed that this mechanism helped mitigate the loss of essential amino acid synthesis in higher organisms. In summary, global expression regulation is invisible to conventional transcriptomic analysis, but its measurement allows a useful distinction between active, promoter-mediated gene expression changes and passive, cell state-dependent transcriptional competence. Linking cell metabolism directly to gene expression offers an entirely new perspective on evolution, disease aetiopathology (including gene x environment - GxE - interactions), and the nature of the pharmacological response.

Cancer is a significant global disease with high mortality and limited therapeutic options. Chemotherapy is a cancer treatment option; however, there are still issues, including severe side effects, inadequate response, and drug resistance. Abietic acid is a natural diterpene with diverse pharmacological properties and can be used for cancer treatment. Therefore, this study aimed to assess the anticancer efficacy of abietic acid in combination with doxorubicin, a highly clinically used chemotherapeutic agent. Biochemical investigations include initial viability assays, combination therapy using isobologram analysis, apoptosis and cell cycle assays, gene expression assay, ELISA analysis of protein expression, DNA fragmentation, and wound healing assays. The data showed that doxorubicin-abietic acid (DOX-AB) is an effective and safe anticancer combination for Caco-2 cells. DOX-AB had a high safety index with minimal cytotoxicity at the combination dose on normal WI-38 fibroblasts cells. DOX-AB significantly decreased the proliferation and viability of Caco-2 cells, with an increase in the apoptosis rate in the late stage and necrosis with cell cycle arrest at the G2/M phase. Significant changes in the expression of modulators related to apoptosis, inflammation, and epigenetics were observed in gene and protein levels. DOX-AB combination had more efficient anticancer activity than doxorubicin alone. This study suggested that the use of abietic acid in combination with doxorubicin is a promising treatment for colorectal cancer because it enhances doxorubicin activity at relatively low doses with minimal cytotoxicity and overcomes multidrug resistance in tumors; these findings merit further investigation.

Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that (R)-WAC-224 is effective against AML with minimal cardiac toxicity. (R)-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that (R)-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. (R)-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and (R)-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. (R)-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and (R)-WAC-224 may be a promising treatment strategy for patients with AML.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with KRAS mutations playing a significant role in its tumorigenesis. Among the KRAS variants, the G13D mutation is associated with poor prognosis and distinctive biological behaviors. This study focuses on the role of HER2, a critical prognostic and predictive biomarker, in modulating the unique characteristics of KRASG13D-mutated CRCs. We identified a novel transcriptional regulatory network involving HER2, ELF3, and KRAS, with ELF3 acting as a key transcription factor (TF) that regulates KRAS expression under conditions of HER2 overexpression. Our findings reveal that this HER2-ELF3-KRAS axis is exclusively activated in KRASG13D, driving aggressive oncogenic features and conferring resistance to cetuximab (CTX) therapy. Through comprehensive analysis of gene expression profiles, we demonstrated that HER2 is a crucial therapeutic target specifically for KRASG13D CRCs. To explore this further, we introduced YK1, a small molecule inhibitor designed to disrupt the ELF3-MED23 interaction, leading to the transcriptional downregulation of HER2 and KRAS. This intervention significantly attenuated the HER2-ELF3-KRAS axis, sensitizing KRASG13D CRCs to CTX and reducing their tumorigenic potential by inhibiting the epithelial-to-mesenchymal transition process. Our study underscores the importance of HER2 as a key determinant in the unique biological characteristics of KRASG13D CRCs and highlights the therapeutic potential of targeting the HER2-ELF3-KRAS axis. By presenting YK1 as a novel pharmacological approach, we provide a promising strategy for developing tailored interventions for KRASG13D CRCs, contributing to the ongoing efforts in precision medicine for CRCs.

Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanoparticles (GNPsanti-SP-C) for the targeted delivery of Growth Differentiation Factor 15 (GDF15) to counteract ACE-II senescence. These nanoparticles (NPs) effectively activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway, inducing the mitochondrial unfolded protein response (UPRmt) and reversing senescence-associated cellular dysfunction. GNPsanti-SP-C were systematically engineered and demonstrated robust pH/ROS sensitivity, efficient GDF15 release, and precise ACE-II targeting. In lipopolysaccharide (LPS)-induced ALI mouse model, GNPsanti-SP-C treatment significantly mitigated lung injury, reduced inflammatory responses, and enhanced pulmonary function, as evidenced by decreased inflammatory markers, lung edema, and improved histopathology. Single-cell transcriptomic and proteomic analyses revealed increased ACE-II cell populations, reduced expression of senescence markers, and upregulation of AMPK/SIRT1 signaling. In vitro studies further demonstrated that UPRmt activation is associated with the NPs' therapeutic effects, suggesting a potential role in their mechanism of action. These findings demonstrate the potential of GDF15-loaded dual-responsive NPs as an innovative strategy to address cellular senescence and alleviate ALI-associated pulmonary damage.

Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.

Lanthanum (La) can enhance crop growth while mitigating cadmium (Cd) accumulation in the edible parts of plants. This study determined the optimal timing of La application‒specifically at the rice heading stage‒to maximize yield and suppress Cd accumulation in grains. In pot experiments, La application at the heading stage increased the grain weight by 24.6 % and reduced Cd content in grains by 60.5 %. La treatment at this stage enhanced the transfer index (TFIN2-N1) of Cd by 29.95 % and reduced TFN1-IN1 by 29.86 %. Low-dose La in hydroponics further inhibited Cd accumulation while supporting growth. Additionally, La treatment significantly reduced Cd levels in root cell sap and xylem sap and downregulated the expression of critical Cd transporter genes, including OsNramp5, OsNramp1, OsIRT1, and OsHMA2 in the roots and OsZIP7 in the nodes. These results reveal that La application at the heading stage minimizes Cd accumulation in rice grains by limiting Cd uptake, translocation, and redistribution through targeted gene downregulation, establishing this stage as key for maximizing yield and ensuring safer rice production.

DS severely impacts tea plant growth and yield. Foliar application of Methyl jasmonate (MJ) -loaded Chitosan nanoparticles (CNPs) (MJ-CNPs) significantly boost tea DS resistance, necessitating further mechanism exploration. This study comprehensively investigated alterations at the phenotypic, biochemical, and genetic levels. Relative water content, total pigment content, and soluble proteins decreased, while soluble sugar increased significantly under DS and with apparent recovery after MJ-CNPs treatment. Catechins exhibited a significant decrease under DS, especially EGCG (24.6 to 13.4 mg•g-1), but were absolutely mitigated by treatment. Antioxidant capacities (DPPH, FRAP, ABTS, and SOA) showed a further improvement by MJ-CNPs treatment. Endogenous ABA and SA increased under DS, further elevated by MJ-CNPs. CsNCED, CsPYL8, CsPP2C, CsMYB, and CsABF genes involved in ABA-dependent pathways were confirmed with promoted expressions by foliar pre-treatment. The CsJAZ and CsMYC2 gene family which involved in the jasmonic acid (JA) pathway, displayed varied expression patterns. The integration of metabolite and gene expression levels provided a comprehensive illustration of tea DS tolerance mechanism and offered promising promotion strategies through foliar application of MJ-CNPs.

Artemisia (Asteraceae) is a diverse genus of plants with ecological, economic, and therapeutic significance. Some species have been traditionally used for neuroprotection; however, their bioactive potential remains underexplored.

Aquatic organisms are increasingly affected by polystyrene nanoplastics (PSNPs), which have the potential to disrupt development, induce oxidative stress, and impair immune function. This study examined the effects of PSNPs on zebrafish (Danio rerio) embryos exposed to 0.01, 0.1, 1, and 10 μg/mL from 2 to 120 h post-fertilization (hpf). The findings indicated that developmental abnormalities occurred in a dose-dependent manner, including delayed hatching, decreased survival rates, reduced body length, smaller eye diameter, and enlarged yolk sac area. PSNPs accumulated in the chorion and yolk sac as early as 6 hpf and were detected in vital tissues, such as the eyes, heart, yolk sac, liver, pancreas, intestine, neuromasts, and tail, immediately after hatching. By 120 hpf, PSNPs significantly reduced swimming distance and velocity. Exposure to PSNPs induced oxidative damage evidenced by altered expression of antioxidant-related genes (CAT1, GPX1A, SOD1, NRF2, KEAP1, HSP70, MT), disrupting cellular homeostasis and causing structural and organ defects. Immune toxicity was marked by dysregulated expression of immune-related genes (IL-1β, IL-6, NF-κB, TNF-α, C3B, TLR-1, TLR-3, TLR-4), indicating inflammation and innate immune activation triggered by oxidative damage. This study highlights the interconnected impacts of developmental abnormalities, oxidative damage, and immune toxicity caused by PSNPs exposure, highlighting the systemic impacts of nanoplastics contamination in aquatic environments.

Sepsis-associated liver injury (SLI) is a common complication of sepsis, for which effective therapeutic strategies are lacking. DNA methylation and hydroxymethylation play crucial roles in the regulation of gene expression. This study investigated the effects of metformin on the DNA methylation landscape in a rat model of cecal ligation and puncture (CLP)-induced SLI. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (ox-RRBS) were used to assess global DNA methylation and hydroxymethylation patterns in the liver tissues. The results showed that CLP-induced SLI was associated with global DNA hypomethylation and hyperhydroxymethylation, which were partially reversed by metformin treatment. The expression levels of DNA methyltransferases and ten-eleven translocation 2 (TET2) were elevated in the CLP group and were modulated by metformin. Functional enrichment analysis of differentially methylated and hydroxymethylated genes revealed their involvement in oxidative phosphorylation and metabolic pathways. Furthermore, integration of DNA methylation, hydroxymethylation, and transcriptome data identified two genes, A1cf and Atxn7l1, that exhibited increased methylation and decreased expression in CLP, which were reversed by metformin treatment. These findings provide novel insights into the epigenetic mechanisms underlying SLI and suggest that metformin exerts hepatoprotective effects by modulating DNA methylation and hydroxymethylation.

The functioning of the photosynthetic electron transport chain and the proceeding of accompanying processes were studied in Arabidopsis thaliana plants acclimated during 2weeks to reduced (150ppm) or elevated (1000ppm) CO2 concentrations in air. Measured at ambient CO2 , the quantum yields of both photosystems were lower in plants acclimated to these CO2 concentrations as compared with control plants grown at ambient CO2 . The difference was more pronounced at the beginning of the illumination. It is discussed that this difference resulted from the difference in Rubisco content, which at both reduced and elevated CO2 in air was lower than in control plants. The quantum yield of regulated non-photochemical energy loss in photosystem II under both reduced and elevated CO2 was lower than in control plants. This correlated with reduced expression of the PsbS protein gene. H2 O2 content in the leaves increased during the first days of plant adaptation to 150ppm CO2 , but then decreased. The increase resulted from enhanced rates of both photorespiration and Mehler reaction, while the following decrease resulted from enhancing contents of ascorbate peroxidases in all cell compartments.

Despite the promise of vastly expanding the druggable genome, rational design of RNA-targeting ligands remains challenging as it requires the rapid identification of hits and visualization of the resulting cocomplexes for guiding optimization. Here, we leveraged high-throughput screening, medicinal chemistry, and structural biology to identify a de novo splicing inhibitor against a large and highly folded fungal group I intron. High-resolution cryoEM structures of the intron in different liganded states not only reveal molecular interactions that rationalize experimental structure-activity relationship but also shed light on a unique strategy whereby RNA-associated metal ions and RNA conformation exhibit exceptional plasticity in response to small-molecule binding. This study reveals general principles that govern RNA-ligand recognition, the interplay between chemical bonding specificity, and dynamic responses within an RNA target.

Natural compounds have gained attention as potential alternatives or adjuvants to antibiotics against several pathogens. Ferulic acid, a natural plant product, has demonstrated promising antimicrobial properties against a wide range of microorganisms. This paper aims to characterize the molecular mechanism underlying the potential inhibitory effects of ferulic acid on Helicobacter pylori.