ABSTRACT
Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.
ABSTRACT
Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.
ABSTRACT
Colorectal cancer (CRC) remains a major global cause of cancer-related mortality, lacking effective biomarkers and therapeutic targets. Revealing the critical pathogenic factors of CRC and the underlying mechanisms would offer potential therapeutic strategies for clinical application. G protein signaling (RGS) protein family modulators play essential role within regulating downstream signaling of GPCR receptors, with function in cancers unclear. Our study focused on the expression patterns of RGS proteins in CRC, identifying Regulator of G protein signaling 16 (RGS16) as a prospective diagnostic and therapeutic target. Analyzing 899 CRC tissues revealed elevated RGS16 levels, correlating with clinicopathological features and CRC prognosis by immunohistochemistry (IHC) combined with microarray. We confirmed the elevated RGS16 protein level in CRC, and found that patients with RGS16-high tumors exhibited decreased disease-specific survival (DSS) and disease-free survival (DFS) compared to those with low RGS16 expression. Functional assays demonstrated that RGS16 promoted the CRC progression, knockdown of RGS16 led to significantly increased apoptosis rates of CRC in vitro and in vivo. Notably, we also confirmed these phenotypes of RGS16 in organoids originated from resected primary human CRC tissues. Mechanistically, RGS16 restrained JNK/P38-mediated apoptosis in CRC cells through disrupting the recruitment of TAB2/TAK1 to TRAF6. This study provides insights into addressing the challenges posed by CRC, offering avenues for clinical translation.
Subject(s)
Apoptosis , Colorectal Neoplasms , MAP Kinase Kinase Kinases , RGS Proteins , Animals , Female , Humans , Male , Mice , Middle Aged , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Intracellular Signaling Peptides and Proteins , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/genetics , MAP Kinase Signaling System , Mice, Nude , p38 Mitogen-Activated Protein Kinases/metabolism , RGS Proteins/metabolism , RGS Proteins/genetics , Signal Transduction , TNF Receptor-Associated Factor 6/metabolism , TNF Receptor-Associated Factor 6/geneticsABSTRACT
A new triterpenoid saponin (1), along with five known compounds (2-6), was isolated from Bupleurum marginatum Wall. ex DC, of which compounds 2-4 were obtained for the first time from this plant. The structures were confirmed by the analysis of 1D, 2D NMR, and HR-ESIMS data, and comparison with previous spectral data. Anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of LPS-induced activation of HSC-T6 in vitro.
Subject(s)
Bupleurum , Saponins , Triterpenes , Saponins/pharmacology , Saponins/chemistry , Saponins/isolation & purification , Bupleurum/chemistry , Triterpenes/pharmacology , Triterpenes/chemistry , Triterpenes/isolation & purification , Molecular Structure , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/isolation & purification , Liver Cirrhosis/drug therapy , Lipopolysaccharides/pharmacology , Animals , Nuclear Magnetic Resonance, BiomolecularABSTRACT
BACKGROUND: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear. METHODS: The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed. RESULTS: APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P < 0.05). APOBEC2 expression status were associated with the infiltration of CD66b+ TANs, differentiation grade, TNM stage, histological type and gender (all P < 0.05) in STAD. Little or no APOBEC2 expression was detected in STAD and adjacent normal tissues by western blot. We failed to show that APOBEC2 was an independent risk factor for OS (Hazard Ratio 0.816, 95%CI 0.574-1.161, P = 0.259) or DFS (Hazard Ratio 0.821, 95%CI 0.578-1.166, P = 0.270) in STAD by multivariate Cox regression analysis, but APOBEC2 negative subgroup has a worse OS and DFS among patients with adjuvant chemotherapy. CONCLUSIONS: APOBEC2 correlates with CD66b, differentiation grade, TNM stages, histological classification, and gender in STAD. APOBEC2 is not an independent prognostic factor for STAD, our results suggest that patients with positive APOBEC2 can benefit from postoperative chemotherapy, and combination of APOBEC2 and CD66b is helpful to further stratify patients into different groups with distinct prognoses.
Subject(s)
APOBEC Deaminases , Adenocarcinoma , Stomach Neoplasms , Humans , Adenocarcinoma/pathology , APOBEC Deaminases/metabolism , Muscle Proteins , Neutrophils/pathology , Nucleotides/metabolism , Prognosis , Proportional Hazards Models , Stomach Neoplasms/metabolismABSTRACT
Six undescribed capnosane-type macrocyclic diterpenes sarcocrassolins A-F (1-6) and one related known analog pavidolide D (7) were isolated from Sarcophyton crassocaule, a soft coral collected off the Nansha Islands, in the South China Sea. Their complete structures, relative configurations and absolute configurations were established through comprehensive spectroscopic analysis, quantum mechanical nuclear magnetic resonance (QM-NMR) and single-crystal X-ray diffraction. Sarcocrassolins D (4) and E (5) showed inhibitory activity against lipopolysaccharide (LPS)-stimulated inflammatory responses in RAW264.7 cells with IC50 values of 76.8 ± 8.0 µM and 93.0 ± 3.8 µM, respectively.
Subject(s)
Anthozoa , Diterpenes , Animals , Magnetic Resonance Spectroscopy , Anthozoa/chemistry , Diterpenes/pharmacology , Diterpenes/chemistry , China , Lipopolysaccharides/pharmacology , Molecular StructureABSTRACT
FKBP10, a member of the FK506-binding protein (FKBP) family, has been implicated in cancer development, although its prognostic function remains controversial. In this study, we analyzed the expression of FKBP10 in tumor tissues using online databases (TCGA) as well as our CRC cohort, and investigated the relationship between its subcellular expression pattern and patient outcomes. Cox regression analysis was used to determine the associations between different subcellular expression patterns of FKBP10 and clinical features of patients. We also discussed the expression level of FKBP10 based on different subcellular expression patterns. Our results showed that FKBP10 was significantly elevated in CRC tissues and exhibited three different subcellular expression patterns which were defined as 'FKBP10-C' (concentrated), 'FKBP10-T' (transitional) and 'FKBP10-D' (dispersive). The FKBP10-D expression pattern was only found in tumor tissues and was associated with unfavorable disease-free survival in CRC patients. High expression levels of FKBP10-C predicted an unfavorable prognosis of recurrence of CRC, while FKBP10-D did not. Our findings suggest that the subcellular expression patterns and expression level of FKBP10 play crucial prognostic roles in CRC, which revealed that FKBP10 may be a viable prognostic and therapeutic target for the diagnosis and treatment of CRC.
Subject(s)
Colorectal Neoplasms , Peptidylprolyl Isomerase , Tacrolimus Binding Proteins , Humans , Clinical Relevance , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Peptidylprolyl Isomerase/metabolism , Tacrolimus Binding Proteins/genetics , Tacrolimus Binding Proteins/metabolismABSTRACT
Three new phenolic compounds, epicocconigrones C-D (1-2) and flavimycin C (3), together with six known phenolic compounds: epicocconigrone A (4); 2-(10-formyl-11,13-dihydroxy-12-methoxy-14-methyl)-6,7-dihydroxy-5-methyl-4-benzofurancarboxaldehyde (5); epicoccolide B (6); eleganketal A (7); 1,3-dihydro-5-methoxy-7-methylisobenzofuran (8); and 2,3,4-trihydroxy-6-(hydroxymethyl)-5-methylbenzyl-alcohol (9), were isolated from fermentation cultures of a deep-sea sediment-derived fungus, Aspergillus insulicola. Their planar structures were elucidated based on the 1D and 2D NMR spectra and HRESIMS data. The absolute configurations of compounds 1-3 were determined by ECD calculations. Compound 3 represented a rare fully symmetrical isobenzofuran dimer. All compounds were evaluated for their α-glucosidase inhibitory activity, and compounds 1, 4-7, and 9 exhibited more potent α-glucosidase inhibitory effect with IC50 values ranging from 17.04 to 292.47 µM than positive control acarbose with IC50 value of 822.97 µM, indicating that these phenolic compounds could be promising lead compounds of new hypoglycemic drugs.
Subject(s)
Glycoside Hydrolase Inhibitors , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/chemistry , alpha-Glucosidases/metabolism , Aspergillus/chemistry , Fungi/metabolism , Molecular StructureABSTRACT
Nine new azaphilones, including penicilazaphilones I-N (1, 2 and 6-9), epi-geumsanol D (3) and penidioxolanes C (4) and D (5) were isolated from the culture of the marine-derived fungus Penicillium sclerotiorum E23Y-1A. The structures of the isolates were deduced from extensive spectroscopic data (1D and 2D NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. All the azaphilones from P. sclerotiorum E23Y-1A were tested for their anti-inflammatory and antitumor activities. Penicilazaphilone N (9) showed moderate anti-inflammatory activity with an IC50 value of 22.63 ± 2.95 µM, whereas penidioxolane C (4) exhibited moderate inhibition against human myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549), and human hela cervical cancer cells, with IC50 values of 23.94 ± 0.11, 60.66 ± 0.13, 46.17 ± 0.17, 60.16 ± 0.26, and 59.30 ± 0.60 µM, respectively.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Penicillium , Humans , Penicillium/chemistry , Anti-Inflammatory Agents , Molecular StructureABSTRACT
Two undescribed p-terphenyl derivatives, asperterphenylcins A-B (1-2), and two undescribed diphenyl ether derivatives, asperdiphenylcins A-B (3-4), together with three previously described p-terphenyl derivatives-4â³-deoxyterprenin (5), terphenyllin (6), and 3â³-hydroxyterphenyllin (7)-were obtained from the solid-rice culture of the marine-derived fungus Aspergillus candidus HM5-4, which was isolated from sponges from the South China Sea. Their structures were elucidated by HRESIMS data and NMR spectroscopic analysis. Compound 1 showed a strong inhibitory effect on Neoscytalidium dimidiatum, with an inhibition circle diameter of 31.67 ± 2.36 mm at a concentration of 10.0 µg/disc. Compounds 5 and 7 displayed cytotoxic activity against human chronic myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549) and human HeLa cervical cancer cells, with IC50 values ranging from 3.32 to 60.36 µM, respectively. Compounds 2, 6 and 7 showed potent inhibitory activity against α-glucosidase, with IC50 values of 1.26 ± 0.19, 2.16 ± 0.44 and 13.22 ± 0.55 µM, respectively.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Aspergillus , FungiABSTRACT
BRD4, a member of the bromodomain and extraterminal (BET) family, is elevated in multiple cancer tissues, including gastric cancer (GC). Targeted therapy with BRD4 may help improve the overall survival of patients with GC. Meanwhile, the approved multi-target kinase inhibitor, dasatinib, was recently reported to show varied tumor-suppressive effects in GC cells. This study investigated BRD4 expression in vivo and in vitro using immunohistochemistry and western blotting, respectively. We discussed the relationship between BRD4 expression and patient prognosis. Next, the antitumor efficacy of dasatinib was measured in BRD4-knockdown GC cells to determine the role of BRD4 blockage in dasatinib treatment. Finally, molibresib, a BET inhibitor, was used to measure the cooperative function of BRD4 inhibition and dasatinib treatment in three GC cell lines. Epithelial BRD4 expression was higher in tumoral and metastatic tissues and was strongly associated with unfavorable tumor, node, and metastasis stages and survival. BRD4 expression was heterogeneous in the three GC cell lines tested in vitro. In SGC7901, a BRD4-high GC cell line, knockdown of BRD4 using specific siRNAs suppressed cell growth individually and cooperatively with dasatinib. Moreover, molibresib and dasatinib showed a cooperative effect in suppressing the proliferation of BRD4-high GC cells. In conclusion, we confirmed that increased epithelial BRD4 expression is associated with poor disease stage and prognosis in GC and BRD4 blockage might be a valuable strategy to improve the sensitivity of dasatinib and other drugs in the chemotherapy of advanced GC.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/genetics , Nuclear Proteins/genetics , Dasatinib/pharmacology , Cell Cycle Proteins/metabolism , Transcription Factors/genetics , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, NeoplasticABSTRACT
Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has shown beneficial physiological effects in various disease models and is used as a prebiotic to regulate intestinal function. However, its role in healthy states remains unclear. The purpose of this study was to investigate the effects of PHGG on gut flora composition and predict metabolic function in healthy mice. Our study showed that PHGG supplementation had significant duration-dependent effects on the composition and function of the intestinal flora of healthy mice. In specific, although the long-term supplementation of PHGG may increase the abundance of some beneficial bacterial species and promote beneficial phenotypes, it may also cause increased body weight and decreased abundance and diversity of gut microorganisms. Therefore, the long-term use of PHGG as a nutritional product still requires further investigation. PRACTICAL APPLICATIONS: As the importance of the gut microbiota has become more widely recognized, interventions that modulate the microbiome and its interaction with the host have gained much attention. While the capability of some prebiotics has largely been shown to have many beneficial effects, the evidence leaves much desirable, and microbiota regulation is explored differently in healthy or diseased states. Currently, the scientific community and regulatory authorities are beginning to pay attention to these unregulated and over-the-counter products claiming to possess probiotic and prebiotic properties. Studies exploring the rationality of these prebiotics as nutraceuticals for use in health states are essential. This study focuses on the effects of PHGG, a prebiotic, on intestinal flora, metabolism, and function when used in a healthy state over a long period. It is helpful to have a clearer understanding of the effect of PHGG on intestinal flora and the possible mechanisms of action to exert effects, which are indicative for the future application of PHGG as a nutraceutical or therapeutic agent..
Subject(s)
Gastrointestinal Microbiome , Mice , Animals , Prebiotics , Galactans , DefecationABSTRACT
This study aimed to explore novel targets for celastrol sensitization in colorectal cancer (CRC) based on differentially regulated signals in response to high- or low-dose celastrol. Targeting signals were investigated using Western blotting or phosphorylated receptor tyrosine kinase (RTK) arrays. Corresponding inhibitors for the signals were individually combined with low-dose celastrol for the assessment of combined anti-CRC effects, based on proliferation, apoptosis, colony assays, and xenograft models. The potential mechanism for the combination of celastrol and SHP2 inhibition was further examined. Low-dose celastrol (<1 µM) did not effectively suppress AKT and ERK signals in CRC cells compared to high-dose celastrol (>1 µM). However, when combined with an AKT or ERK inhibitor, low-dose celastrol could cooperatively suppress CRC proliferation. Furthermore, failed AKT or ERK inhibition by low-dose celastrol may be due to reactivated RTK-SHP2 signaling with negative feedback. The combination of celastrol and the SHP2 inhibitor resulted in greatly reduced AKT and ERK signals, as well as greater inhibition of CRC growth than celastrol alone. Moreover, the mechanism underlying combination suppression was also involved in the activation of immune cell infiltration (mainly for CD8+ cells) in CRC tissues. Failure to inhibit RTK-SHP2-AKT/ERK signaling contributed to the lack of CRC growth suppression by low-dose celastrol. However, the combination of celastrol and the SHP2 inhibitor resulted in synergistic inhibition of CRC growth and provided a promising therapeutic target.
ABSTRACT
Background: Phosphorylated Focal adhesion kinase (FAK) has been reported to be intimately involved in various malignant tumors. The effect of p-FAK on colorectal cancer (CRC) is still disputable. The purpose of this study is to investigate the role of p-FAK in the prognosis of colorectal cancer. Methods: The clinical significance of p-FAK expression in CRC was evaluated by immunohistochemistry in a large cohort, including carcinoma and para-carcinoma tissues from 908 patients, and normal tissues, adenoma, and metastasis tissues. The correlation between p-FAK expression and CRC occurrence was investigated in tumor and other tissues. Factors contributing to prognosis were evaluated using Kaplan-Meier survival analysis and Cox regression model. Results: p-FAK is apparently overexpressed in CRC and metastasis tissues. Compared with low p-FAK expression, patients with high p-FAK expression had shorter overall survival [hazard ratio (HR), 2.200; 95% confidence interval (CI), 1.265-3.452; p < 0.01] and disease-free survival (HR, 2.004; 95% CI 1.262-3.382; p < 0.01) in multivariate Cox analysis after adjusting other prognostic factors. High p-FAK expression was also related to a worse chemotherapeutic response in patients who achieved adjuvant chemotherapy (p < 0.01). Conclusion: Expression level of p-FAK is an independent risk factor and can serve as a prognostic biomarker for CRC. High p-FAK expression predicts an unfavorable prognosis of CRC as well as poor chemotherapeutic response.
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Accumulating evidence indicates that lncRNAs are potential biomarkers and key regulators of tumor development and progression. The present study aimed to screen abnormal expression lncRNAs and investigate the mechanisms underlying the function in the progression of colorectal cancer (CRC). Potential CRC prognosis-associated dysregulated lncRNAs were screened and identified using bioinformatics analysis. Loss/gain-of-function experiments were performed to detect the biological roles of FAM222A-AS1 in CRC cell phenotypes in vitro and in vivo. The potential microRNAs that interact with FAM222A-AS1 were identified using online tools and were verified using qRT-PCR and luciferase reporter assay. The expression of FAM222A-AS1 is significantly upregulated in CRC tumor samples and cell lines. CRC patients with elevated FAM222A-AS1 expression in the tumor samples had unfavorable overall survival and disease-free survival. Silencing FAM222A-AS1 expression significantly inhibited CRC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, FAM222A-AS1 was mainly distributed in the cytoplasm. It may directly bound to miR-let-7f and inhibit its expression and upregulate MYH9. In summary, FAM222A-AS1, as a novel oncogene in CRC, may promote the CRC progression by inhibiting miR-let-7f/MYH9 axis. The FAM222A-AS1/miR-let-7f/MYH9 signaling pathway may be a novel valuable target for inhibiting CRC.
ABSTRACT
SHP2 mediates signaling from multiple receptor tyrosine kinases (RTKs) to extracellular signal-regulated kinase (ERK) and Ser and Thr kinase AKT, and its inhibitors offer an unprecedented opportunity for cancer treatment. Although the ERK signaling variation after SHP2 inhibition has been well investigated, the AKT signaling variation in colorectal carcinoma (CRC) is still unknown. Therefore, we performed immunohistochemistry and bioinformatics analyses to explore the significance of p-SHP2 in CRC. A panel of CRC cell lines with the SHP2 inhibitor, SHP099, was used to assess the effects on viability and signaling. The inhibitors of AKT and focal adhesion kinase (FAK) signaling were examined in combination with SHP099 as potential strategies to enhance the efficacy and overcome resistance. Frequent resistance to the SHP2 inhibitor was observed in CRC cells, even in those without RAS mutations. We observed rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition, possibly driven by the reactivation of RTKs or released p-FAK. High baseline p-FAK may also be associated with CRC cell resistance to SHP2 inhibition. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition. Moreover, the combined inhibition of SHP2 with AKT or FAK resulted in sustained AKT pathway suppression and improved antitumor efficacy in vitro and in vivo. Our study found that reactivation of the AKT pathway is a key mechanism of adaptive resistance to SHP2 inhibition, highlighting the potential significance of AKT and FAK inhibition strategies to enhance the efficacy of SHP2 inhibitors in CRC treatment.
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BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body's defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis. METHODS: The expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1. RESULTS: HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model. CONCLUSIONS: Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.
ABSTRACT
Nicotinamide N-methyltransferase (NNMT), a major metabolic regulator, has been identified as a predictor of cancer prognosis in ovarian and colorectal cancers. The study aims to evaluate the significance of stromal NNMT in gastric cancer (GC). Expression of stromal NNMT in 612 GC and 92 non-malignant tissues specimens was investigated by immunohistochemistry (IHC). The association between NNMT expression and occurrence of cancer or patient outcome was further analyzed, and the factors contributing to disease prognosis were evaluated by multiple Cox models. Stromal NNMT expression was higher in the malignant tissue (p<0.001). NNMT expression was significantly associated with GC stage (p=0.006). Compared to stromal "NNMT-low" cases, "NNMT-high" cases has lower disease-specific survival (hazard ratio [HR], 2.356; 95% confidence interval [CI] = 1.591-3.488; p<0.001) and disease-free survival (HR = 2.265; 95% CI = 1.529-3.354; p<0.001), as observed by multivariate Cox analysis after adjusting for stromal NNMT expression with other factors such as tumor grade and size. Notably, patients with stage II NNMT-low GC might be negatively affected by adjuvant chemotherapy, but lower stromal NNMT expression predicted a more favorable prognosis for GC. Our study confirmed that stromal NNMT expression is significantly increased in GC, which predicts an unfavorable post-operative prognosis for GC.
Subject(s)
Biomarkers, Tumor/metabolism , Cancer-Associated Fibroblasts/metabolism , Nicotinamide N-Methyltransferase/metabolism , Stomach Neoplasms/metabolism , Female , Humans , Male , Middle Aged , Prognosis , Stomach Neoplasms/diagnosisABSTRACT
Background: Patients with severe novel coronavirus disease (COVID-19) can likely develop comorbidities, which can lead to irreversible organ damage and, eventually, death. However, early indicators of disease progression remain unclear. This study aimed to identify early indicators of disease progression to provide a basis for improved prognostic prediction and disease management. Methods: We examined 53 recovered adult COVID-19 patients who were treated at Shanghai Public Health Clinical Center between January 20, 2020, and February 20, 2020. The patients were categorized into the following four groups according to their condition at admission: mild condition (n = 3), moderate (n = 41), severe (n = 7), and critical (n = 2). They were also categorized according to disease progression as mild or moderate conditions that remained stable (n = 26), moderate disease that progressed to severe condition (n = 18), and continuously severe or critical (n = 9). We then focused on investigating the differences in the epidemiological and laboratory indicators between remained stable cases and progressed to severe condition cases. Results: Mild or moderate patients were younger than severe or critical patients. The number of patients with shortness of breath and underlying diabetes and heart disease at admission was higher in the severe or critical group. This group also showed considerably lower or higher values in 28 laboratory indicators. In addition, mild and moderate patients who remained stable were younger than moderate patients progressing to severe disease. Men had a higher risk of disease progression. Patients who progressed had either higher or lower values in 11 laboratory indicators. Survival curve analysis showed that age, procalcitonin, D-dimer, serum C-reactive protein, lactate dehydrogenase, lymphocytes, neutrophils, CD4%, and CD4/CD8 ratio were significant predictors of progression to severe disease. Conclusions: Lactate dehydrogenase, procalcitonin, etc. are early warning indicators of severe COVID-19. Age (>64 years), shortness of breath, past histories of diabetes and heart disease, and abnormality in 28 other indicators at admission are indicative of severe or progression toward severe COVID-19. Meanwhile, abnormalities in 11 indicators and an abnormal coagulation function index at admission are risk factors for progression to severe disease.