Changes In Gene Expression Research Articles

CYP24A1 is overexpressed in keloid keratinocytes and its inhibition alters profibrotic gene expression.

Keloids are disfiguring, fibrotic scar-like lesions that are challenging to treat and commonly recur after therapy. A deeper understanding of the mechanisms driving keloid formation is necessary for the development of more effective therapies. Reduced vitamin D receptor (VDR) expression has been observed in keloids, implicating vitamin D signaling in keloid pathology. Vitamin D exhibits anti-proliferative and anti-inflammatory properties, suggesting it could have therapeutic utility in keloid disorder. The current study investigated vitamin D-regulated gene expression in keloid keratinocytes and the effects of inhibiting an enzyme involved in vitamin D metabolism on the phenotype of keloid-derived keratinocytes. Normal and keloid-derived primary keratinocytes were isolated from normal skin and keloid lesions, respectively, and were cultured in the absence or presence of vitamin D. In some experiments, inhibitors of the vitamin D metabolizing enzyme CYP24A1, ketoconazole or VID400 were added in the absence or presence of vitamin D. Cellular proliferation, migration and gene expression were measured. We observed significant overexpression of CYP24A1 mRNA in keloid versus normal keratinocytes and increased CYP24A1 protein levels in keloids versus normal skin. CYP24A1 encodes 24 hydroxylase and is induced by vitamin D in a feedback loop that regulates vitamin D levels; thus, inhibition of CYP24A1 activity may locally increase active vitamin D levels. Ketoconazole, a non-specific cytochrome P-450 inhibitor, reduced proliferation of keloid and normal keratinocytes, but VID400, a specific CYP24A1 inhibitor, only significantly affected keloid keratinocyte proliferation. Neither inhibitor significantly reduced keratinocyte migration. The two inhibitors had different effects on vitamin D target gene expression in keratinocytes. Specifically, ketoconazole treatment reduced CYP24A1 expression in normal and keloid keratinocytes, whereas VID400 increased CYP24A1 expression. Both inhibitors decreased expression of profibrotic genes, including periostin and hyaluronan synthase 2, in keloid-derived cells. Combined treatment of keloid keratinocytes with vitamin D and ketoconazole or VID400 increased the effects of vitamin D treatment on target genes, although the effects were gene- and cell type-specific. The data suggest that reduction of vitamin D inactivation with CYP24A1 inhibitors may reduce profibrotic gene expression in keloid-derived cells. Therefore, CYP24A1 inhibitors may serve as adjunctive therapies to suppress keloid-associated gene expression changes.

The molecular mechanism of Xiaoyaosan in treating major depressive disorder: Integrated analysis of DNA methylation and RNA sequencing of the arcuate nucleus in rats.

Xiaoyaosan, a classic Chinese herbal formula, exhibits promising antidepressant effects. However, its specific antidepressant mechanisms remain incompletely understood. Previous studies have highlighted the significant role of DNA methylation in the pathogenesis of major depressive disorder (MDD). Yet, whether the effects of Xiaoyaosan are linked to DNA methylation and its regulation remains unclear. This study aims to explore and verify the molecular mechanism of Xiaoyaosan in treating MDD via integrated analysis of DNA methylation and RNA sequencing. In this study, a chronic unpredictable mild stress (CUMS) model was established to induce MDD in rats, which were subsequently orally treated with Xiaoyaosan, with fluoxetine as a positive control. Antidepressant effects were assessed by the open field test, sucrose preference test, and forced swimming test. Whole-genome bisulfite sequencing (WGBS) and bulk RNA sequencing were performed in the arcuate nucleus of hypothalamus to assess methylation changes and identify differentially expressed genes. Bioinformatics analyses were conducted to explore methylation alterations, RNA sequencing profiles, and their shared epigenetic as well as gene expression changes, to identify candidate genes. Finally, RT-PCR was used to validate the key differential genes. Xiaoyaosan effectively reversed depressive-like behaviors. Further, Xiaoyaosan treatment involved multiple epigenetic modifications. The results of differentially methylated genes showed that there were 1353 overlapped genes between M-vs-C-hypo gene and X-vs-M-hyper gene, 5326 overlapped genes between M-vs-C-hyper gene and X-vs-M-hypo gene. GO and KEGG enrichment analyses indicated these intersecting genes were involved in biological regulation, transcription factors, appetite and endocrine control systems, etc. The analysis of differentially expressed genes from RNA sequencing revealed that there were 25 overlapping genes between the M vs C hypomethylated group and the X vs M hypermethylated group, while 81 overlapping genes were identified between the M vs C hypermethylated group and the X vs M hypomethylated group. Those differential genes regulated by methylation enriched in processes related to brain and neuronal growth, neuropeptide and hormone activation, as well as biological processes and molecular functions associated with protein translation, synthesis, transport, and localization. The integrated analysis of DNA methylation and RNA sequencing screened 14 potentially differential genes, which were associated with appetite regulation, energy metabolism, and neuroreceptor ligands. PCR verification found that Lmx1b, Abcc5, Gpc3 and Cfb showed statistical differences. The antidepressant mechanism of Xiaoyaosan involves the biological regulation in the arcuate nucleus of hypothalamus, including transcription factors, neurotransmitter regulation, neural development, appetite regulation peptides, and endocrine control systems. The methylation level and regulation at the gene locus of Lmx1b, Abcc5, Gpc3, and Cfb may play a key role in the treatment of Xiaoyaosan. These findings provide new insights into the therapeutic mechanisms of Xiaoyaosan.

Knocking Down WARS1 in Colorectal Cancer: Implications for Apoptosis and Cell Cycle Arrest via the p53 Signaling Pathway.

Preventing the progression and recurrence of colorectal cancer (CRC) remains a clinical challenge due to its heterogeneity and drug resistance. This underscores the need to discover new targets and elucidate their cancer-promoting mechanisms. This study analyzed the cancer-promoting mechanisms of tryptophanyl-tRNA synthetase 1 (WARS1) in CRC. Clinical data and RNA expression profiles of CRC patients in public databases were analyzed using bioinformatics to determine the expression of WARS1. A WARS1 knockdown assay was conducted with HCT116 and RKO cell lines to systematically assess the effects of WARS1 on CRC cell proliferation, migration, cell cycle, and apoptosis. These assessments employed reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, wound healing and transwell assays, flow cytometry, and xenograft tumor assays. Additionally, RNA sequencing and gene enrichment-based analysis were performed following WARS1 knockdown to detect gene expression changes and related pathways. WARS1 was overexpressed in CRC tissues (p < 0.05). Downregulation of WARS1 inhibited the growth and migration of RKO and HCT116 cell lines (p < 0.05). This inhibitory effect on tumor growth was also observed in xenografts in nude mice after WARS1 knockdown (p < 0.01). Flow cytometry revealed an increase in apoptosis and cell cycle arrest following WARS1 knockdown (p < 0.05). Transcriptome sequencing analysis showed that reduced expression of WARS1 activated the p53 signaling pathway and apoptosis while suppressing DNA replication and the cell cycle. The p53 transcriptional inhibitor pifithrin-α partially prevented the activation of caspase 3 and reduced the levels of c-poly-ADP-ribose polymerases 1 (PARP1) and cyclin-dependent kinase inhibitor 1A (CDKN1A). WARS1 was highly expressed in CRC, and its low expression was identified as a risk factor for CRC progression and recurrence. The current findings provide a theoretical basis for the development of therapeutic agents targeting WARS1 and elucidate its mechanism in CRC progression.

Environmental Enrichment and Epigenetic Changes in the Brain: From the Outside to the Deep Inside.

The brain plays a vital role in maintaining homeostasis and effective interaction with the environment, shaped by genetic and environmental factors throughout neurodevelopment and maturity. While genetic components dictate initial neurodevelopment stages, epigenetics-specifically neuroepigenetics-modulates gene expression in response to environmental influences, allowing for brain adaptability and plasticity. This interplay is particularly evident in neuropathologies like Rett syndrome and CDKL5 deficiency syndrome, where disruptions in neuroepigenetic processes underline significant cognitive and motor impairments. The environmental enrichment paradigm, introduced by Donald Hebb in the late 1940s, demonstrates how enriching stimuli-such as complex sensory, social, and cognitive inputs-affect brain structure and function. Despite methodological variability, evidence reveals that enriched environments catalyze beneficial changes in behavior and neuroanatomy, including increased synaptic plasticity, enhanced motor coordination, and improved cognitive performance in rodent models. Additionally, environmental enrichment induces epigenetic modifications that facilitate these outcomes, highlighting the necessity of understanding the mechanisms driving gene expression changes within the context of enriched experiences. Ultimately, this manifold relationship between environment, neuroepigenetic modulation, and brain function highlights the brain's capacity for change, reinforcing the importance of considering environmental factors in studies of neurodevelopment and therapy for neurological disorders.

Inverse dose protraction effects of high-LET radiation: Evidence and significance.

Biological effects of ionizing radiation vary with radiation quality, which is often expressed as the amount of energy deposited per unit length, i.e., linear energy transfer (LET). For acute irradiation, high-LET radiation generally produces greater biological effects than low-LET radiation, but little knowledge exists as to how dose protraction modifies effects. In this regard, inverse dose protraction effects (IDPEs) are phenomena in which dose protraction enhances effects, contrasting with sparing dose protraction effects in which dose protraction reduces effects. Here, we review the current knowledge on IDPEs of high-LET radiation. To the best of our knowledge, since 1967, 80 biology or epidemiology papers have reported IDPEs following external or internal high-LET irradiation with neutrons, deuterons, α-particles, light ions, or heavy ions. IDPEs of high-LET radiation have been described for biochemical changes in cell-free macromolecules, neoplastic transformation, cell death, DNA damage responses and gene expression changes in mammalian cell cultures of human or rodent origin, gene mutations, cytogenetic changes, cancer, non-cancer effects (e.g., testicular effects, cataracts, cardiovascular diseases) and life shortening in non-human mammals (rodents and dogs), and induction of lung cancer and bone tumors in humans. For external irradiation of mammalian cells in vitro and mammals in vivo, IDPEs of low- and high-LET radiation have been reported for radiation doses spanning in excess of three or four orders of magnitude in slightly different ranges, and for radiation dose rates both spanning over six orders of magnitude in different ranges. IDPEs of high-LET radiation in humans have been reported following internal exposure, but not external exposure. Manifestations and mechanisms of IDPEs of high-LET radiation are far less understood than those of low-LET radiation, warranting further studies that will be pivotal to assess the implications for radiation protection.

Unraveling the transcriptomic effects of leucine supplementation on muscle growth and performance in basketball athletes.

Leucine has gained recognition as an athletic dietary supplement in recent years due to its various benefits; however, the underlying molecular mechanisms remain unclear. In this study, 20 basketball players were recruited and randomly assigned to two groups. Baseline exercise performance-assessed through a 282-foot sprint, free throws, three-point field goals, and self-rated practice assessments-was measured prior to leucine supplementation. Participants were then given a functional drink containing either leucine (50 mg/kg body weight) or a placebo for 28 days. After supplementation, the same exercise performance metrics were reassessed. Following leucine supplementation, biceps brachii muscle tissue from both groups was collected for transcriptome sequencing and qPCR verification. Our results suggested that leucine supplementation significantly improved 282-foot sprint performance, reducing times from 17.4 ± 0.9 to 16.2 ± 0.9 seconds in the leucine group, compared to minimal changes in the control group (from 17.3 ± 0.9 to 17.1 ± 0.8 seconds; P = 0.034). For other exercise performance metrics, no significant differences were observed (P > 0.05); however, trends toward improvement were noted. Transcriptomic analysis revealed 3,658 differentially expressed genes (DEGs) between the two groups. These DEGs were enriched in pathways related to immune response (P < 0.0001), positive regulation of cytokine production (P < 0.0001), and neutrophil extracellular trap formation (P < 0.0001), among others. Weighted Gene Co-expression Network Analysis (WGCNA) identified a module (turquoise) strongly associated with muscle growth, with DEGs in this module enriched in cytoskeletal pathways in muscle cells. Gene expression changes (α-tubulin, β-tubulin, CK18, CK8, vimentin, cofilin, gelsolin, profilin, MAP1, MAP2, MAP4, E-cadherin, and N-cadherin) were verified by qPCR. In summary, leucine supplementation improved exercise performance, particularly by significantly reducing sprint times and showing trends of improvement in other performance metrics, including three-point field goals, free throws, and self-rated well-being. Identified DEGs enriched in pathways related to immune response, cytokine production, and cell adhesion. WGCNA highlighted a key module associated with muscle growth, enriched in cytoskeletal pathways. qPCR validation confirmed the upregulation of cytoskeleton-related genes, supporting the transcriptomic findings. These results suggest that leucine enhances muscle adaptation by regulating cytoskeletal dynamics, providing molecular insights into its role in improving athletic performance.

Exploring seasonal dynamics of sea spray aerosol bioactivity: Insights into molecular effects on human bronchial epithelial cells.

Sea spray aerosol (SSA) is a complex mixture of natural substances that can be inhaled by coastal residents. Previous studies have suggested that SSA may have positive effects on human health, but the molecular mechanisms and the factors influencing these effects are poorly understood. In this study, we exposed human bronchial epithelial cells (BEAS-2B) to natural SSA samples, collected monthly using quartz microfiber filters mounted on tripods within 15m of the waterline, with air drawn through pumps, throughout a one-year period at the Ostend coast, Belgium, and measured cellular gene expression changes using RNA sequencing. To simulate environmentally relevant exposure conditions, SSA extracts were applied at scaled doses equivalent to human alveolar exposure levels (multiplicative factors M = 10, 20, 40, and 80). We found that SSA exposure influenced the expression of genes involved in critical signaling pathways: mTOR, PI3K, Akt, and NF-κB were downregulated, while AMPK was upregulated. Downregulation of mTOR, PI3K, Akt, and NF-κB potentially indicates a protective response against tumor-promoting and inflammatory signals, whereas upregulation of AMPK may confer a beneficial effect on metabolic regulation. The number and direction of differentially expressed genes (DEGs) varied depending on the SSA sampling time and correlated with the phytoplankton density and chemical diversity of the SSA samples. Our results suggest that SSA contains bioactive compounds that may originate from marine algae and modulate cellular processes related to human health. We provide novel insights into the molecular effects of SSA exposure and highlight its potential as a source of natural therapeutics. To our knowledge, this is the first study to expose human lung cells to natural SSA at environmentally relevant levels, presenting a pioneering exploration of seasonal variations in exposure effects.

Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts.

cis-regulatory elements (CREs) control gene transcription dynamics across cell types and in response to the environment. In asthma, multiple immune cell types play an important role in the inflammatory process. Genetic variants in CREs can also affect gene expression response dynamics and contribute to asthma risk. However, the regulatory mechanisms underlying control of transcriptional dynamics across different environmental contexts and cell types at single-cell resolution remain to be elucidated. To resolve this question, we performed single-cell ATAC-seq (scATAC-seq) in peripheral blood mononuclear cells (PBMCs) from 16 children with asthma. PBMCs were activated with phytohemagglutinin (PHA) or lipopolysaccharide (LPS) and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment- and cell-type-specific transcription factors that drive changes in both gene expression mean and variability. We observed a strong positive linear dependence between motif response and their target gene expression changes but a negative relationship with changes in target gene expression variability. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs, followed by computational fine-mapping of expression quantitative trait loci (eQTL) from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.

The role of multiomics in revealing the mechanism of skin repair and regeneration.

Skin repair and regeneration are crucial processes in restoring the integrity of the skin after injury, with significant implications for medical treatments and plastic surgery. Multiomics, an integrated approach combining genomics, transcriptomics, proteomics, and metabolomics, offers unprecedented insights into the complex molecular and cellular mechanisms involved in skin healing. This review explores the transformative role of multiomics in elucidating the mechanisms of skin repair and regeneration. While genomic studies identify the genetic basis of wound healing, transcriptomics and proteomics uncover the dynamic changes in gene and protein expression, and metabolomics provides a snapshot of metabolic alterations associated with wound healing. Integrative multiomics studies can also identify novel biomarkers and therapeutic targets for skin regeneration. Despite the technical and biological challenges, the future of multiomics in skin research holds great promise for advancing personalized medicine and improving wound healing strategies. Through interdisciplinary collaboration, multiomics has the potential to revolutionize our understanding of skin repair, paving the way for innovative treatments in plastic surgery and beyond.

Nuclear calcium signaling in D1 receptor-expressing neurons of the nucleus accumbens regulates molecular, cellular and behavioral adaptations to cocaine.

The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens (NAc)). Notably, activation of the extracellular signal-regulated kinase (ERK) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remains unknown. A genetically-encoded cell-type-specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely-moving mice. A cell-type-specific inhibitor of nuclear calcium signaling, combined with 3D imaging of neuronal morphology, immunostaining and behavior, was used to disentangle the roles of nuclear calcium in NAc medium-sized spiny neurons (MSN) expressing the dopamine D1 (D1R) or D2 (D2R) receptor on cocaine-evoked responses. The D1R-mediated potentiation of calcium influx through glutamate N-methyl-D-aspartate receptors (NMDAR), which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice display a sustained nuclear calcium increase in NAc D1R-MSN. Disrupting nuclear calcium in D1R-MSN, but not D2R-MSN, blocks cocaine-evoked morphological changes of MSN and gene expression, and blunts cocaine's rewarding effects. Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSN on molecular, cellular and behavioral adaptations to cocaine, and brings a significant breakthrough as it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.

Associations between morphometric similarity network and brain gene expression in type 2 diabetes mellitus.

Abnormal functional and structural connectivity of brain networks is commonly observed in patients with type 2 diabetes mellitus (T2DM) and accompanied bycognitive impairment. In this study, we revealed differences in brain structure in T2DM using a Morphometric Similarity Network (MSN) method, which quantifies structural similarities between brain regions. The associations between T2DM-associated changes in morphometric similarity (MS) and gene expression were analyzed to explore the molecular and cellular mechanism underlying MS changes in T2DM. Our research involved 3D-T1WI and DTI data from 157 T2DM patients and 147 healthy controls (HCs) adequately matched. In patients with T2DM, the global MS was decreased. The MS decreased in the regions within the left sensorimotor network and the right salience/ventral attention network and increased in the regions within the bilateral visual network in the patient group. The increased MS of the bilateral visual networks in T2DM patients was negatively correlated with memory function. The transcription-neuroimaging association analysis indicated that the expression of 298 genes was significantly spatially correlated with the T2DM-related MSN abnormalities, and some of these genes are involved in biological processes such as central nervous system development and neurotransmitter transmission, which may provide possible molecular and cellular substrates for MS abnormalities and cognitive decline in T2DM.

A 3D-printed multi-compartment organ-on-chip platform with a tubing-free pump models communication with the lymph node.

Multi-organ-on-chip systems (MOOCs) have the potential to mimic communication between organ systems and reveal mechanisms of health and disease. However, many existing MOOCs are challenging for non-experts to implement due to complex tubing, electronics, or pump mechanisms. In addition, few MOOCs have incorporated immune organs such as the lymph node (LN), limiting their applicability to model critical events such as vaccination. Here we developed a 3D-printed, user-friendly device and companion tubing-free impeller pump with the capacity to co-culture two or more tissue samples, including a LN, under a recirculating common media. Native tissue structure and immune function were incorporated by maintaining slices of murine LN tissue ex vivo in 3D-printed mesh supports for at least 24 h. In a two-compartment model of a LN and an upstream injection site in mock tissue, vaccination of the multi-compartment chip was similar to in vivo vaccination in terms of locations of antigen accumulation and acute changes in activation markers and gene expression in the LN. We anticipate that in the future, this flexible platform will enable models of multi-organ immune responses throughout the body.

Structural and functional changes in the hippocampus induced by environmental exposures.

The hippocampus, noted as (HC), plays a crucial role in the processes of learning, memory formation, and spatial navigation. Recent research reveals that this brain region can undergo structural and functional changes due to environmental exposures, including stress, noise pollution, sleep deprivation, and microgravity. This review synthesizes findings from animal and human studies, emphasizing the HC's plasticity in response to these factors. It examines changes in volume, architecture, neurogenesis, synaptic plasticity, and gene expression and highlights critical periods of vulnerability to environmental influences impacting cognition and behavior. It also investigates underlying mechanisms such as glucocorticoid signaling, epigenetic alterations, and neural circuit adaptations. Understanding how the HC reacts to various environmental exposures is vital for developing strategies to enhance cognitive resilience and mitigate negative effects on this crucial brain region. Further research is needed to identify protective and risk factors and create effective interventions.

Identification and characterization of the Chenopodium quinoa gibberellin oxidase gene family and its role in seed germination

Pre-harvest sprouting (PHS) is an urgent problem in the quinoa breeding process. Gibberellin oxidases are key enzymes in the biosynthesis and degradation of gibberellins, playing a significant role in the regulation of active gibberellins (GAs). In this study, 18 CqGAox genes were identified in quinoa and characterized according to phylogenetic relationships, gene structure, conserved motifs, codon use pattern, and expression patterns. Based on their phylogenetic relationships, the CqGAox genes were classified into four groups: C19CqGA2ox, C20CqGA2ox, CqGA3ox, and CqGA20ox. Evolutionary analyses showed that homologous GAox genes from Arabidopsis, rice, and quinoa have been subject to purifying selection during evolution. According to the codon use patterns, mutational stress may cause codon bias in CqGAox genes. Prediction of promoter cis-regulatory elements suggested that the CqGAox genes contained multiple elements that responded to phytohormones and stress. We further evaluated the transcriptional responses of CqGAox genes during quinoa seed germination and under low-temperature stress treatments of seedlings. Moreover, qRT-PCR was used to confirm the changes in CqGAox gene expression during quinoa seed germination under GA3 and paclobutrazol (PAC) treatments. Compared with the control, expression of CqGAox genes was significantly altered by treatment with GA3 or PAC. These findings indicated that the CqGAox genes are essential for regulating GA biosynthesis and degradation. This study lays the foundation for further investigations of the roles of CqGAox genes in GA-regulated quinoa seed germination and provides potential targets for addressing the challenge of quinoa PHS.

Rosmarinic acid attenuated inflammation and apoptosis in folic acid-induced renal injury: Role of FoxO3/ NFκB pathway.

Rosmarinic acid (RA) is a herbal compound with various antioxidant and anti-inflammatory effects. This study aimed to explore the anti-inflammatory and anti-apoptotic properties of RA in folic acid-induced renal injury. Thirty-six male C57/BL6 mice were randomly divided into six groups (N=6): Control (received normal saline), NaHCO3 (received NaHCO3 as folic acid solvent), FA (received folic acid (FA)(IP) to induce renal injury), RA (received 100 mg/kg RA), RA50-FA (received 50 mg/kg RA solution after folic acid injection), and RA100-FA (received 100 mg/kg RA after folic acid injection). For ten days, the treatment groups received RA by gavage. The effects of RA were assessed using H & E staining, biochemical tests, western blotting, and ELISA in the kidney tissues of the mice. Real-time RT-PCR was also performed to evaluate the expression changes of renal genes. Our data showed that treatment by RA led to the over-expression of FoxO3 (P<0.05) and decrease in NFκB levels (P<0.01 and P<0.05) and expression of TNFα (P<0.05) and IL6 (P<0.001 and P<0.01). Other evaluations showed a decrease in p53 (P<0.01 and P<0.001), Bax/Bcl-2 ratio expression (P<0.01 and P<0.05), and Caspase-3 level (P<0.01 and P<0.05) compared to the folic acid group. Histological and biochemical results also confirmed the attenuation of tissue damage. This study revealed that RA's positive effects on folic acid-induced renal injury might result from the involvement of the FoxO3/NFκB pathway, thereby suppressing inflammation and apoptosis.

BPZ inhibits early mouse embryonic development by disrupting maternal-to-zygotic transition and mitochondrial function.

The use of Bisphenol A (BPA) has been widely restricted due to its adverse health effects. Bisphenol Z (BPZ) is used as an alternative to BPA, and humans are widely exposed to BPZ through various routes. Recent studies have shown that BPZ exposure adversely affects mouse oocyte meiotic maturation. This study investigates the impact of BPZ exposure on early mouse embryonic development alongside an exploration of the underlying mechanisms. The findings reveal that exposure to BPZ leads to a reduction in early embryo quality and hinders developmental progression. RNA sequencing analysis has identified 593 differentially expressed genes as a result of BPZ exposure, highlighting considerable changes in early embryonic gene expression. Mechanistically, BPZ exposure inhibits the activation of the zygotic genome and impedes maternal mRNA degradation, thereby interfering with maternal-to-zygotic transition (MZT). Further analysis indicates compromised mitochondrial function, as evidenced by abnormal distribution, diminished membrane potential, and lower ATP levels. Consequently, BPZ-exposed embryos exhibit elevated levels of reactive oxygen species, superoxide anions, and oxidative DNA damage. Moreover, BPZ exposure is associated with an increase in γ-H2A.X expression. Additionally, BPZ exposure alters the expression levels of histone modifications, including H3K27me2, H3K27me3, H3K9me3, and H3K27ac, in early embryos. Collectively, BPZ exposure significantly impairs early embryo quality by disrupting mitochondrial function, inducing oxidative stress and DNA damage, altering histone modifications, and inhibiting MZT, ultimately resulting in hindered blastocyst formation. These findings underscore the profound adverse effects of BPZ on early embryonic development, indicating the need for caution when considering it as a safe alternative to BPA.

Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.

Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

Adipokines in Breast Cancer: Decoding Genetic and Proteomic Mechanisms Underlying Migration, Invasion, and Proliferation.

Adipokines, bioactive peptides secreted by adipose tissue, appear to contribute to breast cancer development and progression. While numerous studies suggest their role in promoting tumor growth, the exact mechanisms of their involvement are not yet completely understood. In this project, varying concentrations of recombinant human adipokines (Leptin, Lipocalin-2, PAI-1, and Resistin) were used to study their effects on four selected breast cancer cell lines (EVSA-T, MCF-7, MDA-MB-231, and SK-Br-3). Over a five-day proliferation phase, linear growth was assessed by calculating doubling times and malignancy-associated changes in gene and protein expression were identified using quantitative TaqMan real-time PCR and multiplex protein analysis. Migration and invasion behaviors were quantified using specialized Boyden chamber assays. We found significant, adipokine-mediated genetic and proteomic alterations, with PCR showing an up to 6-fold increase of numerous malignancy-associated genes after adipokine-supplementation. Adipokines further altered protein secretion, such as raising the concentrations of different tumor-associated proteins up to 13-fold. Effects on proliferation varied, however, with most approaches showing significant enhancement in growth kinetics. A concentration-dependent increase in migration and invasion was generally observed, with no significant reductions in any approaches. We could show a robust promoting effect of several adipokines on different breast cancer cells in vitro. Understanding the interaction between adipose tissue and breast cancer cells opens potential avenues for innovative breast cancer prevention and therapy strategies. Our findings indicate that antibodies against specific adipokines could become a beneficial component of clinical breast cancer treatment in the future.

Exploration and Identification of Vitamin D and Related Genes as Potential Biomarkers for Colorectal Tumors.

To explore the relationship and underlying mechanisms between vitamin D and CRC, offering valuable insights into the diagnosis and treatment of CRC. Serum levels of 1,25(OH)2D3 were measured using a double-antibody sandwich assay. Bioinformatics analysis identified vitamin D-related CRC genes, which were validated using HCT116 and HT29 cell lines. Changes in hub gene expression were analyzed via RT-qPCR. Serum levels of 1,25(OH)2D3 were 42.99±6.02µg/mL in the normal group, 37.06±9.56µg/mL in the CRA group, and 19.00±5.96µg/mL in the CRC group (p<0.05). No significant differences were observed in VDR SNPs among the groups. Significant expression differences were detected in vitamin D-related colon cancer genes across the groups. LASSO regression analysis identified 5 key genes. The diagnostic model based on these genes demonstrated high diagnostic efficiency and performed well in the TCGA-COAD dataset. RT-qPCR results showed that SOSTDC1, PRKAA2, and CEACAM1 expressions decreased in the CRC and CRA groups, while MMP1 and CCND1 expressions increased. In vitro experiments indicated that calcitriol inhibits the proliferation and migration of HCT116 and HT29 cell lines and significantly alters the expression of hub genes. Serum vitamin D levels are significantly lower in CRC patients. Vitamin D has been shown to inhibit the proliferation and migration of colon cancer cells and reduce the expression of oncogenes. Therefore, vitamin D holds substantial potential for the diagnosis and treatment of CRC.

Systemic and immunotoxicity induced by topical application of perfluoroheptane sulfonic acid (PFHpS) or perfluorooctane sulfonic acid (PFOS) in a murine model

Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic surfactants of over 12,000 compounds that are incorporated into numerous products for their chemical and physical properties. Studies have associated PFAS with adverse health effects. Although there is a high potential for dermal exposure, these studies are lacking. The present study evaluated the systemic and immunotoxicity of subchronic 28- or 10-days of dermal exposure, respectively, to PFHpS (0.3125–2.5% or 7.82–62.5 mg/kg/dose) or PFOS (0.5% or 12.5 mg/kg/dose) in a murine model. Elevated levels of PFHpS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. PFHpS induced significantly increased relative liver weight, significantly decreased relative spleen and thymus weight, altered serum chemistries, and altered histopathology. Additionally, PFHpS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen of genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells and CD11b+ monocyte and/or macrophages in the spleen along with decreases in eosinophils and dendritic cells in the skin. These findings support PFHpS absorption through the skin leading to liver damage and immune suppression.