Repetitive satellite DNAs, divergent in nucleic-acid sequence and size across eukaryotes, provide a physical site for centromere assembly to orchestrate chromosome segregation during the cell cycle. These non-coding DNAs are transcribed by RNA polymerase (RNAP) II and the transcription has been shown to play a role in chromosome segregation, but a little is known about the regulation of centromeric transcription, especially in higher organisms with tandemly-repeated-DNA-sequence centromeres. Using RNA interference knockdown, chemical inhibition and AID/IAA degradation, we show that Topoisomerase I (TopI), not TopII, promotes the transcription of α-satellite DNAs, the main type of satellite on centromeres in human cells. Mechanistically, TopI localizes to centromeres, binds RNAP II and facilitates RNAP II elongation on centromeres. Interestingly, in response to DNA double-stranded breaks (DSBs) induced by chemotherapy drugs or CRSPR/Cas9, α-satellite transcription is dramatically stimulated in a DNA damage checkpoint-independent but TopI-dependent manner. These DSB-induced α-satellite RNAs were predominantly derived from the α-satellite high-order repeats of human centromeres and forms into strong speckles in the nucleus. Remarkably, TopI-dependent satellite transcription also exists in mouse 3T3 and Drosophila S2 cells and in Drosophila larval imaginal wing discs and tumor tissues. Altogether, our findings herein reveal an evolutionally conserved mechanism with TopI as a key player for the regulation of satellite transcription at both cellular and animal levels.
Breast cancer represents the leading cancer type and leading cause of cancer-related death among women in the world. Triple-negative breast cancer (TNBC) is a subset of breast cancer with the poorest prognosis and still lacking of effective therapeutic options. We recently screened a natural product library and identified 3 new hit compounds with selective and prominent anti-TNBC activities on different subtype of TNBC cell lines. Interestingly, all of these 3 hit compounds belong to "cytoskeletal drugs" that target tubulin and microtubule function. Our data also showed that these hit compounds showed consistently effective on TNBC cells which are resistant to those currently used antimicrotubule agents such as Paclitaxel. RNA-Sequencing analyses revealed the anti-TNBC mechanisms of these hit compounds and identified a subset of new cellular factors commonly affected by hit compounds in different subtypes of TNBC cells. Among them, we demonstrated AHCYL1 and SPG21 as new microtubule-associated proteins, which were required for TNBC cell survival with clinical implication through tissue array analysis. Our studies provide new insights into the mechanisms of TNBC pathogenesis and offer promising therapeutic directions for this aggressive breast cancer.
Development of highly efficient, heavy-metal-free electrochemiluminescence (ECL) materials is attractive but still challenging. Herein, we report an aggregation-induced delayed ECL (AIDECL) active organic dot (OD) composed of a tert-butoxy-group-substituted benzophenone-dimethylacridine compound, which shows high ECL efficiency. The resultant ODs exhibit 2.1-fold higher ECL efficiency compared to control AIDECL-active ODs. Molecular stacking combined with theoretical calculations suggests that tert-butoxy groups effectively participate in the intermolecular interactions, further inhibiting the molecular motions in the aggregated states and thus accelerating radiative decay. On the basis of these ODs exhibiting excellent ECL performance, a proof-of-concept biosensor is constructed for the detection of miR-16 associated with Alzheimer's disease, which demonstrates excellent detection ability with the limit of detection of 1.7 fM. This work provides a new approach to improve the ECL efficiency and enriches the fundamental understanding of the structure-property relationship.
BACKGROUND: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets. METHODS: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset. RESULTS: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes. CONCLUSION: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.
Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Background: Lung adenocarcinoma (LUAD) has a complex tumor heterogeneity. Our research attempts to clearness LUAD subtypes and build a reliable prognostic signature according to the activity changes of the hallmark and immunologic gene sets. Methods: According to The Cancer Genome Atlas (TCGA) - LUAD dataset, changes in marker and immune gene activity were analyzed, followed by identification of prognosis-related differential gene sets (DGSs) and their related LUAD subtypes. Survival analysis, correlation with clinical characteristics, and immune microenvironment assessment for subtypes were performed. Moreover, the differentially expressed genes (DEGs) between different subtypes were identified, followed by the construction of a prognostic risk score (RS) model and nomogram model. The tumor mutation burden (TMB) and tumor immune dysfunction and exclusion (TIDE) of different risk groups were compared. Results: Two LUAD subtypes were determined according to the activity changes of the hallmark and immunologic gene sets. Cluster 2 had worse prognosis, more advanced tumor and clinical stages than cluster 1. Moreover, a prognostic RS signature was established using two LUAD subtype-related DEGs, which could stratify patients at different risk levels. Nomogram model incorporated RS and clinical stage exerted good prognostic performance in LUAD patients. A shorter survival time and higher TMB were observed in the high-risk patients. Conclusions: Our findings revealed that our constructed prognostic signature could exactly predict the survival status of LUAD cases, which was helpful in predicting the prognosis and guiding personalized therapeutic strategies for LUAD.
Myeloid-derived suppressor cells (MDSC) are a population of heterogeneous immune cells that are involved in precancerous conditions and neoplasms. The autonomic nervous system (ANS), which is composed of the sympathetic nervous system and the parasympathetic nervous system, is an important component of the tumor microenvironment that responds to changes in the internal and external environment mainly through adrenergic and cholinergic signaling. An abnormal increase of autonomic nerve density has been associated with cancer progression. As we discuss in this review, growing evidence indicates that sympathetic and parasympathetic signals directly affect the expansion, mobilization, and redistribution of MDSCs. Dysregulated autonomic signaling recruits MDSCs to form an immunosuppressive microenvironment in chronically inflamed tissues, resulting in abnormal proliferation and differentiation of adult stem cells. The two components of the ANS may also be responsible for the seemingly contradictory behaviors of MDSCs. Elucidating the underlying mechanisms has the potential to provide more insights into the complex roles of MDSCs in tumor development and lay the foundation for the development of novel MDSC-targeted anticancer strategies.
Reversible adhesives are widely needed in our daily lives and industrial applications. However, robust and switchable adhesion on rough surfaces with on-demand attachment and detachment remains highly challenging. Here, we report a snail-mucus-inspired touch-responsive hydrogel (TRH), whose universal and robust adhesion is triggered by simple contact with the attaching surface. TRH is composed of a polymeric hydrogel and saturated sodium acetate (NaAc) and is prepared by one-pot synthesis. At room temperature, TRH remains in an amorphous and soft state, which allows it to conformally adapt to rough surfaces. The contact with the target surface triggers the crystallization of NaAc, which increases the modulus of TRH by an order of magnitude and interlocks with the target surfaces, achieving an adhesion of up to 204.84 ± 53.98 kPa. Upon heating, TRH returns to a soft state, facilitating easy detachment with adhesion of 5.12 ± 1.34 kPa. Meanwhile, the detached TRH is ready for the next adhesion without the need to be maintained at high temperature. TRH finds applications as a smart material for light-triggered adhesion switching, information encryption, and temperature sensors.
Background: The pathological examination of lymph node metastasis (LNM) is crucial for treating prostate cancer (PCa). However, the limitations with naked-eye detection and pathologist workload contribute to a high missed-diagnosis rate for nodal micrometastasis. We aimed to develop an artificial intelligence (AI)-based, time-efficient, and high-precision PCa LNM detector (ProCaLNMD) and evaluate its clinical application value. Methods: In this multicentre, retrospective, diagnostic study, consecutive patients with PCa who underwent radical prostatectomy and pelvic lymph node dissection at five centres between Sep 2, 2013 and Apr 28, 2023 were included, and histopathological slides of resected lymph nodes were collected and digitised as whole-slide images for model development and validation. ProCaLNMD was trained at a dataset from a single centre (the Sun Yat-sen Memorial Hospital of Sun Yat-sen University [SYSMH]), and externally validated in the other four centres. A bladder cancer dataset from SYSMH was used to further validate ProCaLNMD, and an additional validation (human-AI comparison and collaboration study) containing consecutive patients with PCa from SYSMH was implemented to evaluate the application value of integrating ProCaLNMD into the clinical workflow. The primary endpoint was the area under the receiver operating characteristic curve (AUROC) of ProCaLNMD. In addition, the performance measures for pathologists with ProCaLNMD assistance was also assessed. Findings: In total, 8225 slides from 1297 patients with PCa were collected and digitised. Overall, 8158 slides (18,761 lymph nodes) from 1297 patients with PCa (median age 68 years [interquartile range 64-73]; 331 [26%] with LNM) were used to train and validate ProCaLNMD. The AUROC of ProCaLNMD ranged from 0.975 (95% confidence interval 0.953-0.998) to 0.992 (0.982-1.000) in the training and validation datasets, with sensitivities > 0.955 and specificities > 0.921. ProCaLNMD also demonstrated an AUROC of 0.979 in the cross-cancer dataset. ProCaLNMD use triggered true reclassification in 43 (4.3%) slides in which micrometastatic tumour regions were initially missed by pathologists, thereby correcting 28 (8.5%) missed-diagnosed cases of previous routine pathological reports. In the human-AI comparison and collaboration study, the sensitivity of ProCaLNMD (0.983 [0.908-1.000]) surpassed that of two junior pathologists (0.862 [0.746-0.939], P = 0.023; 0.879 [0.767-0.950], P = 0.041) by 10-12% and showed no difference to that of two senior pathologists (both 0.983 [0.908-1.000], both P > 0.99). Furthermore, ProCaLNMD significantly boosted the diagnostic sensitivity of two junior pathologists (both P = 0.041) to the level of senior pathologists (both P > 0.99), and substantially reduced the four pathologists' slide reviewing time (-31%, P < 0.0001; -34%, P < 0.0001; -29%, P < 0.0001; and -27%, P = 0.00031). Interpretation: ProCaLNMD demonstrated high diagnostic capabilities for identifying LNM in prostate cancer, reducing the likelihood of missed diagnoses by pathologists and decreasing the slide reviewing time, highlighting its potential for clinical application. Funding: National Natural Science Foundation of China, the Science and Technology Planning Project of Guangdong Province, the National Key Research and Development Programme of China, the Guangdong Provincial Clinical Research Centre for Urological Diseases, and the Science and Technology Projects in Guangzhou.
In Asia, some herbal preparations have been found to be adulterated with undeclared synthetic medicines to increase their therapeutic efficiency. Many of these adulterants were found to be toxic when overdosed and have been documented to bring about severe, even life-threatening acute poisoning events. The objective of this study is to develop a rapid and sensitive ambient ionization mass spectrometric platform to characterize the undeclared toxic adulterated ingredients in herbal preparations. Several common adulterants were spiked into different herbal preparations and human sera to simulate the clinical conditions of acute poisoning. They were then sampled with a metallic probe and analyzed by the thermal desorption-electrospray ionization mass spectrometry. The experimental parameters including sensitivity, specificity, accuracy, and turnaround time were prudently optimized in this study. Since tedious and time-consuming pretreatment of the sample is unnecessary, the toxic adulterants could be characterized within 60 s. The results can help emergency physicians to make clinical judgments and prescribe appropriate antidotes or supportive treatment in a time-sensitive manner.
Drug Contamination , Plant Preparations , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Electrospray Ionization/methods , Humans , Plant Preparations/analysis , Plant Preparations/chemistry , Emergency Medical Services/methods
Macrofungi, a class of unique natural resources, are gaining popularity owing to their potential therapeutic benefits and edibility. From Fomitopsis officinalis, a medicinal macrofungus with anticancer activity, a homogeneous heteropolysaccharide (FOBP50-1) with a molecular weight of 2.21â¯×â¯104â¯g/mol has been extracted and purified. FOBP50-1 was found to be composed of 3-O-methylfucose, fucose, mannose, glucose, and galactose with a ratio of 1: 6.5: 4.4: 8.1: 18.2. The sugar fragments and structure of FOBP50-1 were investigated, which included â6)-α-d-Galp-(1â, â2,6)-α-d-Galp-(1â, â3)-α-l-Fucp-(1â, α-d-Glcp-(1â, â3)-ß-d-Manp-(1â, â6)-ß-d-Manp-(1â, 3-O-Me-α-l-Fucp-(1â, according to the UV, FT-IR, GC-MS, and NMR data. Besides the structure elucidation, FOBP50-1 showed promising antitumor activity in the zebrafish assays. The following mechanism examination discovered that FOBP50-1 interacted with TLR-4, PD-1, and VEGF to activate immunity and inhibit angiogenesis according to a series of cell, transgenic zebrafish, and surface plasmon resonance (SPR) experiments. The KD values indicating the association of FOBP50-1 with TLR-4, PD-1, and VEGF, were 4.69â¯×â¯10-5, 7.98â¯×â¯10-6, 3.04â¯×â¯10-6â¯M, respectively, in the SPR experiments. All investigations have demonstrated that the homogenous fungal polysaccharide FOBP50-1 has the potential to be turned into a tumor immunotherapy agent.
Angiogenesis Inhibitors , Antineoplastic Agents , Fungal Polysaccharides , Zebrafish , Fungal Polysaccharides/chemistry , Fungal Polysaccharides/pharmacology , Fungal Polysaccharides/isolation & purification , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/isolation & purification , Humans , Coriolaceae/chemistry , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor A/metabolism , Mice , Angiogenesis
BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.
PURPOSE: Chemoresistance is a major challenge for acute lymphoblastic leukemia (ALL) treatment. Cysteine-rich protein 61 (Cyr61) plays an important role in drug resistance modulation of tumor cells, and Cyr61 levels are increased in the bone marrow of patients with ALL and contribute to ALL cell survival. However, the effect of Cyr61 on B cell acute lymphoblastic leukemia (B-ALL) cell chemosensitivity and the regulatory mechanisms underlying Cyr61 production in bone marrow remain unknown. METHODS: Nalm-6 and Reh human B-ALL cell lines were used in this study. Cyr61 levels were assessed using quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The effect of Cyr61 on B-ALL cell chemosensitivity to daunorubicin (DNR) was evaluated using cell viability and flow cytometry analyses. The regulatory mechanisms of Cyr61 production in bone marrow were examined using qRT-PCR and western blot analysis. RESULTS: Cyr61 knockdown and overexpression increased and decreased the chemosensitivity of B-ALL cells to DNR, respectively. Cyr61 attenuated chemotherapeutic drug-induced apoptosis by upregulating B cell lymphoma-2. Notably, DNR induced DNA damage response and increased Cyr61 secretion in B-ALL cells through the ataxia telangiectasia mutated (ATM)-dependent nuclear factor kappa B pathway. CONCLUSION: DNR induces Cyr61 production in B-ALL cells, and increased Cyr61 levels reduce the chemosensitivity of B-ALL cells. Consequently, targeting Cyr61 or related ATM signaling pathway may present a promising treatment strategy to enhance the chemosensitivity of patients with B-ALL.
Cysteine-Rich Protein 61 , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Cysteine-Rich Protein 61/genetics , Cysteine-Rich Protein 61/metabolism , Cell Line, Tumor , Signal Transduction , NF-kappa B/metabolism
Human endogenous retrovirus sequences (HERVs) constitute up to 8% of the human genome, yet not all HERVs remain silent passengers within our genomes. Some HERVs, especially the HERV type K (HERV-K), have been found to be frequently transactivated in a variety of inflammatory diseases and human cancers. Np9, a 9-kDa HERV-K encoded protein, has been reported as an oncoprotein and found present in a variety of tumors and transformed cells. In the current study, we for the first time reported that ectopic expression of Np9 protein was able to induce DNA damage response from host cells especially through upregulation of γH2AX. Furthermore, we found that direct knockdown of Np9 by RNAi in Kaposi's Sarcoma-associated herpesvirus (KSHV) infected cells effectively reduced LANA expression, the viral major latent oncoprotein in vitro and in vivo, which may represent a novel strategy against virus-associated malignancies.
Endogenous Retroviruses , Herpesvirus 8, Human , Neoplasms , Humans , Endogenous Retroviruses/genetics , Herpesvirus 8, Human/physiology , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , DNA Repair
The conserved MRE11-RAD50-NBS1/Xrs2 complex is crucial for DNA break metabolism and genome maintenance. Although hypomorphic Rad50 mutation mice showed normal meiosis, both null and hypomorphic rad50 mutation yeast displayed impaired meiosis recombination. However, the in vivo function of Rad50 in mammalian germ cells, particularly its in vivo role in the resection of meiotic double strand break (DSB) ends at the molecular level remains elusive. Here, we have established germ cell-specific Rad50 knockout mouse models to determine the role of Rad50 in mitosis and meiosis of mammalian germ cells. We find that Rad50-deficient spermatocytes exhibit defective meiotic recombination and abnormal synapsis. Mechanistically, using END-seq, we demonstrate reduced DSB formation and abnormal DSB end resection occurs in mutant spermatocytes. We further identify that deletion of Rad50 in gonocytes leads to complete loss of spermatogonial stem cells due to genotoxic stress. Taken together, our results reveal the essential role of Rad50 in mammalian germ cell meiosis and mitosis, and provide in vivo views of RAD50 function in meiotic DSB formation and end resection at the molecular level.
DNA Breaks, Double-Stranded , Animals , Male , Mice , DNA Repair/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endodeoxyribonucleases/genetics , Endodeoxyribonucleases/metabolism , Loss of Function Mutation , Mammals/metabolism , Meiosis/genetics , Mutation , Spermatocytes/metabolism , Germ Cells/metabolism , Acid Anhydride Hydrolases/genetics , Acid Anhydride Hydrolases/metabolism
Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.
Berberine Alkaloids , Bone Resorption , Osteoporosis , Female , Humans , Osteogenesis , NF-kappa B/genetics , NF-kappa B/metabolism , Reactive Oxygen Species/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Signal Transduction , Osteoclasts , Bone Resorption/drug therapy , Bone Resorption/genetics , Bone Resorption/metabolism , Osteoporosis/drug therapy , Osteoporosis/genetics , Osteoporosis/metabolism , RANK Ligand/genetics , RANK Ligand/metabolism , Cell Differentiation
Perfluorinated compounds (PFCs) are persistent organic contaminants that are highly toxic to the environment and bioaccumulate, but their ecotoxic effects on aquatic plants remain unclear. In this study, the submerged plant Vallisneria natans was treated with short-term (7 days) and long-term (21 days) exposures to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) at concentrations of 0, 0.01, 0.1, 1.0, 5.0, and 10 mg/L, respectively. The results showed that both high concentrations of PFOA and PFOS inhibited the growth of V. natans and triggered the increase in photosynthetic pigment content in leaves. The oxidative damage occurred mainly in leaves, but both leaves and roots gradually built up tolerance during the stress process without serious membrane damage. Both leaves and roots replied to short-term stress by activating superoxide dismutase (SOD), catalase (CAT) and polyphenol oxidase (PPO), while peroxidase (POD) was involved under high concentration stress with increasing exposure time. Leaves showed a dose-effect relationship in integrated biomarker response (IBR) values under short-term exposure, and the sensitivity of roots and leaves to PFOS was higher than that of PFOA. Our findings help to increase knowledge of the toxic effects of PFCs and have important reference value for risk assessment and environmental remediation of PFCs in the aquatic ecosystem.
Alkanesulfonic Acids , Caprylates , Fluorocarbons , Water Pollutants, Chemical , Fluorocarbons/toxicity , Alkanesulfonic Acids/toxicity , Caprylates/toxicity , Water Pollutants, Chemical/toxicity , Hydrocharitaceae/drug effects , Plant Leaves/drug effects
DNA methylation is an important part of the genomic biology, which recently allowed the identification of key biomarkers for a variety of cancers, including cutaneous melanoma. Despite the current knowledge in cutaneous melanoma, there is a clear need for new efficient biomarkers in clinical application of detection. We use The Cancer Genome Atlas data as a training set and a multi-stage screening strategy to identify prognostic characteristics of melanoma based on DNA methylation. Three DNA methylation CpG sites were identified to be related to the overall survival in the skin cutaneous melanoma cohort. This signature was validated in two independent datasets from Gene Expression Omnibus. The stratified analysis by clinical stage, age, gender, and grade retained the statistical significance. The methylation signature was significantly correlated with immune cells and anti-tumor immune response. Moreover, gene expression corresponding to the candidate CpG locus was also significantly correlated with the survival rate of the patient. About 49% of the prognostic effects of methylation are mediated by affecting the expression of the corresponding genes. The prognostic characteristics of DNA methylation combined with clinical information provide a better prediction value tool for melanoma patients than the clinical information alone. However, more experiments are required to validate these findings. Overall, this signature presents a prospect of novel and wide-ranging applications for appropriate clinical adjuvant trails.
Melanoma , Skin Neoplasms , Humans , Melanoma/diagnosis , Melanoma/genetics , Prognosis , Skin Neoplasms/genetics , Biomarkers , Gene Expression
Hyperuricemia (HUA) is a metabolic syndrome caused by abnormal purine metabolism. Although recent studies have noted a relationship between the gut microbiota and gout, whether the microbiota could ameliorate HUA-associated systemic purine metabolism remains unclear. In this study, we constructed a novel model of HUA in geese and investigated the mechanism by which Lactobacillus rhamnosus GG (LGG) could have beneficial effects on HUA. The administration of antibiotics and fecal microbiota transplantation (FMT) experiments were used in this HUA goose model. The effects of LGG and its metabolites on HUA were evaluated in vivo and in vitro. Heterogeneous expression and gene knockout of LGG revealed the mechanism of LGG. Multi-omics analysis revealed that the Lactobacillus genus is associated with changes in purine metabolism in HUA. This study showed that LGG and its metabolites could alleviate HUA through the gut-liver-kidney axis. Whole-genome analysis, heterogeneous expression, and gene knockout of LGG enzymes ABC-type multidrug transport system (ABCT), inosine-uridine nucleoside N-ribohydrolase (iunH), and xanthine permease (pbuX) demonstrated the function of nucleoside degradation in LGG. Multi-omics and a correlation analysis in HUA patients and this goose model revealed that a serum proline deficiency, as well as changes in Collinsella and Lactobacillus, may be associated with the occurrence of HUA. Our findings demonstrated the potential of a goose model of diet-induced HUA, and LGG and proline could be promising therapies for HUA.
Hyperuricemia , Lacticaseibacillus rhamnosus , Humans , Hyperuricemia/therapy , Nucleosides , Lactobacillus , Proline , Purines
PURPOSE: To assess the predictive value of an ultrasound-based radiomics-clinical nomogram for grading residual cancer burden (RCB) in breast cancer patients. METHODS: This retrospective study of breast cancer patients who underwent neoadjuvant therapy (NAC) and ultrasound scanning between November 2020 and July 2023. First, a radiomics model was established based on ultrasound images. Subsequently, multivariate LR (logistic regression) analysis incorporating both radiomic scores and clinical factors was performed to construct a nomogram. Finally, Receiver operating characteristics (ROC) curve analysis and decision curve analysis (DCA) were employed to evaluate and validate the diagnostic accuracy and effectiveness of the nomogram. RESULTS: A total of 1122 patients were included in this study. Among them, 427 patients exhibited a favorable response to NAC chemotherapy, while 695 patients demonstrated a poor response to NAC therapy. The radiomics model achieved an AUC value of 0.84 in the training cohort and 0.83 in the validation cohort. The ultrasound-based radiomics-clinical nomogram achieved an AUC value of 0.90 in the training cohort and 0.91 in the validation cohort. CONCLUSIONS: Ultrasound-based radiomics-clinical nomogram can accurately predict the effectiveness of NAC therapy by predicting RCB grading in breast cancer patients.
