ABSTRACT
BACKGROUND: The objective of this research is to clarify the impact of periodontitis on overall and cardiovascular-related death rates among hypertensive individuals. METHOD: A total of 5665 individuals with hypertension were included from the National Health and Nutrition Examination Survey (NHANES) data spanning 2001-2004 and 2009-2014. These individuals were divided into two groups based on the presence or absence of periodontitis and further stratified by the severity of periodontitis. We employed weighted multivariate Cox proportional hazards regression and Kaplan-Meier curves (log-rank test) to evaluate the impact of periodontitis on all-cause and cardiovascular mortality. Additional analyses, including adjustments for various covariates, subgroups, and sensitivity analyses, were conducted to ensure the robustness and reliability of our results. RESULT: Over an average follow-up duration of 10.22 years, there were 1,122 all-cause and 297 cardiovascular deaths. Individuals with periodontitis exhibited an elevated risk of all-cause mortality (HR = 1.33, 95% CI 1.18-1.51; p < 0.0001) and cardiovascular mortality (HR = 1.48, 95% CI 1.15-1.89; p = 0.002). Moreover, we observed a progressive increase in both all-cause mortality and cardiovascular mortality (p for trend are both lower than 0.001) and correlating with the severity of periodontitis. These associations remained consistent across various subgroup and sensitivity analyses. CONCLUSION: Our findings suggest a significant association between periodontitis and increased risks of all-cause and cardiovascular mortality among hypertensive individuals. Notably, the severity of periodontitis appears to be a critical factor, with moderate to severe cases exerting a more pronounced impact on all-cause mortality. Additionally, cardiovascular disease mortality significantlly increases in individuals with varying degrees of periodontitis.
Subject(s)
Cardiovascular Diseases , Cause of Death , Hypertension , Nutrition Surveys , Periodontitis , Humans , Periodontitis/complications , Periodontitis/mortality , Hypertension/complications , Male , Female , Middle Aged , Cardiovascular Diseases/mortality , Cardiovascular Diseases/complications , Adult , Cohort Studies , United States/epidemiology , Aged , Risk Factors , Proportional Hazards ModelsABSTRACT
Sorafenib, an anticancer drug, has been shown to induce ferroptosis in cancer cells. However, resistance to sorafenib greatly limits its therapeutic efficacy, and the exact mechanism of resistance is not fully understood. This study investigated the role of N-Acetyltransferase 10 (NAT10) in influencing the anticancer activity of sorafenib in nasopharyngeal carcinoma (NPC) and its molecular mechanism. NAT10 expression was significantly upregulated in NPC. Mechanistically, NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib-induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In vivo knockout of NAT10 inhibited the growth of sorafenib-resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib.
ABSTRACT
Physical processes ultimately shape tissue during development. Two emerging proposals are that cells migrate toward stiffer tissue (durotaxis) and that the extent of cell rearrangements reflects tissue phase, but it is unclear whether and how these concepts are related. Here, we identify fibronectin-dependent tissue stiffness as a control variable that underlies and unifies these phenomena in vivo. In murine limb bud mesoderm, cells are either caged, move directionally, or intercalate as a function of their location along a stiffness gradient. A modified Landau phase equation that incorporates tissue stiffness accurately predicts cell diffusivity upon loss or gain of fibronectin. Fibronectin is regulated by WNT5A-YAP feedback that controls cell movements, tissue shape, and skeletal pattern. The results identify a key determinant of phase transition and show how fibronectin-dependent directional cell movement emerges in a mixed-phase environment in vivo.
Subject(s)
Cell Movement , Fibronectins , Mesoderm , Fibronectins/metabolism , Animals , Mesoderm/metabolism , Mesoderm/cytology , Mice , Wnt-5a Protein/metabolismABSTRACT
BACKGROUND: Simulation-based training is used to improve fiberoptic bronchoscopic skills for novices. We developed a nonanatomical task trainer (named 12-hole clock model) that focused on training manipulation of bronchoscopes. The aim of this study was to evaluate the training effect of this model on bronchoscopic skills and learning interests in simulated normal and difficult airways among anesthesia residents. METHODS: Forty-three anesthesia residents without experience in bronchoscopic intubation were randomly divided into control (nâ =â 22) and intervention groups (nâ =â 21). All participants received standard multimedia learning and a baseline test using a normal airway manikin. Then, the control and intervention groups engaged in 60 minutes of training via a traditional airway manikin or the clock model, respectively. After training, the participants completed bronchoscopic performance assessments in simulated normal and difficult airways, as well as an electronic questionnaire related to the course. RESULTS: During training, the total hands-on time of bronchoscopic practice recorded by trainees' themselves was longer in the intervention group than in the control group (1568â ±â 478 seconds vs 497â ±â 172 s, Pâ <â .0001). Posttraining, the time required to visualize the carina in simulated normal airways was longer in the intervention group than in the control group (22.0 [18.0, 29.0] vs 14.0 [10.8, 18.3], Pâ <â .0001), while it was shorter for simulated difficult airways (24.0 [16.0, 32.0] s vs 27.0 [21.0, 35.5] s, Pâ =â .0425). The survey results indicated that confidence in bronchoscopic intubation increased in both groups, without significant differences in satisfaction, acceptance, or perceived difficulty between the groups. However, the interest ratings were higher in the intervention group than in the control group. CONCLUSIONS: The 12-hole clock model is a simple and feasible method for improving bronchoscopic skills and promoting interest among trainees. TRIAL REGISTRATION: NCT05327842 at Clinicaltrials.gov.
Subject(s)
Anesthesiology , Bronchoscopy , Clinical Competence , Internship and Residency , Simulation Training , Humans , Bronchoscopy/education , Bronchoscopy/methods , Internship and Residency/methods , Female , Male , Anesthesiology/education , Simulation Training/methods , Adult , Manikins , Intubation, Intratracheal/methodsABSTRACT
Despite the remarkable success of chimeric antigen receptor (CAR) T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous interferon (IFN)-γ promoter for transgenic interleukin (IL)-15 expression. We demonstrate that IFN-γ expression is tightly regulated by T cell receptor signaling. By introducing an internal ribosome entry site IL15 into the 3' UTR of the IFN-γ gene via homology directed repair-mediated knock-in, we confirm that IL-15 expression can co-express with IFN-γ in an antigen stimulation-dependent manner. Importantly, the insertion of transgenes does not compromise endogenous IFN-γ expression. In vitro and in vivo data demonstrate that IL-15 driven by the IFN-γ promoter dramatically improves CAR T cells' antitumor activity, suggesting the effectiveness of IL-15 expression. Last, as a part of our efforts toward clinical translation, we have developed an innovative two-gene knock-in approach. This approach enables the simultaneous integration of CAR and IL-15 genes into TRAC and IFN-γ gene loci using a single AAV vector. CAR T cells engineered to express IL-15 using this approach demonstrate enhanced antitumor efficacy. Overall, our study underscores the feasibility of utilizing endogenous promoters for transgenic cytokines expression in CAR T cells.
Subject(s)
Immunotherapy, Adoptive , Interferon-gamma , Interleukin-15 , Promoter Regions, Genetic , Receptors, Chimeric Antigen , Interferon-gamma/metabolism , Humans , Animals , Mice , Immunotherapy, Adoptive/methods , Interleukin-15/genetics , Interleukin-15/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , Genetic Vectors/genetics , Cell Line, Tumor , Transgenes , Cytokines/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Xenograft Model Antitumor Assays , Gene ExpressionABSTRACT
Uncontrolled bleeding and wound infections following severe trauma pose significant challenges for existing tissue adhesives, primarily due to their weak wet adhesion, slow adhesion formation, cytotoxicity concerns, and lack of antibacterial properties. Herein, an injectable hydrogel (denoted as ES gel) with rapid, robust adhesive sealing and inherent antibacterial activity based on ε-polylysine and a poly(ethylene glycol) derivative is developed. The engineered hydrogel exhibits rapid gelation behavior, high mechanical strength, strong adhesion to various tissues, and can sustain an ultrahigh burst pressure of 450 mmHg. It also presents excellent biocompatibility, biodegradability, antibacterial properties, and on-demand removability. Significantly improved hemostatic efficacy of ES gel compared to fibrin glue is demonstrated using various injury models in rats and rabbits. Remarkably, the adhesive hydrogel can effectively halt lethal non-compressible hemorrhages in visceral organs (liver, spleen, and heart) and femoral artery injury models in fully anticoagulated pigs. Furthermore, the hydrogel outperforms commercial products in sutureless wound closure and repair in the rat liver defect, skin incision, and infected full-thickness skin wound models. Overall, this study highlights the promising clinical applications of ES gel for managing uncontrolled hemorrhage, sutureless wound closure, and infected wound repair.
Subject(s)
Anti-Bacterial Agents , Hemostasis , Hydrogels , Wound Healing , Animals , Hydrogels/chemistry , Hydrogels/pharmacology , Wound Healing/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Rats , Rabbits , Hemostasis/drug effects , Pressure , Polylysine/chemistry , Polylysine/pharmacology , Injections , Swine , Polyethylene Glycols/chemistry , Hemorrhage/drug therapy , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Rats, Sprague-Dawley , Tissue Adhesives/chemistry , Tissue Adhesives/pharmacology , Tissue Adhesives/therapeutic useABSTRACT
BACKGROUND: Neuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain. AIMS: In this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain. METHODS: We have summarized studies of HDAC in neuropathic pain in Pubmed. RESULTS: HDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management. CONCLUSIONS: Abnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain.
Subject(s)
Epigenesis, Genetic , Histone Deacetylase Inhibitors , Histone Deacetylases , Neuralgia , Humans , Epigenesis, Genetic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/metabolism , Neuralgia/drug therapy , Neuralgia/metabolismABSTRACT
Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder with no effective interventions for curing or modifying its progression. However, emerging research suggests that vitamin A in the diet may play a role in both the prevention and treatment of AD, although the exact mechanisms are not fully understood. Objectives: This study aims to investigate the dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aß pathology shedding light on its potential as a dietary intervention for AD prevention and treatment. Methods: The APP/PS1-AD mouse model was employed and divided into three dietary groups: vitamin A-deficient (VAD), normal vitamin A (VAN), and vitamin A-supplemented (VAS) for a 12-week study. Neurobehavioral functions were assessed using the Morris Water Maze Test (MWM). Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of Diamine Oxidase (DAO), D-lactate, IL-6, IL-1ß, and TNF-a cytokines. Serum vitamin A levels were analyzed via LC-MS/MS analysis. Immunohistochemical analysis and morphometry were performed to evaluate the deposition of Aß in brain tissue. The gut microbiota of APP/PS1 mice was analyzed using 16S rRNA sequencing analysis. Additionally, transcriptomic analysis was conducted on intestinal tissue from APP/PS1 mice. Results: No significant changes in food intake and body weight were observed among the groups. However, the VAD and VAS groups showed reduced food intake compared to the VAN group at various time points. In terms of cognitive function, the VAN group performed better in the Morris Water Maze Test, indicating superior learning and memory abilities. The VAD and VAS groups exhibited impaired performance, with the VAS group performing relatively better than the VAD group. Serum vitamin A concentrations differed significantly among the groups, with the VAS group having the highest concentration. Aß levels were significantly higher in the VAD group compared to both the VAN and VAS groups. Microbial analysis revealed that the VAS and VAN groups had higher microbial diversity than the VAD group, with specific taxa characterizing each group. The VAN group was characterized by taxa such as Actinohacteriota and Desulfovibrionaceae, while the VAD group was characterized by Parabacteroides and Tannerellaceae. The VAS group showed similarities with both VAN and VAD groups, with taxa like Desulfobacterota and Desulfovibrionaceae being present. The VAD vs. VAS, VAD vs. VAN, and VAS vs. VAN comparisons identified 571, 313, and 243 differentially expressed genes, respectively, which associated with cellular and metabolic processes, and pathway analysis revealed enrichment in pathways related to chemical carcinogenesis, drug metabolism, glutathione metabolism, and immune-related processes. The VAD group exhibited higher levels of D-lactate, diamine oxidase, and inflammatory cytokines (TNF-a, IL-1ß, IL-6) compared to the VAN and VAS groups. Conclusion: Dietary vitamin A supplementation modulates the gut microbiota, intestinal permeability, inflammatory factors, and Aß protein formation, offering insights into the pathogenesis of AD and potential therapeutic avenues for further exploration. This research highlights the intricate interplay between diet, gut microbiota, and neurodegenerative processes, emphasizing the importance of dietary interventions in managing AD-related pathologies.
ABSTRACT
Objective: Ear acupuncture, as a system for treating and preventing diseases through stimulation of points on the auricle, has been systematically introduced during the last 60 years. Although the auricular cartography was described somatotopically as an inverted fetus by Paul Nogier, MD, the underlying mechanism of auricular stimulation remains unclear. The aim of this research was to gain an understanding of the structural basis of auricular stimulation, as well as showing the distribution of the nerve fibers, and the blood and lymphatic vessels. Materials and Methods: The distribution of nerve fibers, and blood and lymphatic vessels was examined in whole-mount auricular skins of mice by combining the biomarkers protein gene product 9.5, cluster of differentiation 31, and lymphatic-vessel endothelial hyaluronan receptor-1 following tissue-clearing treatment with multiple immunofluorescent staining. Results: The labeled nerve fibers, and the blood and lymphatic vessels were distributed extensively in the inner and outer parts of the auricular skin. Auricular nerves aligning with blood vessels ran from the basal region to the peripheral region and crossed over lymphatic vessels, thus forming the neural, vascular, and lymphatic networks. Conclusions: As these are important tissue components of auricular skin, this result implies that the auricular nerve fibers, and blood and lymphatic vessels may coordinate with each other to respond directly to auricular stimulation.
ABSTRACT
BACKGROUND: Current therapeutic agents for AD have limited efficacy and often induce undesirable side effects. Gegen Qinlian tablets (GGQLT) are a well-known clearingheat formula used in clinical treatment of inflammatory diseases. Based on traditional Chinese medicine (TCM) theory, the strategy of clearing-heat is then compatible with the treatment of AD. However, it remains unknown whether GGQLT can exert neuroprotective effects and alleviate neuroinflammation in AD. PURPOSE: This study aimed to evaluate the anti-AD effects of GGQLT and to decipher its intricate mechanism using integrative analyses of network pharmacology, transcriptomic RNA sequencing, and gut microbiota. METHODS: The ingredients of GGQLT were analyzed using HPLC-ESI-Q/TOF-MS. The AD model was established by bilateral injection of Aß1-42 into the intracerebroventricular space of rats. The Morris water maze was used to evaluate the cognitive function of the AD rats. The long-term toxicity of GGQLT in rats was assessed by monitoring their body weights and pathological alterations in the liver and kidney. Reactive astrocytes and microglia were assessed by immunohistochemistry by labeling GFAP and Iba-1. The levels of inflammatory cytokines in the hippocampus were evaluated using ELISA kits, RT-PCR, and Western blot, respectively. The potential anti-AD mechanism was predicted by analyses of RNA-sequencing and network pharmacology. Western blot and immunohistochemistry were utilized to detect the phosphorylation levels of IκBα, NF-κB p65, p38, ERK and JNK. The richness and composition of gut bacterial and fungal microflora were investigated via 16S rRNA and ITS sequencing. RESULTS: Typical ingredients of GGQLT were identified using HPLC-ESI-Q/TOF-MS. GGQLT significantly improved the cognitive function of AD rats by suppressing the activation of microglia and astrocytes, improving glial morphology, and reducing the neuroinflammatory reactions in the hippocampus. RNA-sequencing, network and experimental pharmacological studies demonstrated that GGQLT inhibited the activation of NF-κB/MAPK signaling pathways in the hippocampus. GGQLT could also restore abnormal gut bacterial and fungal homeostasis and no longer-term toxicity of GGQLT was observed. CONCLUSIONS: Our findings, for the first time, demonstrate GGQLT exhibit anti-AD effects and is worthy of further exploration and development.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Drugs, Chinese Herbal , Gastrointestinal Microbiome , Neuroinflammatory Diseases , Rats, Sprague-Dawley , Animals , Gastrointestinal Microbiome/drug effects , Drugs, Chinese Herbal/pharmacology , Alzheimer Disease/drug therapy , Male , Rats , Neuroinflammatory Diseases/drug therapy , Hippocampus/drug effects , Neuroprotective Agents/pharmacology , Homeostasis/drug effects , Tablets , Amyloid beta-Peptides/metabolism , Neuroglia/drug effects , Network Pharmacology , Disease Progression , Cytokines/metabolismABSTRACT
Thyroid dysgenesis (TD) is the common pathogenic mechanism of congenital hypothyroidism (CH). In addition, known pathogenic genes are limited to those that are directly involved in thyroid development. To identify additional candidate pathogenetic genes, we performed forward genetic screening for TD in zebrafish, followed by positional cloning. The candidate gene was confirmed in vitro using the Nthy-ori 3.1 cell line and in vivo using a zebrafish model organism. We obtained a novel zebrafish line with thyroid dysgenesis and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1) by positional cloning. Further molecular studies revealed that taf1 was needed for the proliferation of thyroid follicular cells by binding to the NOTCH1 promoter region. Knockdown of TAF1 impaired the proliferation and maturation of thyroid cells, thereby leading to thyroid dysplasia. This study showed that TAF1 promoted Notch signaling and that this association played a pivotal role in thyroid development.NEW & NOTEWORTHY In our study, we obtained a novel zebrafish line with thyroid dysgenesis (TD) and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1). Further researches revealed that taf1 was required for thyroid follicular cells by binding to the NOTCH1 promoter region. Our findings revealed a novel role of TAF1 in thyroid morphogenesis.
Subject(s)
Cell Proliferation , Signal Transduction , TATA-Binding Protein Associated Factors , Thyroid Gland , Transcription Factor TFIID , Zebrafish , Animals , Zebrafish/genetics , TATA-Binding Protein Associated Factors/genetics , TATA-Binding Protein Associated Factors/metabolism , Transcription Factor TFIID/genetics , Transcription Factor TFIID/metabolism , Signal Transduction/genetics , Cell Proliferation/genetics , Thyroid Gland/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Thyroid Dysgenesis/genetics , Thyroid Dysgenesis/metabolism , Humans , Histone AcetyltransferasesABSTRACT
Uterine corpus endometrial carcinoma (UCEC) is becoming a main malignant cancer that threaten to women's health. Thymidine kinase 1 (TK1) is considering to be associated with tumorigenesis and development. Nevertheless, the function of TK1 in UCEC is still unclear. Herein, we analyzed the TK1 expression level in pan-cancer and found that TK1 was upregulated in a variety of cancers including UCEC. Patients of UCEC with high expression of TK1 were related to poor outcome. TK1 was also related to clinical stage, histologic grade and lymph node metastasis. Abnormal expression of TK1 in UCEC was related to promoter methylation while gene mutation was not frequent. TK1 and its associated genes appeared to be prominent in cell cycle and DNA replication, according to GO and KEGG analysis. Analysis of immune infiltration revealed a negative correlation between TK1 and CD8 + T cells, macrophages, and dendritic cells. In vitro experiments, TK1 knockdown resulted in the inhibition of proliferation, migration, invasion and EMT in UCEC cell lines.
Subject(s)
Carcinoma, Endometrioid , Endometrial Neoplasms , Humans , Female , Thymidine Kinase/genetics , CD8-Positive T-Lymphocytes , Carcinogenesis , Endometrial Neoplasms/geneticsABSTRACT
A troubling feedback loop, where drier soil contributes to hotter climates, has been widely recognized. This study, drawing on climate model simulations, reveals that maintaining current global soil moisture levels could significantly alleviate 32.9% of land warming under low-emission scenarios. This action could also postpone reaching critical warming thresholds of 1.5 °C and 2.0 °C by at least a decade. Crucially, preserving soil moisture at current levels could prevent noticeable climate change impacts across 42% of the Earth's land, a stark deviation from projections suggesting widespread impacts before the 2060s. To combat soil drying, afforestation in mid-to-low latitude regions within the next three decades is proposed as an effective strategy to increase surface water availability. This underscores the substantial potential of nature-based solutions for managing soil moisture, benefiting both climate change mitigation and ecological enhancement.
ABSTRACT
Developing biocompatible injectable hydrogels with high mechanical strength and rapid strong tissue adhesion for hemostatic sealing of uncontrolled bleeding remains a prevailing challenge. Herein, we engineer an injectable and photo-cross-linkable hydrogel based on naturally derived gelatin methacrylate (GelMA) and N-hydroxysuccinimide-modified poly(γ-glutamic acid) (γPGA-NHS). The chemically dual-cross-linked hydrogel rapidly forms after UV light irradiation and covalently bonds to the underlying tissue to provide robust adhesion. We demonstrate a significantly improved hemostatic efficacy of the hydrogel using various injury models in rats compared to the commercially available fibrin glue. Notably, the hydrogel can achieve hemostasis in porcine liver and spleen incision, and femoral artery puncture models. Moreover, the hydrogel is used for sutureless repair of the liver defect in a rat model with a significantly suppressed inflammatory response, enhanced angiogenesis, and superior healing efficacy compared to fibrin glue. Together, this study offers a promising bioadhesive for treating severe bleeding and facilitating wound repair.
Subject(s)
Hemostatics , Hydrogels , Rats , Animals , Swine , Hydrogels/pharmacology , Hydrogels/chemistry , Fibrin Tissue Adhesive , Adhesives , Biocompatible Materials/pharmacology , Biocompatible Materials/chemistry , Hemostatics/pharmacology , Hemorrhage/drug therapy , Wound HealingABSTRACT
Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.
Subject(s)
Ovarian Neoplasms , Proto-Oncogene Proteins c-akt , Animals , Female , Humans , Mice , Carcinoma, Ovarian Epithelial , Cell Proliferation , DNA Topoisomerases, Type II/genetics , Ovarian Neoplasms/genetics , TOR Serine-Threonine KinasesABSTRACT
BACKGROUND: Neuropathic pain is a prevalent and highly debilitating condition that impacts millions of individuals globally. Neuroinflammation is considered a key factor in the development of neuropathic pain. Accumulating evidence suggests that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in regulating neuroinflammation. Nevertheless, the specific involvement of PTP1B in neuropathic pain remains largely unknown. This study aims to examine the impact of PTP1B on neuropathic pain and unravel the underlying molecular mechanisms implicated. METHODS: In the current study, we evaluated the paw withdrawal threshold (PWT) of male rats following spared nerve injury (SNI) to assess the presence of neuropathic pain. To elucidate the underlying mechanisms, western blotting, immunofluorescence, and electron microscopy techniques were employed. RESULTS: Our results showed that SNI significantly elevated PTP1B levels, which was accompanied by an increase in the expression of endoplasmic reticulum (ER) stress markers (BIP, p-PERK, p-IRE1α, and ATF6) and phosphorylated NF-κB in the spinal dorsal horn. SNI-induced mechanical allodynia was impaired by the treatment of intrathecal injection of PTP1B siRNA or PTP1B-IN-1, a specific inhibitor of PTP1B. Moreover, the intrathecal administration of PTP1B-IN-1 effectively suppressed the expression of ER stress markers (BIP, p-PERK/p-eIF2α, p-IRE1α, and ATF6), leading to the inhibition of NF-κB, microglia, and astrocytes activation, as well as a decrease in pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß. However, these effects were reversed by intrathecal administration of tunicamycin (Tm, an inducer of ER stress). Additionally, intrathecal administration of Tm in healthy rats resulted in the development of mechanical allodynia and the activation of NF-κB-mediated neuroinflammatory signaling. CONCLUSIONS: The upregulation of PTP1B induced by SNI facilitates the activation of NF-κB and glial cells via ER stress in the spinal dorsal horn. This, in turn, leads to an increase in the production of pro-inflammatory cytokines, thereby contributing to the development and maintenance of neuropathic pain. Therefore, targeting PTP1B could be a promising therapeutic strategy for the treatment of neuropathic pain.
Subject(s)
NF-kappa B , Neuralgia , Animals , Male , Rats , Cytokines , Endoplasmic Reticulum Stress , Endoribonucleases/therapeutic use , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Neuralgia/metabolism , Neuroglia/metabolism , Neuroinflammatory Diseases , Protein Serine-Threonine Kinases , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/therapeutic use , Rats, Sprague-Dawley , NF-kappa B p50 Subunit/metabolismABSTRACT
5-Methylcytosine (m5C) is one of the most ubiquitous modifications of mRNA and contributes to cancer pathogenesis. Aly/REF export factor (ALYREF), an m5C reader, is associated with the prognosis of liver hepatocellular carcinoma (LIHC). However, the effects of ALYREF on the progression of LIHC and the underlying molecular mechanisms remains elusive. Through an analysis of an online database and 3 independent LIHC cohorts, we found that ALYREF was markedly elevated in human liver cancer tissues and was significantly correlated with LIHC clinicopathological parameters, including Ki67+ cell rate, high-grade TNM stage, and poor prognosis. Several experiments were conducted to investigate the molecular basis and functional role of ALYREF-related progression in this study. ALYREF could enhance LIHC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and tumor formation in vivo. Mechanistically, ALYREF promoted the progression of human LIHC through EGFR pathways. Furthermore, ALYREF could directly bind to the m5C modification site of EGFR 3' untranslated region (3' UTR) to stabilize EGFR mRNA. Collectively, ALYREF played a crucial oncogenic role in LIHC via the stabilization of EGFR mRNA and subsequent activation of the STAT3 signaling pathway. Our results may help to elucidate the potential mechanisms of ALYREF-induced m5C modification in the progression of human LIHC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/genetics , 5-Methylcytosine , RNA, Messenger/genetics , Liver Neoplasms/genetics , 3' Untranslated Regions , ErbB Receptors/genetics , Nuclear Proteins , Transcription Factors , RNA-Binding ProteinsABSTRACT
To explore the exposure level of pesticides and veterinary drugs in an aquaculture environment and its impact on the ecological environment, this study took the aquaculture environment in Shanghai as an example, and samples of water, sediment, and inputs from 40 major aquaculture farms were collected from July to September 2022. The types and contents of pesticides and veterinary drugs were screened using high-performance liquid chromatography-electrostatic field orbital ion trap mass spectrometry, and the risk quotient (RQ) method was used to assess the ecological risk of pesticide contamination in water and sediment. The results showed that 13 drugs were screened out from 204 samples (72 samples of water, 72 samples of mud, and 60 samples of input), namely, chlorpromazine, carbendazim, thiophanate, diazepam, florfenicol, simazine, amantidine, diazepam, trimethoprim, ciprofloxacin, ofloxacin, mebendazole, and enrofloxacin. Among them, 12 species were found in water samples with concentrations ranging from 0.016 µg·L-1 to 2.084 µg·L-1. The concentrations of seven species in the mud samples ranged from 0.018 µg·kg-1 to 23.101 µg·kg-1. The results showed that there were four types of inputs, ranging from 1.979 µg·kg-1 to 101.940 µg·kg-1. Seven drugs were found in both water and sediment. The risk quotient (RQ) results showed that there were some high and middle risks in both water and sediment samples of aquaculture farms, and the ecological risks of carbendazim were the highest in both water and sediment samples of aquaculture farms; the RQ values were 3.848 and 1.580, respectively, indicating high risk. It is suggested to strengthen the control and management of exogenous pesticides and veterinary drugs in aquaculture environments to protect the ecosystem health of the aquaculture environment.