Gene Activation Research Articles

Glycoside-specific metabolomics reveals the novel mechanism of glycinebetaine-induced cold tolerance by regulating apigenin glycosylation in tea plants.

Glycosylation is a key modification that affects secondary metabolites under stress and is influenced by glycinebetaine (GB) to regulate plant stress tolerance. However, the complexity and detection challenges of glycosides hinder our understanding of the regulatory mechanisms of their metabolic interaction with GB during stress. A glycoside-specific metabolomic approach utilizing cone voltage-induced in-source dissociation was developed, achieving precise and high-throughput detection of glycosides in tea plants by narrowing the target ion range by 94.3%. Combined with enzyme activity assays, exogenous spraying, and gene silencing, this approach helps investigate the role of GB-glycosides cascade effect in enhancing cold tolerance of tea plants. Our method demonstrated that silencing betaine aldehyde dehydrogenase (CsBADH1) in tea plants altered 60 glycoside ions while reducing GB content and cold tolerance, indicating that glycosylation affects GB-mediated cold tolerance. By combining glycoside-specific with conventional metabolomics, isorhoifolin, a GB-regulated cold response metabolite was discovered, and its precursor apigenin was found to be a new cold tolerance metabolite that enhanced cold tolerance by scavenging reactive oxygen species. This study reveals a new mechanism by which GB mediated cold tolerance in tea plants through regulating apigenin glycosylation, broadening our understanding of the role of glycosylation in plant cold tolerance.

EXOTLR1/2-STING: A Dual-Mechanism Stimulator of Interferon Genes Activator for Cancer Immunotherapy.

As natural agonists of the stimulator of interferon genes (STING) protein, cyclic dinucleotides (CDNs) can activate the STING pathway, leading to the expression of type I interferons and various cytokines. Efficient activation of the STING pathway in antigen-presenting cells (APCs) and tumor cells is crucial for antitumor immune response. Tumor-derived exosomes can be effectively internalized by APCs and tumor cells and have excellent potential to deliver CDNs to the cytoplasm of APCs and tumor cells. Here, we leverage tumor exosomes as a delivery platform, designing an EXOTLR1/2-STING loaded with CDNs. To achieve efficient loading of CDNs onto exosomes, we chemically conjugated CDNs with Pam3CSK4, a compound featuring multiple fatty acid chains, resulting in Pam3CSK4-CDGSF. Utilizing the high lipophilicity of Pam3CSK4, Pam3CSK4-CDGSF could be efficiently loaded onto the exosomes through simple incubation. Moreover, as an agonist for Toll-like receptor 1/2, Pam3CSK4 also exhibits robust immunological synergistic effects in conjunction with CDNs. EXOTLR1/2-STING effectively induced the activation of APCs and triggered tumor cell death, producing a favorable antitumor therapeutic effect. It also demonstrated significant synergistic effects with immune checkpoint therapies.

Mechanisms of Antitumor Activity of Low Doses of Radiation Associated with Activation of Cells' Defense System.

The effects of ionizing radiation (IR) involve a highly orchestrated series of events in cells, including DNA damage and repair, cell death, and changes in the level of proliferation associated with the stage of the cell cycle. A large number of existing studies in literature have examined the activity of genes and their regulators in mammalian cells in response to high doses of ionizing radiation. Although there are many studies, the research in effect of low doses of ionizing radiation remains limited. Though much progress has been made in understanding the basic principles of effects of low doses of radiation on individual components of biological systems, less is known about how low doses affect target molecules and regulate the cellular networks (e.g., activation of the immune system, genes and their regulators in the phenomenon of hormesis, and the formation of an adaptive response). These observations determined the purpose of the work: to investigate the activity of genes and non-coding RNAs (long non-coding RNAs and microRNAs) in various organs of mice with transplanted Lewis carcinoma after low-dose radiation. Twenty-four female C57Bl/6 mice were transplanted subcutaneously with Lewis carcinoma cells (105 cells in 0.2 mL of Hanks' solution). Total 4-fold X-ray irradiation with an interval of 4 days at a dose of 0.075 Gy (0.85 Gy/min) was performed on the RUST M1 from 6 days after transplantation; the tumor size was measured daily. The mice were divided into the following groups: "Biocontrol", "Biocontrol + irradiation", "Tumor" and "Tumor + irradiation". On the 19th day from the beginning of the experiment, the mice were euthanized. The expression profiles of mRNA genes, long non-coding RNAs, and microRNAs controlling the response to radiation were determined in the bone marrow, thymus, spleen, and tumor of mice. Fractionated low-dose irradiation of mice with transplanted Lewis carcinoma caused a growth decrease of implanted tumor cells compared to the similar group without irradiation. At the same time, there was an activation of oncosuppressors and a decrease in the activity of oncogenes in the thymus and spleen of mice with tumor and irradiation. In the "Tumor" group, without irradiation, the number of activated oncogenes prevailed over the number of inactivated ones. Thus, the low-dose radiation exposure led to the activation of antitumor immunity in mice, which manifested itself in slowing tumor growth in animals and the induction of oncosuppressors and inhibition of oncogene expression.

Transcriptome Analysis Reveals the Key Genes and Pathways for Growth, Ion Transport, and Oxidative Stress in Post-Larval Black Tiger Shrimp (Penaeus monodon) Under Acute Low Salt Stress.

As an abiotic stress factor, salinity significantly affects the physiological activities of crustaceans. In this study, transcriptome sequencing was used to evaluate the mechanism of ion transport and the physiological response of black tiger shrimp (Penaeus monodon) under low salt stress. Four hundred post larval (PL) stage P. monodon were distributed in eight experimental tanks and exposed to 3 or 5 ppt salt concentrations for 96h. Low salinity significantly reduced the survival rate of shrimp but simultaneously activated the activity of ion transporter enzymes Na+/K+-ATPase (NKA) and Ca2+/Mg2+-ATPase), the expression of NKA, galectin 10, and cytochrompe c peroxidase genes, and the activity and expression of antioxidant-related genes (superoxide dismutase, catalase, heat shock protein 60). Low salt stress activated the urea cycle but significantly inhibited glutathione metabolization-related indicators (glutamate dehydrogenase, glutaminase, glutamic acid). RNA-seq analysis identified 221 differentially expressed genes (78 up-regulated and 143 down-regulated). Quantitative real-time PCR and RNA-seq results of 11 of them were consistent, illustrating the validity of the transcriptomic predictions. Gene set enrichment analysis results showed that calcium ion transmembrane transport, calmodulin binding, the stress-activated protein kinase signaling cascade, and regulation of the cytosolic calcium ion concentration process were significantly enriched. These results showed that low salt stress activated the calcium-dominated ion transport pathway and promoted molting growth of P. monodon. They also indicate that there is potential for larval rearing shrimp under low salt conditions.

Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis

Transcription factors guide tissue development by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of transcription factors. However, how transcription factors navigate chromatin features to selectively bind a small subset of all the possible genomic target loci remains poorly understood. Here we show that Cdx2—a lineage defining transcription factor that binds distinct targets in developing versus adult intestinal epithelial cells—has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic Cdx2 targets and methylated state of the CpG during development enables selective Cdx2 binding and activation of developmental enhancers and genes. In adult cells, demethylation at these enhancers prevents ectopic Cdx2 binding, instead directing Cdx2 to its canonical motif without a CpG. This shift in Cdx2 binding facilitates Ctcf and Hnf4 recruitment, establishing super-enhancers during development and homeostatic enhancers in adult cells, respectively. Induced DNA methylation in adult mouse epithelium or cultured cells recruits Cdx2 to developmental targets, promoting corecruitment of partner transcription factors. Thus, Cdx2’s differential CpG motif preferences enable it to navigate distinct DNA methylation profiles, activating genes specific to appropriate developmental stages.

GABA mitigates mitochondrial apoptosis induced by high temperature stress in the Pacific oyster (Crassostrea gigas).

High temperature is a critical environmental factor leading to mass mortality in oyster aquaculture in China. Recent advancements highlight the physiological regulation function of γ-aminobutyric acid (GABA) in the adaptation of environmental stress. This study examined the physiological responses of the Pacific oyster (Crassostrea gigas) upon high temperature exposure, focusing on the histopathological changes in gill, the GABA concentration, the mRNA expression and activities of apoptosis-related genes. Following 24h of exposure to seawater at 28°C, notable histopathological changes, including cellular swelling and vacuolization, along with an increase in TUNEL-positive cells were observed in the oyster gill, compared to the control group maintained at 18°C. Moreover, there was a significant increase in CgCaspase-3 transcripts, Caspase-3 and Caspase-9 activities in the gills, glutamate decarboxylase CgGAD transcripts in the haemocytes, and GABA concentrations in the haemolymph supernatant. Intervention with GABA markedly ameliorated these responses, including reducing the mRNA expression levels of CgBax, CgBak, CgCaspase-3, and CgCaspase-9, as well as the activities of Caspase-3/9. Furthermore, after the treatment with GABAA and GABAB receptor antagonists, the activities and expression levels of Caspase-3 and Caspase-9 significantly up-regulated under hightemperature stress. GABA treatment also significantly diminished the increased Caspase-3 activity by mitochondrial pathway apoptosis inducers. High temperature induced mitochondrial pathway apoptosis via increased caspase activities. The transcripts of CgGAD in haemocytes and GABA concentration in hemolymph supernatant also increased after high-temperature stress. GABA countered these effects through the activation of GABAA and GABAB receptors, reducing both caspase activity and expression of apoptosis-related genes.

The maternal X chromosome affects cognition and brain ageing in female mice.

Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated1-4. This renders either the maternal X (Xm) chromosome or the paternal X (Xp) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active5-7. Parent-of-X origin can modify epigenetics through DNA methylation8,9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active Xm chromosome influences the brain and body-and then delineated unique features of Xm neurons and Xp neurons. An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of Xm-imprinted genes improved cognition in ageing female mice. Thus, the Xm chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how Xm impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.

Genome-wide microsatellite characterization and their marker development and transferability in Broussonetia Species

BackgroundBroussonetia papyrifera, B. monoica, and B. kaempferi belong to the genus Broussonetia (Moraceae). These three species hold significant economic and research values. However, few molecular markers have been effectively utilized for resource development and molecular genetic breeding of these species. Sequencing of their genomes allowed us to develop genomic markers (e.g. simple sequence repeats (SSRs)) and construct a high-density physical map.ResultsA total of 369,557, 332,627, and 276,245 SSRs were identified in 13 high-quality assembled pseudochromosomes and their unassembled scaffolds for B. papyrifera, B. monoica, and B. kaempferi, respectively. Among the identified genomic SSRs across the three species, short repeat sequences were more abundant, while long repeat sequences constituted a smaller proportion. Additionally, the predominant repeat motifs in the SSRs of the three Broussonetia species were composed of ‘A’ and ‘T’ repeats. Using B. papyrifera genome as a reference, 4,419 common SSRs were identified among these three species, while 2,048 SSRs were specific to B. kaempferi, and 4,285 SSRs were specific to B. monoica. Distribution analysis indicated a notable similarity in the distribution patterns of SSRs across the pseudochromosomes of these three species. Furthermore, of the identified SSRs, 28%, 31%, and 24% were mapped to genes in B. papyrifera, B. kaempferi, and B. monoica, respectively. Genic-mapped SSRs may regulate biological processes by influencing gene activity and protein function. To verify SSRs polymorphism, we selected 30 ones from 10,752 potentially polymorphic SSRs loci for PCR amplification among these three species, all of which were successfully amplified and exhibited polymorphism across these three species.ConclusionsThese findings are helpful for further research on the origin, evolution, and migration of Broussonetia species and also laid the foundation for the precise identification, systematic evaluation, and efficient utilization of the germplasm resources of Broussonetia species.

Novel translational mouse models of Metabolic Dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome. TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin. After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH. Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.

Improving the odds of survival: transgenerational effects of infections.

Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes. This review focuses on intergenerational and transgenerational epigenetic inheritance in different plants, animal species and humans, presenting the up-to-date evidence and arguments for such effects in light of Darwinian and Lamarckian evolutionary theories. An overview of the epigenetic changes induced by infection or other immune challenges is presented, and how these changes, known as epimutations, contribute to shaping offspring phenotypes. The mechanisms that mediate the transmission of epigenetic alterations via the germline are also discussed. Understanding the relationship between environmental fluctuations, epigenetic changes, resistance, and susceptibility to diseases is critical for unraveling disease etiology and adaptive evolution.

Characterizing the regulatory effects of H2A.Z and SWR1-C on gene expression during hydroxyurea exposure in Saccharomyces cerevisiae.

Chromatin structure and DNA accessibility are partly modulated by the incorporation of histone variants. H2A.Z, encoded by the non-essential HTZ1 gene in S. cerevisiae, is an evolutionarily conserved H2A histone variant that is predominantly incorporated at transcription start sites by the SWR1-complex (SWR1-C). While H2A.Z has often been implicated in transcription regulation, htz1Δ mutants exhibit minimal changes in gene expression compared to wild-type. However, given that growth defects of htz1Δ mutants are alleviated by simultaneous deletion of SWR1-C subunits, previous work examining the role of H2A.Z in gene expression regulation may be confounded by deleterious activity caused by SWR1-C when missing its H2A.Z substrate (apo-SWR1-C). Furthermore, as H2A.Z mutants only display significant growth defects in genotoxic stress conditions, a more substantive role for H2A.Z in gene expression may only be uncovered after exposure to cellular stress. To explore this possibility, we generated mRNA transcript profiles for wild-type, htz1Δ, swr1Δ, and htz1Δswr1Δ mutants before and after exposure to hydroxyurea (HU), which induces DNA replication stress. Our data showed that H2A.Z played a more prominent role in gene activation than repression during HU exposure, and its incorporation was important for proper upregulation of several HU-induced genes. We also observed that apo-SWR1-C contributed to gene expression defects in the htz1Δ mutant, particularly for genes involved in phosphate homeostasis regulation. Furthermore, mapping H2A.Z incorporation before and after treatment with HU revealed that decreases in H2A.Z enrichment at transcription start sites was correlated with, but generally not required for, the upregulation of genes during HU exposure. Together this study characterized the regulatory effects of H2A.Z incorporation during the transcriptional response to HU.

Identification and characterization of CD83 and CD276 as markers of dendritic cells in olive flounder (Paralichthys olivaceus).

Dendritic cells (DCs) play a pivotal role in activating naïve T-cells and bridging innate and adaptive immunity. This study aimed to identify and characterize CD83 and CD276 as potential markers for DCs in olive flounder (Paralichthys olivaceus). Specific antibodies against these markers were developed and used to analyze their distribution in peripheral blood leukocytes (PBLs) and intestinal tissues. Flow cytometry and immunohistochemistry revealed that CD83 and CD276 are expressed on DCs, with peak expression observed one week after oral administration of an inactivated viral hemorrhagic septicemia virus (VHSV) vaccine. Gene expression analysis further demonstrated significant activation of immune-related genes, including CD3, IgM, and TLRs, indicating that oral vaccine administration effectively activates the intestinal mucosal immune system. These findings provide valuable insights into fish immune responses and establish CD83 and CD276 as promising DC markers, contributing to the development of mucosal vaccine strategies in aquaculture.

Bacterium-Phage Symbiosis Facilitates the Enrichment of Bacterial Pathogens and Antibiotic-Resistant Bacteria in the Plastisphere.

The plastisphere, defined as the ecological niche for microbial colonization of plastic debris, has been recognized as a hotspot of pathogenic and antibiotic-resistant bacteria. However, the interactions between bacteria and phages facilitated by the plastisphere, as well as their impact on microbial risks to public health, remain unclear. Here, we analyzed public metagenomic data from 180 plastisphere and environmental samples, stemming from four different habitats and two plastic types (biodegradable and nonbiodegradable plastics) and obtained 611 nonredundant metagenome-assembled genomes (MAGs) and 4061 nonredundant phage contigs. The plastisphere phage community exhibited decreased diversity and virulent proportion compared to those found in environments. Indexes of phage-host interaction networks indicated significant associations of phages with pathogenic and antibiotic-resistant bacteria (ARB), particularly for biodegradable plastics. Known phage-encoded auxiliary metabolic genes (AMGs) were involved in nutrient metabolism, antibiotic production, quorum sensing, and biofilm formation in the plastisphere, which contributed to enhanced competition and survival of pathogens and ARB hosts. Phages also carried transcriptionally active virulence factor genes (VFGs) and antibiotic resistance genes (ARGs), and could mediate their horizontal transfer in microbial communities. Overall, these discoveries suggest that plastisphere phages form symbiotic relationships with their hosts, and that phages encoding AMGs and mediating horizontal gene transfer (HGT) could increase the source of pathogens and antibiotic resistance from the plastisphere.

Induction of DNA damage and growth arrest by citalopram in breast cancer cells mediated via activation of Gadd45a and apoptotic genes

ABSTRACT Breast cancer patients experience more severe emotional distress and depression compared to those with other cancers. Selective serotonin reuptake inhibitors (SSRIs), like citalopram, are commonly used to treat depression. However, the link between SSRI use and breast cancer progression is debated. This study examined the cytotoxic effects of citalopram on triple-negative (MDA-MB231) and ER-positive (MCF-7) breast cancer cells. Results showed a significant decrease in cell viability in both cell lines following citalopram treatment. Interestingly, flow cytometry analysis revealed increased apoptotic cells and induction of cell cycle arrest upon treatment of the cells with citalopram. MCF-7 cells were arrested in the sub-G0-G1 phase, while MDA-MB231 cells accumulated in the S phase. Gene expression analysis demonstrated increased Bax expression and decreased Bcl2 levels. Moreover, cytochrome c and NF-κB were upregulated upon treatment with citalopram. Furthermore, transmission electron microscopy (TEM) analysis of treated cells showed apoptotic morphological changes including shrunken nuclei, membrane blebbing, and chromatin condensation with prominent appearance of autophagosomes and autolysosomes. Additionally, GADD45a and p21, involved in growth arrest and DNA damage, were significantly upregulated. In conclusion, citalopram’s ability to induce apoptosis and alter cell cycle suggests its potential in breast cancer treatment.

Hedgehog signaling directs cell differentiation and plays a critical role in tendon enthesis healing

A high prevalence of rotator cuff tears presents a major clinical challenge. A better understanding of the molecular mechanisms underlying enthesis development and healing is needed for developing treatments. We recently identified hedgehog (Hh)-lineage cells critical for enthesis development and repair. This study revealed cell-cell communication within the Hh-lineage cell population. To further characterize the role of Hh signaling, we used mouse models to activate and inactivate the Hh pathway in enthesis progenitors. Activation of Hh target genes during enthesis development increased its mineralization and mechanical properties. Activation of Hh signaling at the injured mature enthesis promoted fibrocartilage formation, enhanced mineralization, and increased expression of chondrogenic and osteogenic markers, which implies that Hh signaling drives cell differentiation to regenerate the damaged enthesis. Conversely, deletion of Hh target genes impaired enthesis healing. In summary, this study revealed a new strategy for enthesis repair via activation of Hh signaling in endogenous cells.

Phlorofucofuroeckol-A: A Natural Compound with Potential to Attenuate Inflammatory Diseases Caused by Airborne Fine Dust.

Background and Objectives: Persistent exposure to airborne fine dust (FD) particles contributing to air pollution has been linked to various human health issues, including respiratory inflammation, allergies, and skin diseases. We aimed to identify potential seaweed anti-inflammatory bioactive reagents and determine their effects on systemic inflammatory responses induced by FD particles. Materials and Methods: While exploring anti-inflammatory bioactive reagents, we purified compounds with potential anti-inflammatory effects from the seaweed extracts of Ecklonia cava, Ecklonia stolonifera, and Codium fragile. Structural analyses of the purified compounds siphonaxanthin (Sx), fucoxanthin (Fx), dieckol (Dk), and phlorofucofuroeckol-A (PFF-A) were performed using NMR and LC-MS/MS. Results: Notably, these compounds, especially PFF-A, showed significant protective effects against FD-induced inflammatory responses in RAW 264.7 cells without cytotoxicity. Further investigation of inflammatory-associated signaling demonstrated that PFF-A inhibited IL-1β expression by modulating the NF-κB/MAPK signal pathway in FD-induced RAW 264.7 cells. Additionally, gene profiling revealed the early activation of various signature genes involved in the production of inflammatory cytokines and chemokines using gene profiling. Treatment with PFF-A markedly reduced the expression levels of pro-inflammatory and apoptosis-related genes and even elevated the Bmp gene families. Conclusions: These results suggested that PFF-A is a potential natural therapeutic candidate for managing FD-induced inflammatory response.

A Study of the Different Strains of the Genus Azospirillum spp. on Increasing Productivity and Stress Resilience in Plants.

One of the most important and essential components of sustainable agricultural production is biostimulants, which are emerging as a notable alternative of chemical-based products to mitigate soil contamination and environmental hazards. The most important modes of action of bacterial plant biostimulants on different plants are increasing disease resistance; activation of genes; production of chelating agents and organic acids; boosting quality through metabolome modulation; affecting the biosynthesis of phytochemicals; coordinating the activity of antioxidants and antioxidant enzymes; synthesis and accumulation of anthocyanins, vitamin C, and polyphenols; enhancing abiotic stress through cytokinin and abscisic acid (ABA) production; upregulation of stress-related genes; and the production of exopolysaccharides, secondary metabolites, and ACC deaminase. Azospirillum is a free-living bacterial genus which can promote the yield and growth of many species, with multiple modes of action which can vary on the basis of different climate and soil conditions. Different species of Bacillus spp. can increase the growth, yield, and biomass of plants by increasing the availability of nutrients; enhancing the solubilization and subsequent uptake of nutrients; synthesizing indole-3-acetic acid; fixing nitrogen; solubilizing phosphorus; promoting the production of phytohormones; enhancing the growth, production, and quality of fruits and crops via enhancing the production of carotenoids, flavonoids, phenols, and antioxidants; and increasing the synthesis of indoleacetic acid (IAA), gibberellins, siderophores, carotenoids, nitric oxide, and different cell surface components. The aim of this manuscript is to survey the effects of Azospirillum spp. and Bacillus spp. by presenting case studies and successful paradigms in several horticultural and agricultural plants.

Hyperosmotic stress-induced NLRP3 inflammasome activation via the mechanosensitive PIEZO1 channel in dry eye corneal epithelium.

PIEZO1 modulates the inflammatory response by translating mechanical signals from osmotic pressure into biological processes. This study investigates the functional role of PIEZO1 in activating the NLRP3 inflammasome in corneal epithelial cells under hyperosmotic stress and evaluates its contribution to the pathogenesis of dry eye disease (DED). In the in vitro experiments, immortalized human corneal epithelial cells (HCECs) were cultured under hyperosmotic conditions (450mOsm). For in vivo studies, a dry eye disease mouse model was established by subcutaneous injection of scopolamine (SCOP) in C57BL/6 mice. After successfully inducing the dry eye model, corneal epithelial cell damage was assessed through corneal fluorescein staining scores and TUNEL assays. Protein expression levels were examined via western blotting and immunofluorescence staining, while mRNA expression was analyzed using quantitative RT-PCR. Activation of the NLRP3 inflammasome was evaluated by measuring IL-1β protein cleavage and the formation of ASC speckles. In the DED model, activation of the NLRP3 inflammasome was detected in corneal epithelial cells, along with increased expression of PIEZO1. The PIEZO1-specific agonist Yoda1 induced upregulation of NLRP3 inflammasome-related gene expression and triggered NLRP3 inflammasome activation. Conversely, silencing PIEZO1 using siRNA or inhibiting its activity suppressed hyperosmotic stress-induced changes in NLRP3 inflammasome-related gene expression and activation. In vivo, PIEZO1 inhibition effectively prevented NLRP3 inflammasome activation in corneal epithelial cells and restored the damaged phenotype associated with dry eye disease. Hyperosmotic stress-induced activation of the NLRP3 inflammasome in corneal epithelial cells is mediated through PIEZO1 activation. The identification of PIEZO1's role in this DED-related pathophysiological response highlights its potential as a therapeutic target for mitigating inflammation in clinical settings.

Histone Deacetylation in Alzheimer's Diseases (AD); Hope or Hype.

Histone acetylation is the process by which histone acetyltransferases (HATs) add an acetyl group to the N-terminal lysine residues of histones, resulting in a more open chromatin structure. Histone acetylation tends to increase gene expression more than methylation does. In the central nervous system (CNS), histone acetylation is essential for controlling the expression of genes linked to cognition and learning. Histone deacetylases (HDACs), "writing" enzymes (HATs), and "reading" enzymes with bromodomains that identify and localize to acetylated lysine residues are responsible for maintaining histone acetylation. By giving animals HDAC inhibitors (HDACis), it is possible to intentionally control the ratios of "writer" and "eraser" activity, which will change the acetylation of histones. In addition to making the chromatin more accessible, these histone acetylation alterations re-allocate the targeting of "readers," including the transcriptional co-activators, cAMP response element-binding protein (CBP), and bromodomain-containing protein 4 (Brd4) in the CNS. Conclusive evidence has shown that HDACs slow down the progression of Alzheimer's disease (AD) by reducing the amount of histone acetylation, decreasing the activity of genes linked to memory, supporting cognitive decline and Amyloid beta (Aβ) protein accumulation, influencing aberrant tau phosphorylation, and promoting the emergence of neurofibrillary tangles (NFTs). In this review, we have covered the therapeutic targets and functions of HDACs that might be useful in treating AD.

Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer.

The human nuclear receptor (NR) superfamily consists of 48 genes that are ligand-activated transcription factors that play a key role in maintaining cellular homeostasis and in pathophysiology. NRs are important drug targets for both cancer and non-cancer endpoints as ligands for these receptors can act as agonists, antagonists or inverse agonists to modulate gene expression. With two exceptions, the classical mechanism of action of NRs involves their interactions as monomers, dimers or heterodimers with their cognate response elements (cis-elements) in target gene promoters. Several studies showed that a number of NR-regulated genes did not directly bind their corresponding cis-elements and promoter analysis identified that NR-responsive gene promoters contained GC-rich sequences that bind specificity protein 1 (Sp1), Sp3 and Sp4 transcription factors (TFs). This review is focused on identifying an important sub-set of Sp-regulated genes that are indirectly coregulated through interactions with NRs. Subsequent studies showed that many NRs directly bind Sp1 (or Sp3 and Sp4), the NR/Sp complexes bind GC-rich sites to regulate gene expression and the NR acts as a ligand-modulated nuclear cofactor. In addition, several reports show that NR-responsive genes contain cis-elements that bind both Sp TFs and NRs, and mutation of either cis-element results in loss of NR-responsive (inducible and/or basal). Regulation of these genes involves interactions between DNA-bound Sp TFs with proximal or distal DNA-bound NRs, and, in some cases, other nuclear cofactors are required for gene expression. Thus, many NR-responsive genes are regulated by NR/Sp complexes, and these genes can be targeted by ligands that target NRs and also by drugs that induce degradation of Sp1, Sp3 and Sp4.