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Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.
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Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.
Subject(s)
DNA Methylation , Paired Box Transcription Factors , SOXB1 Transcription Factors , Uterine Cervical Dysplasia , Uterine Cervical Neoplasms , Humans , Female , Paired Box Transcription Factors/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/virology , SOXB1 Transcription Factors/genetics , Adult , Middle Aged , Sensitivity and Specificity , Young AdultABSTRACT
Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).
Subject(s)
Anti-HIV Agents , HIV-1 , vif Gene Products, Human Immunodeficiency Virus , HIV-1/drug effects , vif Gene Products, Human Immunodeficiency Virus/antagonists & inhibitors , vif Gene Products, Human Immunodeficiency Virus/metabolism , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Humans , Structure-Activity Relationship , Molecular Structure , Benzamides/pharmacology , Benzamides/chemistry , Benzamides/chemical synthesis , Drug Discovery , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Proteolysis/drug effects , Molecular Dynamics SimulationABSTRACT
Introduction: The sowing date plays a crucial role in influencing the growth and reproduction of plants, with its specific impact on biomass allocation and allometric growth remaining unclear. Understanding these effects is essential for optimizing agricultural practices and enhancing crop productivity. Methods: To investigate the effects of sowing dates on biomass allocation and allometric growth, a field experiment was conducted with sequential sowings of Fagopyrum esculentum from April 12th to August 11th in 2018. Biomass measurements were taken across various plant organs, and corresponding allocation calculations were made. A detailed analysis of the allometric growth relationship involving organ biomass variations was performed. Results: The study revealed that the accumulation and allocation of organ biomass in buckwheat were significantly impacted by the sowing dates. Delayed planting led to reduced vegetative growth and increased biomass allocation towards reproduction. Allometric parameters such as exponent, constant, and individual size of buckwheat were notably affected by delayed planting. Interestingly, the allometric exponents governing the relationships between reproductive vs. vegetative biomass and belowground vs. aboveground biomass exhibited varying trends across different sowing dates. Discussion: Notably, late sowings resulted in significantly higher reproductive biomass compared to early and middle sowings. These findings highlight the nuanced relationship between plant size and reproductive biomass under different sowing dates, emphasizing the critical role of planting timing in shaping mature plant sizes and reproductive outcomes. The study underscores the importance of considering sowing dates in agricultural practices to optimize plant growth and productivity.
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The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.
Subject(s)
Antineoplastic Agents , B7-H1 Antigen , Breast Neoplasms , Proteolysis , Proteolysis/drug effects , Animals , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , Humans , Mice , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Mice, Inbred BALB C , Cell Proliferation/drug effects , Drug Discovery , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/chemistry , Immune Checkpoint Inhibitors/chemical synthesis , Acetamides , PyridinesABSTRACT
Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.
Subject(s)
Anaplastic Lymphoma Kinase , Polyethylene Glycols , Proteolysis , Animals , Humans , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/metabolism , Proteolysis/drug effects , Mice , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Biological Availability , Xenograft Model Antitumor Assays , Micelles , Mice, NudeABSTRACT
PURPOSE: With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can't receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear. METHODS: The alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT-PCR. RESULTS: We found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8+ T cells and the level of IFN-γ, granzyme B in vivo. CONCLUSION: Our findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.
Subject(s)
B7-H1 Antigen , Indazoles , Piperidines , Uterine Cervical Neoplasms , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/pathology , Female , Humans , Animals , Piperidines/pharmacology , Piperidines/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Indazoles/pharmacology , Indazoles/therapeutic use , Mice , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Cell Line, TumorABSTRACT
Yam (Dioscorea) is a tuber crop cultivated for food security, revenue, and medicinal purposes. It has been used to treat diabetes, asthma, diarrhea, and other diseases. The main active ingredients in yam, polysaccharides, are regarded to be the important reason for its widespread applications. Now, a comprehensive review of research developments of yam polysaccharides (YPs) was presented to explore their prospects. We outlined the structural characteristics, biological activities, structure-activity relationships, and potential applications. Around 13 neutral components and 17 acidic components were separated. They exhibited various bioactivities, including immunomodulatory, hypoglycemic, hypolipidemic, antioxidant, gastrointestinal protective, anti-fatigue, and senile disease treatment activities, as well as prebiotic effect. Structure-activity relationships illustrated that unique structural properties, chemical modifications, and carried biopolymers could influence the bioactivities of YPs. The potential applications in medicine, food, and other fields have also been summarized.
Subject(s)
Dioscorea , Dioscorea/chemistry , Polysaccharides/pharmacology , Polysaccharides/chemistry , Hypoglycemic AgentsABSTRACT
Enhancing the performance of layered nickel-cobalt double hydroxides (NiCo-LDH) as electrode materials for supercapacitors represents a promising strategy for optimizing energy storage systems. However, the complexity of the preparation method for electrode materials with enhanced electrochemical performance and the inherent defects of nickel-cobalt LDH remain formidable challenges. In this study, we synthesized acetate-ion-intercalated NiCo-LDH (NCLA) through a simple one-step hydrothermal method. The physical and chemical structural properties and supercapacitor characteristics of the as-prepared NCLA were systematically characterized. The results indicated that the introduction of Ac- engendered a distinctive tetragonal crystal structure in NiCo-LDH, concomitant with a reduced interlayer spacing, thus enhancing structural stability. Electrochemical measurements revealed that NCLA-8 exhibited a specific capacitance of 1032.2 F g-1 at a current density of 1 A g-1 and a high specific capacitance of 922 F g-1 at 10 A g-1, demonstrating a rate performance of 89.3%. Furthermore, NCLA-8 was used to construct the positive electrode of an asymmetric supercapacitor, while the negative electrode was composed of activated carbon. This configuration resulted in an energy density of 67.7 Wh kg-1 at a power density of 800 W kg-1. Remarkably, the asymmetric supercapacitor retained 82.8% of its initial capacitance following 3000 charge-discharge cycles at a current density of 10 A g-1. Thus, this study demonstrates the efficacy of acetate-ion intercalation in enhancing the electrochemical performance of NiCo-LDH, establishing it as a viable electrode material for supercapacitors.
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Genetically modified (GM) maize is one of the earliest GM crops to have achieved large-scale commercial cultivation globally, and it is of great significance to excel in the development and implementation of safety policy regarding GM, and in its technical oversight. This article describes the general situation regarding genetically modified maize, including its varieties, applications, relevant laws and regulations, and so on. From a technical point of view, we summarize and critically analyze the existing methods for detecting nucleic acid levels in genetically modified maize. The nucleic acid extraction technology used for maize is explained, and the introduction of traditional detection techniques, which cover variable-temperature and isothermal amplification detection technology and gene chip technology, applications in maize are described. Moreover, new technologies are proposed, with special attention paid to nucleic acid detection methods using sensors. Finally, we review the current limitations and challenges of GM maize nucleic acid testing and share our vision for the future direction of this field.
Subject(s)
Nucleic Acid Amplification Techniques , Zea mays , Plants, Genetically Modified/genetics , Zea mays/genetics , Nucleic Acid Amplification Techniques/methods , Crops, Agricultural/genetics , TechnologyABSTRACT
Purpose: Non-small-cell lung cancer (NSCLC) is a major public health concern with a high incidence worldwide. Coal-derived fulvic acids (FAs) contain functional groups in their chemical structures. Overexpression of cyclooxygenases-2 (COX-2), prostaglandin E2 (PGE2), and the PGE2 receptor EP4 subtype (EP4) can have a potential link with the increased tumor incidence and promoted tumor growth and metastasis in NSCLC. This study aimed to assess the biological roles of coal-derived FAs in the growth and development of NSCLC and to elucidate the underlying molecular mechanisms. Methods: A web-based tool for predicting small-molecule pharmacokinetics (pkCSM) was used to analyze the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of FAs. Molecular docking and dynamic simulations were performed to analyze the binding affinities of COX-2 and EP4 to FA. An acute toxicity test and an antitumor study were used to analyze the toxicity and anti-NSCLC effects of FAs. Thirty NSCLC-bearing nude mice were randomly divided into five groups (six mice per group): vehicle control, positive control with 20 mg/kg body weight (BW) 5-fluorouracil, and three treatments with 25, 50, and 100 mg/kg BW FAs. The BW and tumor volume were recorded, and the COX-2, PGE2, and EP4 protein expression were measured and analyzed. Results: Using the predictive pkCSM algorithm, we found that FA did not cause developmental toxicity. Molecular simulations revealed that COX-2 and EP4 expression was inhibited by FA. An acute toxicity test conformed that the maximum tolerated FAs dose was >3.0 g/kg BW. The animal study demonstrated that FA treatment significantly downregulated the expression of COX-2, PGE2, and EP4 in NSCLC-bearing mice compared to that in vehicle control mice (p < 0.01). Conclusions: Natural FAs may exert anti-NSCLC effects through the COX-2/PGE2/EP4 axis.
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Colon adenocarcinoma (COAD) is one of the most common carcinomas worldwide. The main causes of cancer-related mortality of COAD are metastases. The fundamental processes for how angiogenesis and neutrophil extracellular traps (NETs) contributing to tumor progression and metastasis are still uncertain. In our study, The Cancer Genome Atlas (TCGA)-COAD dataset (train set) and GSE17536 (test set) were analyzed. Angiogenesis potential index (API) and NETs potential index (NPI) based on angiogenesis and NETs-related genes were respectively built using bioinformatic methods and machine learning algorithms. Subjects were split into groups with low API/NPI or high API/NPI. Survival analysis showed the high API and high NPI patients with the worst survival compared with the others. Between the high API/NPI group and the other groups, differentially expressed genes (DEGs) were found. A four-gene signature (TIMP1, FSL3, CALB2, and FABP4) was included in a risk model based on least absolute shrinkage and selection operator (LASSO) analysis. Additionally, the model displayed a significant association with many immune microenvironment characteristics. Finally, we verified the clinical significance of CALB2 expression and its role to promote the invasion and migration of colon cancer cells in vitro.
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Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/metabolism , Cell Proliferation , Cell Line, Tumor , Cell Cycle , Cell Division , Cyclin-Dependent Kinase 4ABSTRACT
Combination of different molecular target inhibitors is an available method to improve the therapeutic effect on tumors. Herein, to achieve both tumor cell targeting and ALK degradation & CDK4/6 inhibition in one molecule, we designed and synthesized a novel GSH responsive "Y-PROTACs", Y5-3, a highly potent molecule with an IC50 value of 90 nM against H3122 cells, which can be cleaved into ALK PROTAC and CDK4/6 inhibitor moieties in tumor cells. Mechanism studies revealed that Y5-3 exert anti-tumor proliferation activity in vitro not only by ALK degradation and CDK4/6 inhibition, but also by ALK/CDK4 dual degradation. These properties make Y5-3 a GSH responsive multifunctional antitumor agent, and our work provide a new strategy for the development of multifunctional PROTACs.
Subject(s)
Antineoplastic Agents , Neoplasms , Proteolysis Targeting Chimera , Anaplastic Lymphoma Kinase , Cell Proliferation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Proteolysis , Neoplasms/drug therapyABSTRACT
Purpose: The aim of this study is to evaluate whether concentrated growth factor (CGF) and photobiomodulation (PBMT) can show synergistic effect on bone healing process. Methods: In vivo osteogenesis studies were performed in a rabbit critical-sized calvarial defect model. Four 8 mm critical-sized bone defects were created on each rabbit calvarium, and these 4 defects were randomly divided into 4 groups: 1-control (defect filled with autologous blood clot); 2-CGF (defect filled with CGF); 3-LLLT (defect filled with autologous blood clot and received Nd:YAG low-level laser irradiation); 4-CGF + LLLT (defect filled with CGF and received LLLT). 15 Japanese big-ear white rabbits were operated on using the same procedure in this study. Then, 5 rabbits were selected randomly and sacrificed at 4th, 6th and 8th week postoperatively and respectively. The calvariums were harvested and scanned by micro-CT. The volumes of new bone formation of these defects were calculated by analyzing the micro-CT image. Data were analyzed as mean values of each group, comparisons were made for statistical analysis with the group and among the 4 groups using analysis of variance (ANOVA, P < 0.05). Results: At the 4th, 6th and 8th weeks, compared with the control group, the volume of new bone formed in each experimental group was significantly increased. Both CGF and LLLT can accelerate bone healing, but the effect of LLLT is better than that of CGF, and the difference between the two is statistically significant (P < 0.01). There was no statistically significant difference in the osteogenic effect between the combined application of CGF + LLLT and the application of CGF alone. And the osteogenic effect of the former two groups was weaker than that obtained by laser irradiation alone. Conclusions: Both CGF and LLLT can promote osteogenesis effectively, but the combination of the two did not show a synergistic effect. The pro-osteogenic effect of Nd:YAG low-level laser irradiation is superior to that of CGF, and also superior to the combined effect of the two.
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The simultaneous-source technology for high-density seismic acquisition is a key solution to efficient seismic surveying. It is a cost-effective method when blended subsurface responses are recorded within a short time interval using multiple seismic sources. A following deblending process, however, is needed to separate signals contributed by individual sources. Recent advances in deep learning and its data-driven approach toward feature engineering have led to many new applications for a variety of seismic processing problems. It is still a challenge, though, to collect enough labeled data and avoid model overfitting and poor generalization performance over different datasets with a low resemblance from each other. In this article, we propose a novel self-supervised learning method to solve the deblending problem without labeled training datasets. Using a blind-trace deep neural network and a carefully crafted blending loss function, we demonstrate that the individual source-response pairs can be accurately separated under three different blended-acquisition designs.
Subject(s)
Deep Learning , Neural Networks, Computer , Generalization, Psychological , Supervised Machine LearningABSTRACT
c-Myc is a transcription factor that is aberrantly expressed in the majority of human cancers. Recent studies unveiled that abnormal expression of c-Myc protein is involved in the development of colorectal cancer (CRC). Previously, we reported a novel phenoxy-N-phenylaniline derivative A-42 that can inhibit c-Myc protein and the growth of different CRC cancer cells potently. To look for a better candidate, the structure-activity relationship (SAR) of A ring, D ring and the linker between A and B rings of A-42 was investigated, and a series of compounds were synthesized. Among them, compound B13 was identified as the most active c-Myc inhibitor with cytotoxicity activity against HT29 and HCT116 cells at IC50 0.29 µM and IC50 0.64 µM, respectively, which is superior to that of A-42. According to the bioassays, compound B13 not only can suppress CRC cells proliferation and migration, but also inhibit the binding of c-Myc/Max dimer to DNA, which further interfere with the expression of the relevant proteins of apoptosis pathway. Furthermore, B13 could inhibit HT29 tumor growth in xenograft mouse models potently with tumor growth inhibitions (TGIs) up to 65.49% at dose of 40 mg/kg, which is superior to A-42 (55.82%, 40 mg/kg). Overall, B13 may potentially serve as an effective CRC therapy via blocking c-Myc/Max binding with DNA.
Subject(s)
Colorectal Neoplasms , Proto-Oncogene Proteins c-myc , Humans , Mice , Animals , Proto-Oncogene Proteins c-myc/genetics , Cell Proliferation , HCT116 Cells , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , DNA/pharmacology , Cell Line, TumorABSTRACT
PURPOSE: To evaluate the prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumor (iGCT), and to explore the risk factors of it. METHODS: iGCT patients visiting Peking Union Medical College Hospital between Jan 2008 to Oct 2020 were included. The prevalence of overweight/obesity and dyslipidemia was calculated. Mixed-effects models were used to evaluate the relationship between BMI z-scores, concentration of lipid profiles and potential risk factors. RESULTS: One hundred and six patients were included. The median follow-up time was 27 (IQR 5-59) months. The number of patients diagnosed with overweight/obesity and dyslipidemia were 49 (46.2%) and 86 (81.1%) during visits. Higher BMI z-scores were associated with treatment (mean difference (MD) 0.51, 95%CI 0.31-0.72), surgical biopsies (MD 0.71, 95%CI 0.16-1.25), adrenal insufficiency (MD 0.37, 95%CI 0.07-0.68), hypothyroidism (MD 0.35, 95%CI 0.06-0.63), glucocorticoid supplementation (MD 0.64, 95%CI 0.40-0.87), and thyroxine supplementation (MD 0.48, 95%CI 0.24-0.72). Hypothalamus involvement was associated with increased TC (MD 0.52, 95%CI 0.06-0.98), TG (MD 0.36, 95%CI 0.01-0.72), LDL-C (MD 0.60, 95%CI 0.20-0.98), and decreased HDL-C (MD - 0.23, 95%CI - 0.44 to - 0.02). Higher TC (MD 0.53, 95%CI 0.26-0.80) and LDL-C (MD 0.39, 95%CI 0.17-0.62) were observed in patients after treatment. Glucocorticoid supplementation was associated with increased TC (MD 0.70, 95%CI 0.38-1.03), LDL-C (MD 0.51, 95%CI 0.24-0.78), and HDL-C (MD 0.25, 95%CI 0.09-0.40), while sex hormone supplementation was associated with decreased TC (MD - 0.74, 95%CI - 1.2 to - 0.29) and TG (MD - 0.47, 95%CI - 0.86 to - 0.08). CONCLUSION: Overweight/obesity and dyslipidemia were high prevalent in iGCT patients and should be screened during follow-ups.
Subject(s)
Dyslipidemias , Neoplasms, Germ Cell and Embryonal , Humans , Overweight/epidemiology , Prevalence , Cholesterol, LDL , Glucocorticoids , Triglycerides , Dyslipidemias/epidemiology , Obesity/epidemiology , Neoplasms, Germ Cell and Embryonal/epidemiologyABSTRACT
Background: Fine particulate matter (PM2.5), one of the most common air pollutants worldwide, has been associated with many adverse birth outcomes in some studies. Pre-pregnancy body mass index (BMI) is an important indicator of maternal obesity that may also contribute to a wide range of birthweight outcomes. Both PM2.5 and maternal obesity have been found associated with issues on neonatal birthweight respectively, and more attentions and interests are focusing on their combined effect on pregnancy outcomes. Purpose: To explore the modifying effect of pre-pregnancy BMI on the association between gestational PM2.5 and birthweight; to investigate the interactive effect between gestational PM2.5 and pre-pregnancy BMI on birthweight among pregnant women during three trimesters and the whole pregnancy. Methods: This nationwide cohort study used the National Free Preconception Health Examination Project (NFPHEP) data collected from January 1, 2010, to December 31, 2012. A total population of 248,501 Chinese women from 220 counties registered this project. Pre-pregnancy BMI as a common anthropometric examination was collected during preconception investigation, and gestational PM2.5 was derived from a hindcast model for historical PM2.5 estimation from satellite-retrieved aerosol optic depth. Subgroup analysis was conducted to explore a potential modifying effect on the association between PM2.5 and birthweight during pregnancy by four pre-pregnancy BMI subgroups. Interaction analysis by introducing product terms to multivariable linear regression was also used to examine whether there was an interactive relationship between PM2.5 and pre-pregnancy BMI. Results: Totally, 193,461 participants were included in our study. The average concentration of PM2.5 was 75.33 µg/m3. Higher exposure of PM2.5 during the entire pregnancy was associated with higher birthweight (17.15 g per 10 µg/m3; 95% CI:16.15, 18.17). Each 10 µg/m3 increase in PM2.5 during the first, second, and third trimesters was associated with increases in birthweight by 14.93 g (95%CI: 13.96, 15.89), 13.75 g (95% CI: 12.81, 14.69), and 8.79 g (95% CI: 8.09, 9.49), respectively. Higher pre-pregnancy BMI per kg/m2 was associated with an increase of birthweight by 7.012 g (95% CI: 6.121, 7.902). Product terms between PM2.5 and pre-pregnancy BMI were significant for the first, second trimesters, and the entire duration of pregnancy. Conclusions: Our results found both gestational PM2.5 exposure and pre-pregnancy BMI respectively correlated with the increase of birthweight. A negative interaction between pre-pregnancy BMI and gestational PM2.5 was discovered in term of birthweight gain. Avoidance of high-dose exposure to PM2.5 during the early and middle stages of pregnancy and pre-pregnancy overweight/obesity may help prevent high birthweight.