ABSTRACT
Nonreceptor tyrosine phosphatases (NTPs) play an important role regulating protein phosphorylation and have been proposed as attractive therapeutic targets for cancer and metabolic diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine stimulation leading to increased reactivation of latent HIV and effector functions of NK and CD8 T cells. Here, we demonstrated that HODHBt interacts with and inhibits the NTPs PTPN1 and PTPN2 through a mixed inhibition mechanism. We also confirmed that PTPN1 and PTPN2 specifically control the phosphorylation of different STATs. The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.
ABSTRACT
Low accuracy of diagnosing prostate cancer (PCa) was easily caused by only assaying single prostate specific antigen (PSA) biomarker. Although conventional reported methods for simultaneous detection of two specific PCa biomarkers could improve the diagnostic efficiency and accuracy, low detection sensitivity restrained their use in extreme early-stage PCa clinical assay applications. In order to overcome above drawbacks, this paper herein proposed a multiplexed dual optical microfibers separately functionalized with gold nanorods (GNRs) and Au nanobipyramids (Au NBPs) nanointerfaces with strong localized surface plasmon resonance (LSPR) effects. The sensors could simultaneously detect PSA protein biomarker and long noncoding RNA prostate cancer antigen 3 (lncRNA PCA3) with ultrahigh sensitivity and remarkable specificity. Consequently, the proposed dual optical microfibers multiplexed biosensors could detect the PSA protein and lncRNA PCA3 with ultra-low limit-of-detections (LODs) of 3.97 × 10-15 mol/L and 1.56 × 10-14 mol/L in pure phosphorus buffer solution (PBS), respectively, in which the obtained LODs were three orders of magnitude lower than existed state-of-the-art PCa assay technologies. Additionally, the sensors could discriminate target components from complicated physiological environment, that showing noticeable biosensing specificity of the sensors. With good performances of the sensors, they could successfully assay PSA and lncRNA PCA3 in undiluted human serum and urine simultaneously, respectively. Consequently, our proposed multiplexed sensors could real-time high-sensitivity simultaneously detect complicated human samples, that providing a novel valuable approach for the high-accurate diagnosis of early-stage PCa individuals.
Subject(s)
Antigens, Neoplasm , Biosensing Techniques , Gold , Limit of Detection , Nanotubes , Prostate-Specific Antigen , Prostatic Neoplasms , RNA, Long Noncoding , Surface Plasmon Resonance , Humans , Prostate-Specific Antigen/blood , Male , Gold/chemistry , RNA, Long Noncoding/genetics , RNA, Long Noncoding/blood , RNA, Long Noncoding/urine , Antigens, Neoplasm/urine , Antigens, Neoplasm/blood , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/blood , Prostatic Neoplasms/urine , Nanotubes/chemistry , Metal Nanoparticles/chemistry , Biomarkers, Tumor/blood , Biomarkers, Tumor/urineABSTRACT
Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.
Subject(s)
Cholesterol , Ferroptosis , Neoplastic Stem Cells , Signal Transduction , Squalene Monooxygenase , Stearoyl-CoA Desaturase , Stomach Neoplasms , TOR Serine-Threonine Kinases , Ferroptosis/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stearoyl-CoA Desaturase/metabolism , Stearoyl-CoA Desaturase/genetics , TOR Serine-Threonine Kinases/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Humans , Squalene Monooxygenase/metabolism , Squalene Monooxygenase/genetics , Cholesterol/metabolism , Cell Line, Tumor , Animals , Mice , Gene Expression Regulation, NeoplasticABSTRACT
Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.
Subject(s)
Flavonoids , Gastrointestinal Neoplasms , Immunotherapy , Membrane Proteins , TRPV Cation Channels , Humans , TRPV Cation Channels/metabolism , TRPV Cation Channels/antagonists & inhibitors , Membrane Proteins/metabolism , Animals , Immunotherapy/methods , Cell Line, Tumor , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/immunology , Gastrointestinal Neoplasms/pathology , Flavonoids/pharmacology , Tumor Microenvironment/drug effects , Up-Regulation/drug effects , Signal Transduction/drug effects , Mice , Drug Synergism , Immune Checkpoint Inhibitors/pharmacology , Female , Mice, Inbred BALB C , DNA, Mitochondrial , Molecular Docking SimulationABSTRACT
It is an important thing to identify internal crack in seeds from normal seeds for evaluating the quality of rice seeds (Oryza sativa L.). In this study, non-destructive discrimination of internal crack in rice seeds using near infrared spectroscopy and chemometrics is proposed. Principal component analysis (PCA) was used to analyze the rice seeds spectra. Four supervised classification techniques(partial least squares discriminate analysis (PLS-DA), support vector machines (SVM), k-nearest neighbors (KNN) and random forest (RF)) with four different pre-processing techniques (standard normal variate (SNV), multiplicative scatter correction (MSC), first and second derivative with Savitzky-Golay (SG) smoothing) were applied. The best results (Sn = 0.8824, Sp = 0.9429, Acc = 0.913) were achieved by PLS-DA with the raw spectral data. The performance of the best SVM model was inferior to that of PLS-DA, but superior to that of RF and KNN. Except for PLS-DA, four different preprocessing techniques were improved the performance of the developed models. The important variables for discriminating internal cracks in rice seeds were related to the amylose. Overall, the all results demonstrated the feasibility of non-destructive discrimination of internal crack for rice seeds (Oryza sativa L.) using near infrared spectroscopy and chemometrics.
Subject(s)
Oryza , Principal Component Analysis , Seeds , Spectroscopy, Near-Infrared , Support Vector Machine , Oryza/chemistry , Spectroscopy, Near-Infrared/methods , Seeds/chemistry , Least-Squares Analysis , Discriminant AnalysisABSTRACT
Aerobic glycolysis accelerates tumor proliferation and progression, and inhibitors or drugs targeting abnormal cancer metabolism have been developing. Cancer stem-like cells (CSCs) significantly contribute to tumor initiation, metastasis, therapy resistance, and recurrence. Formyl peptide receptor 3 (FPR3), a member of FPR family, involves in inflammation, tissue repair, and angiogenesis. However, studies in exploring the regulatory mechanisms of aerobic glycolysis and CSCs by FPR3 in gastric cancer (GC) remain unknown. Here, we demonstrated that overexpressed FPR3 suppressed glycolytic capacity and stemness of tumor cells, then inhibited GC cells proliferation. Mechanistically, FPR3 impeded cytoplasmic calcium ion flux and hindered nuclear factor of activated T cells 1 (NFATc1) nuclear translocation, leading to the transcriptional inactivation of NFATc1-binding neurogenic locus notch homolog protein 3 (NOTCH3) promoter, subsequently obstructing NOTCH3 expression and the AKT/mTORC1 signaling pathway, and ultimately downregulating glycolysis. Additionally, NFATc1 directly binds to the sex determining region Y-box 2 (SOX2) promoter and modifies stemness in GC. In conclusion, our work illustrated that FPR3 played a negative role in GC progression by modulating NFATc1-mediated glycolysis and stemness in a calcium-dependent manner, providing potential insights into cancer therapy.
Subject(s)
Cell Proliferation , Glycolysis , Neoplastic Stem Cells , Signal Transduction , Stomach Neoplasms , Animals , Humans , Male , Mice , Calcium/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics , Receptor, Notch3/metabolism , Receptor, Notch3/genetics , Receptors, Formyl Peptide/metabolism , Receptors, Formyl Peptide/genetics , Receptors, Lipoxin/metabolism , Receptors, Lipoxin/genetics , SOXB1 Transcription Factors/metabolism , SOXB1 Transcription Factors/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Stomach Neoplasms/geneticsABSTRACT
Salmonella exhibits a strong inducible acid tolerance response (ATR) under weak acid conditions, and can also induce high-risk strains that are highly toxic, acid resistant, and osmotic pressure resistant to aquatic products. However, the induction mechanism is not yet clear. Therefore, this study aims to simulate the slightly acidic, low-temperature, and high-protein environment during squid processing and storage. Through λRed gene knockout, exploring the effects of low-acid induction, long-term low-temperature storage, and two-component regulation on Salmonella ATR. In this study, we found the two-component system, PhoP/PhoQ and PmrA/PmrB in Salmonella regulates the amino acid metabolism system and improves bacterial acid tolerance by controlling arginine and lysine. Compared with the two indicators of total biogenic amine and diamine content, biogenic amine index and quality index were more suitable for evaluating the quality of aquatic products. The result showed that low-temperature treatment could inhibit Salmonella-induced ATR, which further explained the ATR mechanism from the amino acid metabolism.
Subject(s)
Arginine , Diamines , Animals , Decapodiformes , Salmonella/genetics , Biogenic AminesABSTRACT
Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.
Subject(s)
Lactic Acid , Stomach Neoplasms , Animals , Mice , Humans , Lactic Acid/metabolism , Lactic Acid/pharmacology , T-Lymphocytes, Regulatory/metabolism , Chemokine CX3CL1 , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Tumor MicroenvironmentABSTRACT
Carbohydrate is one kind of the most important additives in the production of surimi and surimi products, mainly due to its wide range of sources and superior functionality. In recent years, new carbohydrates (oligosaccharides and polysaccharides) have been gradually applied in the production of surimi and surimi products which is mainly driven by consumer requirement on nutritional and the flavors or taste quality and producer requirement on extending the shelf life, like low calorie intake, dietary fiber enrichment, rich taste and improvement of antioxidant properties. Besides anti-freezing and improvement in gelling ability, novel functionalities have been explored such as fat substitution, improving flavor, antibacterial effect, antioxidant effect and improving three-dimensional printability. With an in-depth study of the mechanism of carbohydrate improving the qualities of surimi and surimi products, the application of carbohydrates in surimi would be more effective. Therefore, this review summarizes the new carbohydrates applied in the processing of surimi and surimi products, and their novel functionalities. Additionally, progress of the research on the mechanism of carbohydrate improving the qualities of surimi is also reviewed. © 2023 Society of Chemical Industry.
Subject(s)
Anti-Bacterial Agents , Antioxidants , Gels/chemistry , Carbohydrates , Fish Products/analysisABSTRACT
Circadian disruption is being increasingly recognized as a critical factor in the development and progression of Parkinson's disease (PD). This review aims to provide an in-depth overview of the relationship between circadian disruption and PD by exploring the molecular, cellular, and behavioral aspects of this interaction. This review will include a comprehensive understanding of how the clock gene system and transcription-translation feedback loops function and how they are diminished in PD. The article also discusses the role of clock genes in the regulation of circadian rhythms, as well as the impact of clock gene dysregulation on mitochondrial function, oxidative stress, and neuroinflammation, including the microbiota-gut-brain axis, which have all been proposed as being crucial mechanisms in the pathophysiology of PD. Finally, this review highlights potential therapeutic strategies targeting the clock gene system and circadian rhythm for the treatment of PD.
ABSTRACT
Carbohydrate is widely used in the production of surimi and surimi products to improve their qualities, such as anti-freezing capability, gelling ability, nutrition, flavor and 3D printability. More and more native carbohydrates have been modified through physical methods (e.g., ball milling, irradiation and differential sedimentation), chemical method (e.g., deacetylation, hydroxypropylation and acetic acid esterification) or enzymatic method (e.g., chitosanase) before being used in the processing of surimi and surimi products in recent years. At the same time, different carbohydrates are compounded and applied to surimi and surimi products. The modified and compounded carbohydrates in surimi have been proved to improve quality of surimi and surimi products more pronouncedly than native carbohydrates. Therefore, this review summarizes the manipulation of carbohydrate by modification and compounding to improve the qualities of surimi and surimi products. Moreover, the prospects for carbohydrate modification and compounding for use in surimi and surimi products are discussed. © 2023 Society of Chemical Industry.
Subject(s)
Carbohydrates , Fish Products , Gels , Fish Products/analysisABSTRACT
Background and purpose: Basilar-artery occlusion (BAO) usually accounts for devastating neurologic sequelae, poor prognosis, and even death. While endovascular thrombectomy (EVT) is the most successful treatment for anterior circulation stroke with large vessel occlusion, its effectiveness in treating acute BAO is still debatable. Our aim is to compare the efficacy and safety between EVT and conservative medical treatment (CMT) in BAO. Methods: Up until May 2022, relevant literature was gathered using searches in Embase, PubMed, and the Cochrane Library. The primary outcomes were defined as good functional outcome (modified Rankin Scale 0-2) and favorable functional outcome (modified Rankin Scale 0-3) at 3 months between EVT and CMT groups. The secondary outcomes included mortality at 3 months, symptomatic intracerebral hemorrhage (ICH), and any ICH. Results: Eight studies involving 3733 patients with BAO were enrolled 2573 individuals underwent EVT, and the remaining 1160 patients received CMT. Compared with CMT, EVT achieved more favorable functional outcome (odds ratio (OR) 1.26, 95% CI 1.03-1.55, I2 = 54%, p = 0.05) in BAO. The good functional outcome showed a similar tendency (OR 1.23, 95% CI 0.97-1.57, I2 = 63%, p = 0.02) as well. EVT decreased mortality at 3 months (OR 0.81, 95% CI 0.70-0.93, I2 = 31 %, p = 0.19), although having a tendency to cause symptomatic ICH (OR 2.91, 95% CI 1.38-6.18, I2 = 22 %, p = 0.27). Conclusions: EVT in BAO provides superior functional outcomes and less mortality compared with CMT. Even though EVT has the propensity to cause symptomatic ICH, EVT nevertheless improved posterior circulation stroke.
ABSTRACT
Background: Chorea is a movement disorder characterized by abrupt, rapid, and uncontrollable, random movements from one part of the body to another with motor impersistence. Sporadic chorea is rarely caused by either thyrotoxicosis or Moyamoya disease (MMD). Methods and results: In this case report, we describe a female patient with chorea with the rare coexistence of Graves' disease and Moyamoya disease. Tc-99m ethyl cysteinate dimer (ECD) brain perfusion single-photon emission computed tomography (SPECT) showed mild to moderate hypoperfusion in bilateral frontal and left temporal regions. After administering dexamethasone 20 mg for 5 days, her choreic movement symptoms recovered rapidly. Conclusion: Although uncommon, thyrotoxicosis and Moyamoya disease can co-occur, especially in Asian female adults. Excessive thyroid hormones contribute to the dysregulation of neurotransmitters in basal ganglia-thalamocortical circuits. Moyamoya disease is responsible for ischemic changes affecting the excitatory-inhibitory circuits between the basal ganglia and the neocortex. Under a state of coexistence, thyrotoxicosis exaggerates cerebral metabolism, aggravating the impaired cerebral perfusion induced by Moyamoya disease. Moreover, inflammatory reactions caused by thyroid autoantibodies may also promote the progression of Moyamoya disease. In our experience, treatment with steroids may not only synergize the anti-thyroid effect but may also be a way to modulate the neurotransmitters within the basal ganglia or restore cerebral perfusion. We suggest that evaluation of the thyroid function status in Moyamoya disease is essential.
ABSTRACT
Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.
Subject(s)
Membrane Proteins , Neoplasms , Humans , Membrane Proteins/metabolism , Immunity, Innate , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Neoplasms/therapy , DNA , Cell Membrane/metabolism , Immunotherapy/methodsABSTRACT
In the face of imminent predatory danger, animals quickly detect the threat and mobilize key survival defensive actions, such as escape and freezing. The dorsomedial portion of the ventromedial hypothalamus (VMH) is a central node in innate and conditioned predator-induced defensive behaviours. Prior studies have shown that activity of steroidogenic factor 1 (sf1)-expressing VMH cells is necessary for such defensive behaviours. However, sf1-VMH neural activity during exposure to predatory threats has not been well characterized. Here, we use single-cell recordings of calcium transients from VMH cells in male and female mice. We show this region is activated by threat proximity and that it encodes future occurrence of escape but not freezing. Our data also show that VMH cells encoded proximity of an innate predatory threat but not a fear-conditioned shock grid. Furthermore, chemogenetic activation of the VMH increases avoidance of innate threats, such as open spaces and a live predator. This manipulation also increased freezing towards the predator, without altering defensive behaviours induced by a shock grid. Lastly, we show that optogenetic VMH activation recruited a broad swath of regions, suggestive of widespread changes in neural defensive state. Taken together, these data reveal the neural dynamics of the VMH during predator exposure and further highlight its role as a critical component of the hypothalamic predator defense system.
Subject(s)
Fear , Hypothalamus , Male , Female , Mice , Animals , Hypothalamus/physiology , Fear/physiology , Ventromedial Hypothalamic NucleusABSTRACT
Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse models induces largely similar rates of proliferative mammary disease in prereproductive senescent mice. Herein, with natural reproductive senescence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer. Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence, Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes, including members of prognostic platforms for women with early-stage hormone receptor-positive disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression. This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted intrusions into estrogen signaling during reproductive senescence.
Subject(s)
Aromatase , Epithelial Cells , Estrogen Receptor alpha , Mammary Glands, Animal , Animals , Female , Mice , Pregnancy , Epithelial Cells/metabolism , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogens , Letrozole , Tamoxifen/pharmacology , Gene Expression , Mammary Glands, Animal/metabolism , Aromatase/genetics , Aromatase/metabolismABSTRACT
Age is a risk factor for human estrogen receptor-positive breast cancer, with highest prevalence following menopause. While transcriptome risk profiling is available for human breast cancers, it is not yet developed for prognostication for primary or secondary breast cancer development utilizing at-risk breast tissue. Both estrogen receptor α (ER) and aromatase overexpression have been linked to human breast cancer. Herein, conditional genetically engineered mouse models of estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) were used to show that induction of Esr1 overexpression just before or with reproductive senescence and maintained through age 30 months resulted in significantly higher prevalence of estrogen receptor-positive adenocarcinomas than CYP19A1 overexpression. All adenocarcinomas tested showed high percentages of ER+ cells. Mammary cancer development was preceded by a persistent proliferative transcriptome risk signature initiated within 1 week of transgene induction that showed parallels to the Prosigna/Prediction Analysis of Microarray 50 human prognostic signature for early-stage human ER+ breast cancer. CYP19A1 mice also developed ER+ mammary cancers, but histology was more divided between adenocarcinoma and adenosquamous, with one ER- adenocarcinoma. Results demonstrate that, like humans, generation of ER+ adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER+ mammary adenocarcinomas.
Subject(s)
Adenocarcinoma , Breast Neoplasms , Mammary Glands, Animal , Animals , Female , Mice , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Aging/genetics , Aging/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Gene Expression , Aromatase/genetics , Aromatase/metabolism , Reproduction/genetics , Reproduction/physiologyABSTRACT
Bacteria or viral outbreaks can cause tilapia hemorrhage, ensuring considerable volume of hemoglobin (Hb) into the tissue. However, the hemoglobin toxicity on tissue and high doses also effect on tissue this phenomena is still under consideration. Therefore, current study exploited Nile tilapia kidney (NTK) cells to deeply expose the toxic effect of Hb on NTK cells. Toxicity of Hb on NTK cells was determined in terms of cells growth, expression of iron metabolism and inflammation-related genes, consequently examined antioxidant-related enzymes genes expression, intracellular iron and reactive oxygen species (ROS) contents, and apoptosis-related genes expression. The results showed that Hb and heme significantly inhibited NTK cells growth and up-regulated iron metabolism-related genes expression in different degrees. The Hb and heme activated the expression of pro-inflammatory cytokines (TNF-α, tumor necrosis factor-α; IL-1ß, interleukin 1ß; IL-6, interleukin 6), the anti-inflammatory factor (IL-10, interleukin 10) and the chemotactic factors (IL-4, interleukin 4; IL-8, interleukin 8) through NF-κB pathway, meanwhile activated the expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Moreover, the Hb significantly increased intracellular iron and ROS contents while the expression of apoptosis-related genes was significantly activated by both Hb and heme. Current investigation suggested that high oxidative activity of Hb could activate iron metabolism- and inflammation-related genes expression, and increase intracellular iron and ROS levels, lead to up-regulated the expression of apoptosis genes in NTK cells.
Subject(s)
Cichlids , Animals , Reactive Oxygen Species/metabolism , Antioxidants/metabolism , Kidney/metabolism , Cell Line , Hemoglobins/metabolism , Inflammation/genetics , Inflammation/veterinary , Inflammation/metabolism , Iron/metabolism , Heme/metabolism , Heme/pharmacology , Oxidative Stress , Animal Feed/analysisABSTRACT
In this study, we aim to elucidate the association between nondiabetic hyperglycemia and the short-term prognosis of critically ill patients with acute ischemic stroke. We extracted data using the Medical Information Mart for Intensive Care IV from 2008 to 2019. The primary outcomes were set as intensive care units (ICU) and in-hospital mortality. We developed a Cox proportional hazards model to determine the nonlinear association between serum glucose levels and primary outcomes. Of the 1086 patients included, 236 patients had hyperglycemia. Patients with hyperglycemia were associated with higher ages, female gender, higher Charlson Comorbidity Index scores, and higher Acute Physiology Score III scores. After propensity score matching, 222 pairs remained. The hyperglycemia group had a significantly higher ICU mortality (17.6% vs. 10.8%; p = 0.041). Meanwhile, no significant differences in ICU length of stay (5.2 vs. 5.2; p = 0.910), in-hospital mortality (26.6% vs. 18.9%, p = 0.054), and hospital length of stay (10.0 vs. 9.1; p = 0.404) were observed between the two groups. The Kaplan-Meier curves for ICU and in-hospital survival before matching suggested significant differences; however, after matching, they failed to prove any disparity. Non-diabetic patients with acute ischemic stroke have poor clinical characteristic while encountering hyperglycemic events; therefore, careful monitoring in the acute phase is still required.
ABSTRACT
Mammographic density is associated with increased breast cancer risk. Conventional visual assessment of murine mouse models does not include quantified total density analysis. A bifurcated method was sufficient to obtain relative density scores on a broad range of two-dimensional whole mount images that contained both normal and abnormal findings. Image processing techniques, including a ridge operator and a gaussian denoising method, were used to isolate background away from mammary epithelium and use mean pixel intensity to represent mammary density on genetically engineered mouse models for breast cancer in mice 4 to 29 months of age. The bifurcated method allowed for application of an optimal image processing approach for the structural elements present in the whole mount images. Gaussian denoising was the optimal approach when more dense lobular growth and tertiary branching dominate and a ridge operator when epithelial growth was more sparse and secondary branching was the more dominant structural feature. The two processing approaches were combined in a single experimental flow program using an initial image density measurement as the decision point between the two approaches. Higher density was associated with lobular growth, tertiary branching, fibrotic stroma, and presence of cancer. The significance of the study is development of a readily accessible program for digital assessment of mammary gland whole mount density across a range of mammary gland morphologies.