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Natural Nicotinamide Adenine Dinucleotide (NAD+) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD+ at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD+ plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD+ levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD+ systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD+ are intricately intertwined. They provide multiple sources and techniques for NAD+ synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD+ levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD+ precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value.
Assuntos
NAD , Niacinamida , Ovário , Humanos , NAD/metabolismo , NAD/biossíntese , Ovário/metabolismo , Feminino , Animais , Niacinamida/metabolismo , Niacinamida/biossíntese , Vias Biossintéticas , Mononucleotídeo de Nicotinamida/metabolismoRESUMO
BACKGROUND: Gastric cancer (GC) is a common malignancy and a leading cause of cancer-related death with high morbidity and mortality. Methyl-CpG binding domain protein 3 (MBD3), a key epigenetic regulator, is abnormally expressed in several cancers, participating in progression and metastasis. However, the role of MBD3 in GC remains unknown. METHODS: MBD3 expression was assessed via public databases and validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The prognosis of MBD3 was analysed via bioinformatics based on the TCGA dataset. The migration, invasion and proliferation of GC cells were examined by transwell, wound healing, cell counting kit (CCK)-8, colony-formation and xenograft mouse models. Epithelial-mesenchymal transition (EMT) and phosphatidylinositide 3-kinases/ protein Kinase B (PI3K/AKT) pathway markers were evaluated by Western blotting. RNA sequencing was used to identify the target of MBD3. RESULTS: MBD3 expression was higher in GC tissues and cells than in normal tissues and cells. Additionally, high MBD3 levels were associated with poor prognosis in GC patients. Subsequently, we proved that MBD3 enhanced the migration, invasion and proliferation abilities of GC cells. Moreover, western blot results showed that MBD3 promoted EMT and activated the PI3K/AKT pathway. RNA sequencing analysis showed that MBD3 may increase actin γ1 (ACTG1) expression to promote migration and proliferation in GC cells. CONCLUSION: MBD3 promoted migration, invasion, proliferation and EMT by upregulating ACTG1 via PI3K/AKT signaling activation in GC cells and may be a potential diagnostic and prognostic target.
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The microecological stability of the gut microbiota plays a pivotal role in both preventing and treating colorectal cancer (CRC). This study investigated whether Lactobacillus plantarum CBT (LP-CBT) prevents CRC by inducing alterations in the gut microbiota composition and associated metabolites. The results showed that LP-CBT inhibited colorectal tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS)-treated mice by repairing the intestinal barrier function. Furthermore, LP-CBT decreased pro-inflammatory cytokines and anti-inflammatory cytokines. Importantly, LP-CBT remodeled intestinal homeostasis by increasing probiotics (Coprococcus, Mucispirillum, and Lactobacillus) and reducing harmful bacteria (Dorea, Shigella, Alistipes, Paraprevotella, Bacteroides, Sutterella, Turicibacter, Bifidobacterium, Clostridium, Allobaculum), significantly influencing arginine biosynthesis. Therefore, LP-CBT treatment regulated invertases and metabolites associated with the arginine pathway (carbamoyl phosphate, carboxymethyl proline, L-lysine, 10,11-epoxy-3-geranylgeranylindole, n-(6)-[(indol-3-yl)acetyl]-L-lysine, citrulline, N2-succinyl-L-ornithine, and (5-L-glutamyl)-L-glutamate). Furthermore, the inhibitory effect of LP-CBT on colorectal cancer was further confirmed using the MC38 subcutaneous tumor model. Collectively, these findings offer compelling evidence supporting the potential of LP-CBT as a viable preventive strategy against CRC.
Assuntos
Colite , Neoplasias Colorretais , Microbioma Gastrointestinal , Lactobacillus plantarum , Animais , Camundongos , Lactobacillus plantarum/metabolismo , Lisina/farmacologia , Citocinas/metabolismo , Metaboloma , Neoplasias Colorretais/metabolismo , Arginina/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Colite/microbiologia , Camundongos Endogâmicos C57BLRESUMO
Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.
Assuntos
Vacinas Anticâncer , Ácido Hialurônico , Hidrogéis , Indóis , Nanopartículas , Polímeros , Ácido Hialurônico/química , Polímeros/química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Indóis/química , Indóis/farmacologia , Animais , Camundongos , Hidrogéis/química , Nanopartículas/química , Humanos , Imiquimode/química , Imiquimode/farmacologia , Células Dendríticas/imunologia , Vacinação , Linhagem Celular Tumoral , Imunoterapia/métodos , Reagentes de Ligações Cruzadas/química , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacosRESUMO
Extracellular vesicles released by probiotics have been demonstrated to effectively alleviate intestinal inflammation, yet the precise underlying mechanisms remain unclear. In this research, for the first time, Lactobacillus plantarum UJS001 (LP-UJS) was isolated from fermented sauerkraut in Zhenjiang, China. Thereafter, the therapeutic effect of LP-UJS-derived extracellular vesicles (LP-UJS-EVs) on dextran sulfate sodium-induced ulcerative colitis (UC) in mice was analyzed to elucidate the immune mechanisms. According to our findings, LP-UJS-EVs played a pivotal role in restoring the intestinal barrier and alleviating intestinal inflammation. Notably, LP-UJS-EVs induced M2 polarization of macrophages, promoted the release of IL-10 and TGF-ß, inhibited the release of histamine, IL-6, and TNF-α, and exerted regulatory effects on intestinal microflora, as evidenced by the reduced abundances of Coprococcus, Parabacteroides, Staphylococcus, and Allobaculum, alongside the enhanced abundance of Prevotella. Furthermore, both LP-UJS and LP-UJS-EVs affected the lysine degradation pathway and significantly increased the abundance of related metabolites, especially oxoadipic acid. In summary, our results underscore the substantial therapeutic potential of LP-UJS and its secreted EVs in the treatment of UC.
Assuntos
Colite Ulcerativa , Vesículas Extracelulares , Microbioma Gastrointestinal , Lactobacillus plantarum , Macrófagos , Camundongos Endogâmicos C57BL , Probióticos , Colite Ulcerativa/microbiologia , Colite Ulcerativa/terapia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/imunologia , Lactobacillus plantarum/metabolismo , Animais , Camundongos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/química , Macrófagos/imunologia , Macrófagos/metabolismo , Probióticos/farmacologia , Probióticos/administração & dosagem , Masculino , Humanos , Homeostase , Interleucina-10/metabolismo , Interleucina-10/genética , Interleucina-10/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/genética , Sulfato de Dextrana/efeitos adversos , Fator de Crescimento Transformador beta/metabolismoRESUMO
Background: In spite of numerous existing bio-surveillance systems for predicting glioma (GBM) prognosis, enhancing the efficacy of immunotherapy remains an ongoing conundrum. The continual scrutiny of the dynamic interplay between the sphingolipid metabolic pathway and tumor immunophenotypes has unveiled potential implications. However, the intricate orchestration of functional and regulatory mechanisms by long non-coding RNAs (lncRNAs) in GBM, particularly in the context of sphingolipid metabolism, remains cryptic. Methods: We harnessed established R packages to intersect gene expression profiles of GBM patients within the The Cancer Genome Atlas (TCGA) database with the compilation of sphingolipid metabolism genes from GeneCards. This enabled us to discern markedly distinct lncRNAs, which were subsequently deployed to construct a robust prognostic model utilizing Lasso-Cox regression analysis. We then scrutinized the immune microenvironment across various risk strata using the ssGSEA and CIBERSORT algorithms. To evaluate mutation patterns and drug resistance profiles within patient subgroups, we devised the "Prophytic" and "Maftools" packages, respectively. Results: Our investigation scrutinized lncRNAs linked to sphingolipid metabolism, utilizing glioma specimens from TCGA. We meticulously curated 1224 sphingolipid-associated genes gleaned from GeneCards and pinpointed 272 differentially expressed mRNAs via transcriptomic analysis. Enrichment analyses underscored their significance in sphingolipid processes. A prognostic model founded on 17 meticulously selected lncRNAs was systematically constructed and validated. This model adeptly stratified GBM patients into high- and low-risk categories, yielding highly precise prognostic insights. We also discerned correlations between immune cell infiltration and genetic mutation discrepancies, along with distinct therapeutic responses through drug sensitivity analysis. Notably, computational findings were corroborated through experimental validation by RT-PCR. Conclusion: In summation, our exhaustive inquiry underscores the multifaceted utility of the sphingolipid metabolic pathway as an autonomous diagnostic and prognostic indicator for glioma patients. Furthermore, we amalgamate a profusion of substantiated evidence concerning immune infiltration and gene mutations, thereby reinforcing the proposition that sphingolipid metabolism may function as a pivotal determinant in the panorama of immunotherapeutic interventions.