Gaseous chlorine dioxide (ClO2) is a potent antimicrobial agent used to control microbial contamination in food and water. This study evaluates the bactericidal activity of gaseous ClO2 released from a sodium chlorite (NaClO2) pad against Campylobacter jejuni. Exposure to a low concentration (0.4 mg/L) of dissolved ClO2 for 2 h resulted in a >93% reduction of C. jejuni, highlighting the bacterium's extreme sensitivity to gaseous ClO2. To elucidate the molecular mechanism of ClO2-induced bactericidal action, transcriptomic analysis was conducted using RNA sequencing (RNA-seq). The results indicate that C. jejuni responds to ClO2-induced oxidative stress by upregulating genes involved in reactive oxygen species (ROS) detoxification (sodB, ahpC, katA, msrP, and trxB), iron transport (ceuBCD, cfbpABC, and chuBCD), phosphate transport (pstSCAB), and DNA repair (rdgB and mutY). Reverse transcription-quantitative PCR (RT-qPCR) validated the increased expression of oxidative stress response genes but not general stress response genes (spoT, dnaK, and groES). These findings provide insights into the antimicrobial mechanism of ClO2, demonstrating that oxidative damage to essential cellular components results in bacterial cell death.

Breast cancer is a heterogeneous disease with varying responses to therapies. While targeted treatments have advanced, conventional therapies inducing oxidative stress remain widely used. H2O2 has emerged as a therapeutic candidate due to its role in signaling and cell-function regulation. Its transport is tightly regulated through peroxiporins such as AQP5, expression of which is linked to poor prognosis and metastatic spread, and its role in therapy resistance remains underexplored. This study examined AQP5's role in the acute oxidative stress response. We overexpressed AQP5 in breast cancer cell lines with low basal levels-HR+ (MCF7), HER2+ (SkBr-3), and TNBC (SUM 159)-and exposed them to H2O2 for 24 h. We assessed cell viability, intracellular ROS, changes in AQP3 and AQP5, and key antioxidative and cancer-related pathways (NRF2, PI3K/AKT, FOXOs). AQP5 overexpression elicited a cell-type-specific response. H2O2 treatment reduced viability in SkBr-3-AQP5 and MCF7-AQP5 cells, increased ROS levels in MCF7-AQP5, and decreased ROS in SUM 159-AQP5. It also increased AQP3 in MCF7-AQP5 and differentially affected NRF2, FOXOs, and PI3K/AKT signaling, notably activating NRF2/AKR1B10 axis in MCF7-AQP5 and decreasing FOXO1 in SUM 159-AQP5. These findings highlight the need for further research into AQP5's role in the oxidative stress response in breast cancer cells.

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial-mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment.

Resistance to platinum-based chemotherapy is a major clinical problem in ovarian cancers. The development of predictive biomarkers and therapeutic approaches is an area of unmet need. p73, a member of the p53 family of transcription factors, has essential functions during DNA repair, proliferation, invasion, and apoptosis. The role of p73 in ovarian cancer pathogenesis and response to therapy is largely unknown. The clinicopathological significance of p73 protein expression was evaluated in 278 human ovarian cancers. TP73 transcripts were investigated in publicly available clinical data sets (n = 522) and bioinformatics analysis was completed in the ovarian TCGA cohort (n = 182). Preclinically, p73 was overexpressed in A2780 platinum-sensitive ovarian cancer cells or depleted in platinum-resistant A2780cis cells and investigated for aggressive phenotypes, as well as platinum sensitivity. High p73 protein expression was linked with high grade (p < 0.001), advanced-stage disease (p = 0.002), and shorter progression-free survival (p < 0.0001). TP73 transcripts were significantly higher in tumours compared to normal tissue (p < 0.0001) and linked with shorter PFS (p = 0.047). Preclinically, p73 overexpression in A2780 cells increased proliferation, invasion, spheroid formation, and DNA repair capacity, and was associated with the upregulation of multiple DNA repair and platinum resistance-associated genes. In contrast, p73 deletion in A2780cis led to reduced proliferation and enhanced sensitivity to cisplatin, along with DNA double-strand break accumulation, G2/M cell cycle arrest, and increased apoptosis. We conclude that p73 is a predictor of platinum resistance. p73 can be exploited for targeted ovarian cancer therapy.

This study utilized MAC-T cells cultured in vitro as a model to investigate the effects of varying concentrations of valine on α-casein synthesis and its underlying regulatory mechanisms. In this experiment, MAC-T cells were subjected to a 12 h starvation period, followed by the addition of valine in a range of concentrations (a total of seven concentrations: 0.000, 1.596, 3.192, 6.384, 12.768, 25.536, and 51.072 mM, as well as in 10% Fetal Bovine Serum). The suitable range of valine concentrations was determined using enzyme-linked immunosorbent assays (ELISAs). Real-time fluorescent quantitative PCR (RT-qPCR) and Western blot analyses were employed to evaluate the expression levels and phosphorylation states of the casein alpha s1 gene (CSN1S1), casein alpha s2 gene (CSN1S2) and mTOR signaling pathway-related genes. The functionality of the mTOR signaling pathway was further validated through rapamycin (100.000 nM) inhibition experiments. Results indicated that 1× Val (6.384 mM), 2× Val (12.768 mM), 4× Val (25.536 mM), and 8× Val (51.072 mM) significantly enhanced α-casein synthesis (p < 0.01). Within this concentration range, valine significantly upregulated the expression of CSN1S1, CSN1S2, and mTOR signaling pathway-related genes including the RagA gene (RRAGA), RagB gene (RRAGB), RagC gene (RRAGC), RagD gene (RRAGD), mTOR, raptor gene (RPTOR), and 4EBP1 gene (EIF4EBP1), eukaryotic initiation factor 4E (EIF4E), and S6 Kinase 1 (S6K1) (p < 0.01). Notably, the expression of the eukaryotic elongation factor 2 (EEF2) gene peaked at 1× Val (6.384 mM), while the expression of other genes reached their maximum at 4× Val (25.536 mM). Additionally, valine significantly increased the phosphorylation levels of mTOR, S6K1, 4E-binding protein-1 (4EBP1), ribosomal protein S6 (RPS6), and eEF2 (p < 0.01), with the highest phosphorylation levels of mTOR, S6K1, and RPS6 observed at 4× Val (25.536 mM). Rapamycin treatment significantly inhibited mTOR phosphorylation and α-casein synthesis (p < 0.01); however, the addition of 4× Val (25.536 mM) partially mitigated this inhibitory effect. In conclusion, valine promotes α-casein synthesis by activating the mTOR signaling pathway, with an optimal concentration of 4× Val (25.536 mM).

Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer in the head and neck region. In advanced stages of OSCC, chemotherapy is commonly used for treatment, despite some cancer cells having low sensitivity to anticancer drugs. We focused on RBM17/SPF45 as an essential drug-sensitizing factor in the context of malignant cells acquiring chemoresistance. Here, we demonstrate how RBM17 affects anticancer drug resistance in OSCC and we suggest the possible mechanism underlying its effects. After exposing oral cancer cell lines to fluorouracil (5-FU) and cisplatin, but not paclitaxel, the gene and protein expression of RBM17 increased. We found that siRNA-mediated RBM17-knockdown of the cell lines gained a significantly higher sensitivity to 5-FU, which was remarkably followed by a decrease in the expression of checkpoint kinase 1 (CHEK1) protein, whereas treatment with a CHEK1 inhibitor did not affect RBM17 protein expression in the oral cancer cell lines. These results indicate that RBM17 is a factor involved in the development of resistance to cytotoxic chemotherapy. We propose the underlying mechanism that RBM17 promotes CHEK1 protein expression in the ATM/ATR pathway, triggering the development of chemoresistance in cancer cells.

Alzheimer's disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis. Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment. Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model. Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the "Alzheimer's disease-amyloid secretase pathway". Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis. These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model.

The Candida tropicalis (C. tropicalis) named YB-3 was isolated by the Atmospheric and room temperature plasma mutagenesis from 6.5 g/L furfural tolerance. The comprehensive transcriptomic analysis of YB-3 was performed. During the stress of furfural treatment, C. tropicalis YB-3 protected cells from oxidative stress damage by increasing the accumulation of the glutathione reductase gene and the expression of antioxidant enzymes, with the enhancement of the inositol phosphate synthase to maintain the structural integrity and transport function of the inner membrane system, thereby affecting the cells' tolerance. Through the gene knockout and exogenous verification, it was further confirmed that the pathways involved in the three genes of sulfate adenosine transferase gene, glutathione reductase gene, and inositol phosphate synthase gene had significant effects on improving the tolerance of the strain to furfural. The deep excavation of furfural-tolerant gene components and directional modification of C. tropicalis to enhance tolerance are key steps for improving the utilization rate of biomass.

Oxidative stress is prevalent in organisms, and excessive oxidative damage can trigger cell death. Bacteria have evolved multiple pathways to cope with adverse stress, including the regulation of the cell cycle. Previous studies show that non-lethal exposure to H2O2 and mutations in antioxidant enzymes suppress replication initiation in Escherichia coli. The existence of common regulatory factors governing replication initiation across diverse causes-induced oxidative stress remains unclear. In this study, we utilized flow cytometry to determine the replication pattern of E. coli, and found that oxidative stress also participated in the inhibition of replication initiation by a defective iron regulation (fur-bfr-dps deletion). Adding a certain level of ATP promoted replication initiation in various antioxidant enzyme-deficient mutants and the ΔfurΔbfrΔdps mutant, suggesting that low ATP levels could be a common factor in the inhibition of replication initiation by different causes-induced oxidative stress. More potential common factors were screened using proteomics, followed by genetic validation with H2O2 stress. We found that oxidative stress might mediate the inhibition of replication initiation by interfering with the metabolism of glycine, glutamate, ornithine, and aspartate. Blocking CcmA-dependent cytochrome c biosynthesis, deleting the efflux pump proteins MdtABCD and TolC, or the arabinose transporter AraFHG eliminated the replication initiation inhibition by H2O2. In conclusion, this study uncovers a common multifactorial pathway of different causes-induced oxidative stress inhibiting replication initiation. Dormant and persistent bacteria exhibit an arrested or slow cell cycle, and non-lethal oxidative stress promotes their formation. Our findings contribute to exploring strategies to limit dormant and persistent bacterial formation by maintaining faster DNA replication initiation (cell cycle progression).

Ferrochelatase is the terminal enzyme in heme biosynthesis. Bacillus thuringiensis (Bt) 97-27 contains two ferrochelatases, HemH1 and HemH2, but their regulatory mechanisms and functional differences under virous environmental stimuli remain unclear. This study confirmed that the iron uptake regulator protein (Fur) bound to the promoters of hemH1 and hemH2, with Fe2+ or Fe3+ enhancing this binding. Heterologous expression of HemH1 and HemH2 in Escherichia coli showed that pEH2/BL grew better than pEH1/BL under different 2,2'-Bipyridyl, Fe2+, and Fe3+ concentrations. Under iron limitation, the heme precursor ALA production decreased significantly in both strains. The heme production of pEH2/BL decreased sharply under iron-limited conditions, while that of pEH1/BL decreased significantly under iron-rich conditions. The H2O2 sensitivity experiment revealed that E. coli pEH1/BL was more tolerant to H2O2 than pEH2/BL. In Bt, ΔhemH2 was most sensitive to H2O2 stress, but complementation of hemH1 or hemH2 partially restored H2O2 resistance, with the overexpressed strain pHH2/Bt being most tolerant. β-galactosidase assays indicated that Fur positively regulated hemH1 and negatively regulated hemH2 under normal conditions, but this regulation reversed with 2.5 mM Fe3+. qRT-PCR showed upregulation of genes related to heme synthesis, oxidative stress, and ferrous iron transport. This study reveals the functional differentiation of HemH1 and HemH2 under the joint regulation of Fur and environmental factors, highlighting their synergistic roles in heme synthesis, heavy metal detoxification, and oxidative stress resistance to maintain bacterial physiological homeostasis.

Periodontitis is unanimously accepted to be the sixth complication of diabetes mellitus (DM), while the inverse relationship of causality is still to be deciphered. Among the proposed mechanisms is gut dysbiosis, which is responsible for the systemic release of proinflammatory mediators. In this process, Gram-negative bacteria from the oral cavity enter the general circulation, leading to the emergence of bi-hormonal beta-pancreatic cells that lack the ability to secrete insulin. Additionally, epigenetic and adaptive mechanisms in affected cells may play a role in reducing inflammation. The release of reactive oxygen species, proinflammatory cytokines, and adipokines, such as interleukins, tumor necrosis factor alpha, leptin, prostaglandin E2, C-reactive protein, or matrix metalloproteinases, determine epigenetic changes, such as the methylation of DNA nucleotides or changes in the activity of histone acetylases/deacetylases. The management of periodontitis involves targeting inflammation, and its potential connection to epigenetic modulation observed in other chronic conditions may help to explain its role in preventing DM in affected patients. This review focuses on the key epigenetic changes in periodontitis that might contribute to DM development, and explores the mechanisms and novel multi-drug therapies that could help to prevent these effects.

Fructose catabolism by Streptococcus mutans is initiated by three phosphotransferase (PTS) transporters yielding fructose-1-phosphate (F-1-P) or fructose-6-phosphate. Deletion of one such F-1-P-generating PTS, fruI, was shown to reduce the cariogenicity of S. mutans in rats fed a high-sucrose diet. Moreover, a recent study linked fructose metabolism in S. mutans to a reactive electrophile species methylglyoxal. Here, we conducted a comparative transcriptomic analysis of S. mutans treated briefly with 50 mM fructose, 50 mM glucose, 5 mM methylglyoxal, or 0.5 mM hydrogen peroxide (H2O2). The results revealed a striking overlap between the fructose and methylglyoxal transcriptomes, totaling 176 genes, 61 of which were also shared with the H2O2 transcriptome. This core of 61 genes encompassed many of the same pathways affected by exposure to low pH or zinc intoxication. Consistent with these findings, fructose negatively impacted the metal homeostasis of a mutant deficient in zinc expulsion and the growth of a mutant of the major oxidative stress regulator SpxA1. Importantly, fructose metabolism lowered culture pH at a faster pace, allowed better survival under acidic and nutrient-depleted conditions, and enhanced the competitiveness of S. mutans against Streptococcus sanguinis, although a moderated level of F-1-P might further boost some of these benefits. Conversely, several commensal streptococcal species displayed a greater sensitivity to fructose that may negatively affect their persistence and competitiveness in dental biofilm. In conclusion, fructose metabolism is integrated into the stress core of S. mutans and regulates critical functions required for survival and its ability to induce dysbiosis in the oral cavity.IMPORTANCEFructose is a common monosaccharide in the biosphere, yet its overconsumption has been linked to various health problems in humans including insulin resistance, obesity, diabetes, non-alcoholic liver diseases, and even cancer. These effects are in large part attributable to the unique biochemical characteristics and metabolic responses associated with the degradation of fructose. Yet, an understanding of the effects of fructose on the physiology of bacteria and its implications for the human microbiome is severely lacking. Here, we performed a series of analyses on the gene regulation of a dental pathogen Streptococcus mutans by exposing it to fructose and other important stress agents. Further supported by growth, persistence, and competition assays, our findings revealed the ability of fructose to activate a set of stress-related functions that may prove critical to the ability of the bacterium to persist and cause diseases both within and without the oral cavity.

Glioblastoma (GBM) is a disease with high morbidity and poor prognosis. The combination of traditional Chinese and Western medicine and cuproptosis are known to serve important roles in the treatment of GBM. However, targeting cuproptosis to treat GBM by combining traditional Chinese and Western medicine has not been extensively investigated. Therefore, the present study focused on the diagnosis and treatment of GBM based on cuproptosis. Through a bioinformatics approach, a cuproptosis‑related prognostic model was first constructed. Next, this prognostic model was found to be closely related to immune infiltration, DNA mutation and DNA methylation through multi‑omics analysis. The present study indicated the cell clusters in GBM tissues and the risk scores in each cluster based on single‑cell sequencing data derived from Gene Expression Omnibus. Notably, by screening the CellMiner database, EMD‑1204831 was found to exhibit a high correlation with the risk score. Next, through network pharmacology and molecular docking analysis, the risk score‑related gene collagen type XXII α1 chain (COL22A1) was identified as the target of kaempferol, which is the active component of Ginseng. Notably, kaempferol could decrease the proliferation of GBM cells by inhibiting COL22A1 expression in cell experiments. Finally, kaempferol and EMD‑1204831 had an obvious inhibitory effect on the growth of GBM and sensitized GBM to cuproptosis inducers via COL22A1 in cell and animal experiments. Overall, the present study revealed a cuproptosis‑related combined regimen for GBM.

MicroRNAs (miRs) serve a pivotal role in the regulation of non‑small cell lung carcinoma (NSCLC). The present study aimed to investigate the antitumor effects of 7‑difluoromethoxyl‑5,4'‑di‑n‑octylygenistein (DFOG), a novel synthetic genistein derivative, on NSCLC, and to elucidate its molecular mechanism. The research focused on whether DFOG inhibited self‑renewal and tumor growth in NSCLC by modulating the miR‑152‑3p/STAT3 signaling pathway. Reverse transcription‑quantitative PCR and western blot analyses were employed to assess miR‑152‑3p expression and phosphorylated‑STAT3 (p‑STAT3) levels. The effects of DFOG on self‑renewal and tumor growth were evaluated via sphere formation and clonogenic assays. Additionally, sphere‑forming cells (SFCs) were enriched using a suspension culture method, and western blot analysis was conducted to examine stemness markers (CD133, CD44, Oct4 and Sox2). The results demonstrated that DFOG inhibited self‑renewal and tumor growth in NSCLC. This effect was associated with increased miR‑152‑3p expression, decreased STAT3 mRNA levels and reduced p‑STAT3 levels in NSCLC cells. Furthermore, inhibition or overexpression of STAT3 did not alter miR‑152‑3p expression but modulated the inhibitory effects of DFOG on self‑renewal and tumor growth. These findings highlighted that DFOG suppressed self‑renewal and tumor growth in SFCs derived from NSCLC by directly targeting STAT3 through the upregulation of miR‑152‑3p.

Liver cancer is the third most lethal and prevalent cancer in the Asia‑Pacific regions. Despite the use of tyrosine kinase inhibitors as first‑ and second‑line therapies, the overall survival rate for advanced liver cancer remains dismal and has not improved over the past decade. The present study, through high‑throughput screening, identified and demonstrated that PD161570, a new tyrosine kinase inhibitor, inhibited cell growth and proliferation in liver cancer cells. Mechanistically, PD161570 induced autophagy and enhanced autophagic flux in an autophagy‑related gene (ATG5)‑dependent and mammalian target of rapamycin kinase‑independent manner. Furthermore, when combined with chloroquine treatment, PD161570 not only suppressed cell proliferation but also increased cell apoptosis due to autophagy inhibition. RNA sequencing analysis revealed 1,121 differentially expressed genes in liver cancer cells following PD161570 treatment under autophagy inhibition via ATG5 knockdown. Notably, key molecules involved in autophagy (such as Damage Regulated Autophagy Modulator 1) and apoptosis regulators (including HRK, CTSS, BIRC3, BBC3, DDIT3 and GADD45B), were identified. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), demonstrated enrichment in apoptotic and cell death signaling pathways, highlighting the critical role of the mitogen‑activated protein kinases signaling pathway. In conclusion, PD161570 elicited an ATG5‑dependent autophagic process in liver cancer cells, while simultaneously enhancing apoptosis under conditions of autophagy inhibition.

HIV-1 can establish a lifelong infection by incorporating its proviral DNA into the host genome. Once integrated, the virus can either remain dormant or start active transcription, a process governed by the HIV Tat protein, host transcription factors and the chromatin landscape at the integration site. Histone-modifying enzymes and chromatin-remodeling enzymes play crucial roles in regulating this chromatin environment. Chromatin remodelers, a group of ATP-dependent proteins, collaborate with host proteins and histone-modifying enzymes to restructure nucleosomes, facilitating DNA repair, replication, and transcription. Recent studies have highlighted the importance of chromatin remodelers in HIV-1 latency, spurring research focused on developing small molecule modulators that can either reactivate the virus for eradication approaches or induce long-term latency to prevent future reactivation. Research efforts have primarily centered on the SWI/SNF family, though much remains to be uncovered regarding other chromatin remodeling families. This review delves into the general functions and roles of each chromatin remodeling family in the context of HIV and discusses recent advances in small molecule development targeting chromatin remodelers and the HIV Tat protein, aiming to improve therapeutic approaches against HIV.

Takifugu rubripes is an economically valuable fish species in Asia. The implementation of all-male culture for T. rubripes is highly anticipated in aquaculture. Aromatase inhibitor (AI, letrozole) treatment was found to be an efficient method to induced masculinization in T. rubripes, as reported in our previous study. Here, to further explore the underlying regulation mechanism of AI-induced masculinization, a whole-transcriptome analysis comparing was conducted between AI-induced masculinized XX (AI-XX) gonads and control (Con) gonads in T. rubripes.

Glucosamine (GlcN) is a common supplement used to alleviate osteoarthritis, but it may dysregulate glucose tolerance and induce insulin resistance, thereby increasing metabolic burden. The liver is a vital organ that modulates the Akt/mTOR/p70S6K signaling pathway in response to growth and metabolism. Fibroblast growth factor 21 (FGF21) is a hepatokine involved in regulating glucose and lipid metabolism. Additionally, increased circulating FGF21 levels have been linked to the prediction of metabolic disorders and type 2 diabetes. However, the regulatory mechanism controlling FGF21 expression by GlcN remains unclear. In the present study, GlcN stimulation led to several outcomes, including an increase in cell content, secretion, and mRNA and protein levels of FGF21 in hepatocytes. Moreover, inhibition of the Akt/mTOR/p70S6K axis resulted in reduced FGF21 expression in response to GlcN. Importantly, GlcN-mediated expression of FGF21 relies on PGC-1α upregulation. These results suggest that GlcN increases FGF21 expression through the activation between Akt/mTOR/p70S6K pathway and PGC-1α dependent manner.

Autism spectrum disorder (ASD) involves a complex neurodevelopmental pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) plays a crucial role in embryonic brain development and neural network stability. This study aimed to investigate the influence of ADAM10 on excitation/inhibition (E/I) balance, autism-like behaviors, and learning and memory dysfunction in rats prenatally exposed to valproic acid (VPA) and determine potential intervention strategies. The VPA-exposed group exhibited increased levels of ADAM10 and secreted amyloid precursor protein-α (sAPPα). Moreover, overexpression of glutamate decarboxylase 1 and N-methyl-D-aspartate receptors was observed. High-performance liquid chromatography-mass spectrometry revealed elevated levels of glutamate, glutamine, and γ-aminobutyric acid, as well as an E/I imbalance in the VPA group. Additionally, narrower synaptic clefts as well as increased postsynaptic density and synaptic vesicles were observed. Remarkably, intraperitoneal administration of ADAM10 inhibitor during the critical period of synaptic development significantly improved ASD-like behavior and learning and memory function in VPA-exposed rats. This intervention effectively reduced abnormally high sAPPα levels in the prefrontal cortex and corrected abnormal E/I balance. Thus, inhibiting ADAM10 overexpression may improve the E/I imbalance, alleviate core symptoms of ASD, and improve learning and memory dysfunction. The use of ADAM10 inhibitor represents a potential therapeutic strategy for treating ASD patients with intellectual disabilities.

Liver metastasis is the most common site of metastasis in colorectal cancer, and the prognosis of colorectal cancer patients with liver metastasis is extremely poor. Revealing the key genes of CLM and implementing targeted interventions is of great significance for colorectal cancer patients. By using the weighted gene co-expression network analysis (WGCNA) algorithm, key gene modules related to metastasis in colorectal cancer were identified. Subsequently, immune-regulating and prognostic-influencing key gene sets were identified from these modules to construct a prognostic model related to colorectal cancer metastasis. Genetic background differences underlying this model were analyzed using colorectal cancer methylation and mutation data, followed by Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) analysis of the relevant biological processes associated with the model. The value of predicting tumor drug response through the model was assessed using drug half maximal inhibitory concentration (IC50) data from colorectal cancer cell lines. Subsequently, utilizing single-cell sequencing data about liver metastasis, the colorectal cancer immune microenvironment reflected in the predictive model was analyzed, and a key gene set of the model was identified. Lastly, experimental validation was conducted to investigate the regulatory effects of photodynamic therapy (PDT) on the key genes of the model, and the cytotoxic effect of PDT on colorectal cancer was confirmed. An immune-related gene prognostic model regulating CLM was constructed, consisting of HSPA1A, ULBP2, RBP7, OXT, SLC11A1, INHBB, and ICOS. This model can predict the clinical response of colorectal cancer patients to Oxaliplatin, Cisplatin, Irinotecan, and 5-Fluorouracil. Single-cell sequencing results demonstrate that the model is associated with an immunosuppressive microenvironment in CLM. The higher the model's riskscore, the weaker the MHC-I, MHC-II, and various tumor immune signaling pathway networks in the colorectal cancer microenvironment. Causal analysis reveals that SLC11A1, ICOS, and HSPA1A play key roles in this model. PDT can kill colorectal cancer cells, inhibit colorectal cancer cell metastasis, significantly influence the expression of genes such as SLC11A1, ICOS, and HSPA1A in these processes, and suppress the infiltration of macrophages in the colorectal microenvironment, inhibiting the immune escape process of PD-1/PD-L1. A prognostic model based on immunity regulated by PDT has been established for assessing the prognosis of CLM patients, as well as clinical responses to chemotherapy drugs and immunotherapy.