ETV4 (ETS-transformation-specific variant 4) is a member of the ETS transcription factor family that has been extensively studied for its oncogenic functions in cancers. Here, we summarize the role and mechanisms of ETV4 in cancer biology, with a particular focus on colorectal cancer (CRC), as well as its biomarkers and therapeutic potential. As a transcription factor, ETV4 regulates the expression of target genes by recognizing the GGA(A/T) core conserved sequence. It is frequently overexpressed in pan-cancer, where its overexpression associated with poor prognosis. Upon activation by oncogenic signaling pathways (e.g., MAPK, PI3K/Akt, and WNT), ETV4 transcriptionally regulates downstream genes to promote tumor cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), chemoresistance, metabolic reprogramming, and immune evasion. It also form a vicious positive feedback loop that continuously activates oncogenic signaling. In CRC, ETV4 is overexpressed, correlating with advanced disease, lymph node metastasis, and poor prognosis. Upon activation by oncogenic signals, ETV4 directly activate target genes (such as matrix metalloproteinases) to mediate adenoma-to-adenocarcinoma progression, proliferation, EMT, ferroptosis, invasion, metastasis, metabolic reprogramming, and tumor microenvironment remodeling in CRC. ETV4 also forms transcriptional complexes with certain epigenetic factors, such as miRNAs and p300. Moreover, ETV4 is a promising biomarker for CRC diagnosis, prognosis, and adenoma-to-adenocarcinoma progression. Targeting ETV4 or its upstream pathways represents a potential therapeutic strategy for CRC. However, there are still many unresolved issues in current research. For example, the role of ETV4 in immune evasion and tumor microenvironment remodeling remains at the descriptive stage, and the specific mechanisms by which it regulates immune cell recruitment have not yet been elucidated. Future efforts include utilizing multi-omics approaches to elucidate the mechanisms by which ETV4 shapes the CRC microenvironment and exploring the application prospects in tumor immunotherapy.

Pancreatic adenocarcinoma (PAAD) has a poor prognosis. Its microenvironment is closely associated with tumor progression and immune evasion. This study combines single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to reveal the critical role of tumor-associated macrophages (TAMs) in PAAD. Ras association domain family member 1 C (RASSF1C) is significantly upregulated under hypoxia, enhancing glycolysis by promoting the Warburg effect. This generates lactate and contributes to acidification of the tumor microenvironment (TME). Lactate activates TAMs and reprograms their lipid metabolism, promoting PAAD migration and invasion. Further investigation demonstrated that lactate suppressed ubiquitin-fold modifier 1 ligating enzyme 1 (UFL1) protein levels in macrophages, thereby weakening the protective effect of UFL1-mediated interferon regulatory factor 7 (IRF7) UFMylation. This suppression led to enhanced K48-linked ubiquitination of IRF7 and accelerated proteasomal degradation, ultimately reducing IRF7 stability and impairing lipid metabolic functions in macrophages. Additional mechanistic evidence showed that UFL1-UFMylation axis maintains IRF7 homeostasis by counteracting K48-linked ubiquitin-mediated degradation. Moreover, immunohistochemical (IHC) validation using tissue microarrays from 20 human pancreatic ductal adenocarcinoma (PDAC) specimens revealed that the overall expression of RASSF1C and hypoxia-inducible factor-1 alpha (HIF-1α) was higher than that of UFL1 and IRF7. RASSF1C expression was significantly positively correlated with HIF-1α and negatively correlated with UFL1 and IRF7. Clinicopathological correlation analysis further showed that high RASSF1C expression was associated with poor differentiation and advanced TNM stage, whereas low UFL1 and IRF7 expression was associated with lymph node metastasis. Collectively, this study demonstrated that the hypoxia-RASSF1C-HIF-1α axis reshaped TAM function through lactate-mediated immunometabolic regulation and promoted PAAD progression by inhibiting UFL1-mediated IRF7 UFMylation, thereby reducing IRF7 stability. These findings identify potential therapeutic targets for combined metabolic and immune interventions in PAAD. Graphic abstract. Schematic illustration of the molecular mechanism by which the RASSF1C-HIF-1α axis induces glycolytic reprogramming, drives lactate accumulation in the acidic TME, and promotes lactate flux into macrophages, thereby facilitating UFL1-IRF7 interaction and ultimately accelerating PAAD progression.

Sepsis is a life-threatening condition characterized by systemic inflammatory response syndrome, and often results in cardiac damage and poor prognosis. This study aimed to explore the protective effects of Poria cocos polysaccharides (PCP) on sepsis-induced cardiac injury and elucidate the underlying molecular mechanisms. An in vivo sepsis model was established, and an in vitro myocardial cell model was induced using lipopolysaccharide (LPS) to mimic a sepsis environment. Histopathological analysis revealed morphological changes in the myocardial tissue, while apoptosis and oxidative stress in the myocardial cells were assessed using immunofluorescence staining. The Western blot assay was employed to measure the expression levels of CaMKII, NF-[Formula: see text]B, and NLRP3, and myocardial cell apoptosis was quantified by flow cytometry. Inflammatory cytokine levels were determined via ELISA. The results indicated that PCP treatment significantly alleviated myocardial injury, reduced myocardial apoptosis, and lowered the levels of inflammatory markers when compared to the sepsis group. Mechanistic studies revealed that PCP inhibited the P38/NF-[Formula: see text]B/NLRP3 signaling pathway activation induced by CaMKII to thereby mitigate apoptosis and the inflammatory response in sepsis-induced cardiomyocytes. In conclusion, PCP exerts a protective effect against sepsis-induced cardiac injury by inhibiting the CaMKII-mediated P38/NF-[Formula: see text]B/NLRP3 signaling pathway. This study provides a novel theoretical framework and identifies potential therapeutic targets for the prevention and treatment of sepsis-associated cardiac injury.

Histone demethylases (HDMs) play a pivotal role in colorectal cancer (CRC) progression through dynamic epigenetic regulation. This review summarizes the role and therapeutic potential of HDM in CRC. HDMs primarily target lysine (K) for demethylation (lysine demethylase, KDM). The KDM family is divided into the lysine-specific demethylase family and the Jumonji C domain-containing family. HDMs play complex roles in CRC cell proliferation, invasion, migration, stemness, epithelial–mesenchymal transition, immune response, and chemoresistance through epigenetic regulation of different histone demethylation sites. Increasing evidence suggests that KDM may interact with certain factors and regulate CRC tumorigenesis by modulating multiple signaling pathways and affecting the transcription of target genes. These processes may be regulated by upstream genes and thus form a complex epigenetic regulatory network. However, the potential roles and regulatory mechanisms of some HDMs in CRC remain understudied. Preclinical studies have revealed that small-molecule inhibitors targeting HDM impact the activity of specific genes and pathways by inhibiting specific HDM expression, thereby reshaping the tumorigenic landscape of CRC. However, the clinical translational potential of these inhibitors remains unexplored. In conclusion, HDMs play a complex and critical role in CRC progression by dynamically regulating histone methylation patterns. These HDMs shape the malignant behavior of CRC by influencing the activity of key pathways and target genes through epigenetic reprogramming. Targeting HDM may be a promising direction for CRC treatment. Further exploration of the role of specific HDMs in CRC and the therapeutic potential of HDM-specific inhibitors is needed in the future.

Background Cardiac hypertrophy is characterized by the upregulation of fetal genes, increased protein synthesis, and enlargement of cardiac myocytes. The mechanistic target of rapamycin complex 1 (mTORC1), which responds to fluctuations in cellular nutrient and energy levels, plays a pivotal role in regulating protein synthesis and cellular growth. While attempts to inhibit mTORC1 activity, such as through the application of rapamycin and its analogs, have demonstrated limited efficacy, further investigation is warranted. Methods and results Here, we show that Serinc2 expression is downregulated in the transverse aortic constriction (TAC)-induced hypertrophic myocardium. Both in vivo and in vitro, the reduction of Serinc2 expression results in pathological hypertrophic growth, whereas Serinc2 overexpression exhibits a protective effect. RNA sequencing analysis following Serinc2 knockdown reveals a transcriptomic shift toward a pro-hypertrophic profile and suggests a significant interplay between Serinc2, amino acid, mTOR, and the lysosome, a hub for mTOR activation. Moreover, we show that Serinc2 localizes to lysosomes and hinders mTORC1 recruitment to the lysosomal membrane in response to amino acid stimulation, playing a critical role in regulating amino acid signaling pathway involved in the activation of p70S6K, S6, and 4EBP1 in Hela cells. And its deficiency exacerbates mTORC1 activity and mTORC1-dependent subsequent protein synthesis, which can be abrogated by rapamycin. In line with our in vitro findings, Serinc2 knockout mice subjected to TAC surgery exhibit elevated phosphorylation of p70S6K and 4EBP1, while inhibition of mTORC1 signaling through amino acid deprivation prevents this activation and impedes the progression to pathological cardiac remodeling. Conclusions We have illustrated that Serinc2 localizes to the lysosomal membrane and modulates amino acid /mTORC1 signaling in cardiomyocytes. Serinc2 therefore presents a potential therapeutic target for mitigating excessive protein synthesis and improving heart failure under hemodynamic stress.

Objective To investigate the effect of Asiaticoside(ASI)on liver injury in non-alcoholic fatty liver disease(NAFLD)and its impacts on the microRNA-29b-3p(miR-29b-3p)/forkhead box protein O3(FoxO3)axis.Methods Rats were stochastically grouped into a Control group,a Model group,a low-dose ASI-L group(ASI-L),a high-dose ASI-H group(ASI-H),a high-dose ASI+blank vector group(ASI-H+Vector),and a high-dose ASI+miR-29b-3p over expression group(ASI-H+OV-miR-29b-3p),with 12 rats in each group.The changes in rat liver index were analyzed.HE staining method was applied to observe the pathological changes of liver tissue.Biochemical analyzer was used to detect lipid metabolism indicators and indicators reflecting liver parenchymal damage in rats.The levels of oxidative stress and inflammatory cytokines were detected by the ELISA method.The RT-qPCR method was applied to detect the mRNA levels of miR-29b-3p and FoxO3 in rat liver tissue.The Western blot method was applied to detect the expression levels of FoxO3 and apoptosis-related proteins in rat liver tissue.Dual luciferase activity was applied to validate the targeting relationship between miR-29b-3p and FoxO3.Results Compared with the Control group,rats in the Model group showed severe liver tissue damage,liver cell rupture,and extensive infiltration of inflammatory cells,the liver weight and liver index increased,the levels of TC,TG,AST,ALT,MDA,TNF-α,IL-6 obviously increased,the levels of SOD and CAT obviously reduced,the expression level of miR-29b-3p and expression level of Caspase 3 protein in liver tissue obviously increased,the expression level of FoxO3 mRNA and expression levels of FoxO3,Bcl-2 proteins decreased(P＜0.05).Compared with the model group,as the dose of ASI increased,the degree of liver tissue damage,liver cell rupture,and inflammatory cell infiltration of rats in the ASI-L and ASI-H groups decreased,the liver weight and liver index gradually decreased,the levels of TC,TG,AST,ALT,MDA,TNF-α,IL-6 in serum gradually decreased,the levels of SOD and CAT gradually increased,the expression level of miR-29b-3p and expression level of Caspase 3 protein in liver tissue gradually decreased,the expression level of FoxO3 mRNA and the expression levels of FoxO3 and Bcl-2 proteins gradually increased.miR-29b-3p overexpression reversed the improvement effect of ASI on liver tissue in NAFLD rats.Dual luciferase activity confirmed the targeting relationship between miR-29b-3p and FoxO3.Conclusion ASI can enhance the antioxidant function,regulate lipid metabolism,alleviate inflammation and liver tissue damage in NAFLD rats,which may be related to the down-regulation of miR-29b-3p and the up-regulation of FoxO3 expression.

BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is a disease of increasing global prevalence and an important risk factor for the development of insulin resistance, type 2 diabetes, non-alcoholic steatohepatitis and hepatocellular carcinoma, but the pathogenesis is not clear. The aim of this study was to explore the role of ILF3 in NAFLD. AIM:To investigate the molecular processes through which ILF3 facilitates the advancement of NAFLD by inhibiting the expression of p-AMPK. This exploration seeks to provide new insights into the etiology of NAFLD and evaluate the potential of ILF3 as a diagnostic marker and potential treatment focus for future interventions. METHODS:In vitro and in vivo experiments were conducted using HepG2 cells and NAFLD animal models. The effects of ILF3 knockdown on lipid synthesis and triglyceride (TG) secretion were examined by analyzing the expression levels of p-AMPK. Additionally, the roles of ILF3 and the AMPK signaling pathway were verified using techniques such as Western blotting, quantitative reverse transcription PCR, Oil Red O staining, and immunohistochemistry. RESULTS:Investigations revealed an increase in ILF3 Levels within both HepG2 cells and animal models of NAFLD, concurrently with a decrease in p-AMPK expression. Knocking down ILF3 activated the AMPK pathway, reducing lipid production and TG secretion in hepatocytes, thereby mitigating the advancement of NAFLD. CONCLUSION:ILF3 promotes the evolution of NAFLD by inhibiting the expression of p-AMPK. The knockdown of ILF3 activates the AMPK signaling pathway, alleviating the severity of NAFLD. These findings underscore the function of ILF3 in the pathogenesis of NAFLD and demonstrate its viability as a treatment focus and diagnostic indicator.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Body mass index (BMI) is the most used obesity index but has important limitations. The weight-adjusted waist index (WWI) is a novel obesity metric and accurately reflects body composition. We explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in MASLD.MethodsAdult participants with MASLD were included from NHANES 1999-2018. WWI was calculated by dividing the waist circumference (WC) by the square root of body weight. MASLD was diagnosed by the presence of hepatic steatosis and at least one cardiometabolic risk factor in the absence of other causes of steatosis. A fatty liver index ≥60 suggested the presence of hepatic steatosis. Mortality data was obtained by prospectively linking to the National Death Index. Multivariate Cox proportional hazards regression analyses were used to explore these associations and multiple adjustment models were constructed including crude, partial, and fully adjusted models.ResultsAfter adjusting for all covariates including BMI, WWI remained positively and linearly associated with all-cause and CVD mortality in MASLD (hazard ratios [HR] 1.247 and 1.218, respectively). Higher WWI was associated with a significantly increased risk of mortality (both p for trend <0.05). There was an “obesity paradox” between BMI and all-cause mortality in MASLD, with significantly lower all-cause mortality in those with overweight/obesity compared to normal BMI (HR 0.625 and 0.596, respectively, p for trend = 0.024), and no association between BMI and CVD mortality. Interaction analyses indicated that these associations were influenced by several demographic variables and disease status. Time-dependent receiver operating characteristic curves indicated that the predictive value of WWI for mortality in MASLD was higher than that of BMI, WC, and waist-to-height ratio across all follow-up durations.ConclusionsWWI was positively and linearly associated with all-cause and CVD mortality in MASLD, whereas BMI did not accurately reflect mortality risk. WWI provided the optimal predictive value for mortality compared to traditional obesity indicators. These findings emphasize the potential use of WWI as a novel obesity indicator for mortality risk assessment, stratification, and prevention in MASLD.

To develop and validate a machine learning (ML) model which combined computed tomography (CT) semantic and radiomics features to preoperatively predict Ki-67 expression in gastrointestinal stromal tumors (GISTs) patients. We retrospectively collected the clinical, imaging and pathological data of 149 GISTs patients. We randomly assigned the patients in a ratio of 7:3 to a training set (104 cases) and a validation (45 cases) set. We divided the patients into low and high Ki-67 expression group according to postoperative pathology. CT semantic features were analyzed from preoperative enhancement CT images and radiomics features were extracted from venous phase-enhanced images. We used intraclass correlation coefficient, maximal relevance and minimal redundancy and least absolute shrinkage and selection operator method to screen radiomics features and build radiomics label. 6 ML models were used for model construction. Receiver operating characteristic curves were used to evaluate the predictive efficiency of ML models. SHAP analysis was used to explain the contribution of different variables and their risk threshold. AUC of radscores in predicting Ki-67 expression of GIST patients were 0.749 and 0.729 in training and validation set. Among the 6 ML models, SVM exhibited best prediction accuracy. AUC of SVM model in predicting Ki-67 expression of GIST patients were 0.840, 0.767 and 0.832 in training, validation and test set. SHAP analysis showed that radscores and tumor diameter had highly positive contribution to the model. Therefore, the interpretable SVM model can predict Ki-67 expression of GISTs patients individually before surgery, which can provide reliable imaging biomarkers for clinical treatment decisions.

Bone marrow mesenchymal stem cell (BSMC)-derived extracellular vehicles (EVs) have a pivotal therapeutic potential in hepatic fibrosis (HF). Activation of hepatic stellate cells (HSCs) is the key mechanism in HF progression. Downregulation of miR-192-5p was previously observed in activated HSCs. Nonetheless, the functions of BSMC-derived exosomal miR-192-5p in activated HSCs remain unclear. In this study, transforming growth factor (TGF)-beta 1 was used to activate HSC-T6 cells to mimic HF in vitro. Characterization of BMSCs and BMSC-derived EVs was performed. Cell-counting kit-8 assay, flow cytometry, and western blotting revealed that TGF-beta 1 increased cell viability, promoted cell cycle progression, and induced upregulation of fibrosis markers in HSC-T6 cells. Overexpression of miR-192-5p or BMSC-derived exosomal miR-192-5p suppressed TGF-beta 1-triggered HSC-T6 cell activation. RT-qPCR revealed that protein phosphatase 2 regulatory subunit B'' alpha (PPP2R3A) was downregulated in miR-192-5p-overexpressed HSC-T6 cells. Luciferase reporter assay was used for verifying the relation between miR-192-5p and PPP2R3A, which showed that miR-192-5p targeted PPP2R3A in activated HSC-T6 cells. Collectively, BMSC-derived exosomal miR-192-5p targets PPP2R3A and inhibits activation of HSC-T6 cells.

Doxorubicin (DOX) is used extensively in anticancer therapy, but its clinical application is limited due to its cardiotoxicity. Carnosic acid (CA) is a bioactive compound found in rosemary. It has been shown to reduce inflammation and reactive oxygen species. The purpose of this study was to investigate the potential cardioprotective effects of CA in response to DOX-induced cardiotoxicity. Here, C57BL/6 mice were administered an intraperitoneal injection of DOX (5 mg kg-1, ip) once a week for three consecutive weeks and treated with CA (40 mg kg-1, ig) for a three-week experimental period. For in vitro study, neonatal rat ventricular cardiomyocytes were used to validate the protective effects of CA (20 μM) in response to DOX-induced cardiotoxicity. CA markedly suppressed oxidative stress, apoptosis, and pyroptosis responses in the mouse hearts, eventually improving cardiac function. CA showed its antioxidant effect by activating nuclear factor erythroid 2-related factor (Nrf2) and its downstream heme oxygenase-1 (HO-1); CA also reduced oxidative stress by lowering the MDA and lipid ROS levels and raising the SOD and GSH-px levels. Additionally, CA treatment significantly increased Bcl-2 and inhibited Bax and Caspase-3 cleavage in DOX-induced cardiotoxicity. Moreover, CA suppressed the NOD-like receptor protein 3 (NLRP3) pathway to mitigate pyroptosis, as evidenced by lowered caspase1, interleukin-18, and interleukin-1β. Consistently, the transfection of Nrf2-siRNA eliminated the protective effects of CA on cardiomyocytes. Altogether, our findings demonstrated that CA inhibited NLRP3 inflammasomes via activating the Nrf2-related cytoprotective system and protected the heart from oxidative damage, apoptosis, and pyroptosis, implying that the use of CA could be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.

In critical care medicine, sepsis is a potentially fatal syndrome characterized by multi-organ dysfunction and eventual failure. Sepsis-induced cardiomyopathy (SIC) is characterized by decreased venstricular contractility. Serine incorporator 2 (Serinc2) is a protein involved in phosphatidylserine biosynthesis and membrane incorporation. It may also be a protective factor in septic lung injury. However, it is unknown whether Serinc2 influences SIC onset or progression. In the present study, we found that Serinc2 was downregulated in the cardiomyocytes of cecal ligation and puncture (CLP)-induced SIC and in neonatal rat cardiomyocytes (NRCMs) exposed to lipopolysaccharides (LPS). Serinc2 knockout (KO) exacerbated sepsis-induced myocardial inflammation, necroptosis, apoptosis, myocardial damage, and contractility impairment. Furthermore, the lack of Serinc2 in cardiomyocytes aggravated LPS-induced cardiomyopathic inflammation, necroptosis, and apoptosis. An adenovirus overexpressing Serinc2 inhibited the inflammatory response and favored cardiomyocyte survival. A mechanistic analysis revealed that Serinc2 deficiency exacerbated LPS-induced cardiac dysfunction by inhibiting the protein kinase B (Akt)/glycogen synthase kinase 3 beta (GSK-3β) signaling pathway that regulates necrotic complex formation and apoptotic pathways in cardiomyopathy. The findings of the present work demonstrated that Serinc2 plays an essential role in SIC and is, therefore, promising as a prophylactic and therapeutic target for this condition.

This work aimed to investigate the protective effects of phlorizin on hyperlipidemia in mice and the mechanisms. Forty mice were randomly divided into control, model and low-, middle- and high-dose phlorizin groups, with 8 mice in each group. The hyperlipidemia model was established in latter four groups. Then, the latter three groups were treated with low-, middle- and high-dose phlorizin, respectively, for four weeks. At the end of treatment, compared with model group, in phlorizin groups the body weight gain and liver index were decreased, the serum total cholesterol, triacylglycerol and low-density lipoprotein cholesterol levels were decreased, the serum high-density lipoprotein cholesterol level was increased, the serum aspartate transaminase and alanine transaminase levels were decreased, the liver tissue superoxide dismutas and glutathione peroxidase levels were increased, the liver tissue malondialdehyde level was decreased, and the liver tissue tumor necrosis factor a and interleukin 6 levels were decreased. In conclusion, phlorizin can lower the blood lipid level and mitigate the liver injury in hyperlipidemia mice. The mechanism may be related to its resistance of oxidative stress and reduction of inflammatory response.

Background: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), have fever, dry cough, dyspnea, and fatigue. The disease has now become a global pandemic. The purpose of this study was to explore the relationship between COVID-19 and gastrointestinal (GI) symptoms. Methods: We collected and analyzed data on patients with laboratory-confirmed COVID-19 by high-throughput sequencing or reverse transcription-polymerase chain reaction. We reviewed electronic medical records of 405 hospitalized COVID-19 patients in the Third Hospital of Wuhan. Results: Among the 405 confirmed patients, 210 had no GI symptoms, 195 had GI symptoms, and the first symptom of 155 patients was GI. The prevalence of vascular and digestive diseases in the group with GI symptoms was significantly higher than in the group without GI symptoms. In patients with GI symptoms, the proportion with fever, cough, dysphoria, chest tightness, poor appetite, chest pain, and pharyngeal pain was significantly higher than in those without GI symptoms. There was no significant difference in imaging between the 2 groups. In patients with GI symptoms, the proportion with increased procalcitonin (PCT) level and decreased lymphocyte count was significantly higher than in those without GI symptoms. Conclusion: COVID-19 patients with GI symptoms had significantly more vascular and digestive system diseases and were more likely to have clinical manifestations of fever, cough, poor appetite, chest tightness, chest pain, insomnia, and pharyngeal pain. There were more patients with diarrhea, nausea, and vomiting. Patients with GI symptoms were more likely to have increased PCT and decreased lymphocyte count.

A major cause of treatment failure in advanced colon cancer is resistance to chemotherapy. p38 mitogen-activated protein kinase (MAPK) has been associated with cellular apoptosis and plays an important role in multidrug resistance (MDR) in cancer cells. In the present study the effect of p38 MAPK on the sensitivity of 5-fluorouracil (5-FU)-resistant SW480 (SW480/5-FU) human colon cancer cells to noscapine was investigated. Following p38 MAPK interference, the inhibitory effect of noscapine on cell viability and proliferation was increased in the SW480/5-FU cells and there was also a decrease in the expression level of minichromosome maintenance proteins, recombinant Ki-67 and proliferating cell nuclear antigen. Inhibition of p38 MAPK also enhanced noscapine-induced G(1)-phase cell cycle arrest in the SW480/5-FU cells and there was also a decrease in the protein and mRNA expression level of cyclin D, cyclin E and cyclin-dependent kinase 2, and an increase in the expression level of P57. Furthermore, p38 MAPK interference increased noscapine-induced apoptosis of the SW480/5-FU cells and there was an increase in the protein and mRNA expression level of caspases-3 and 8 and Bax, and decreased Bcl-2 expression level. The sensitivity of the SW480/5-FU cells to noscapine was also increased following p38 MAPK interference, as demonstrated by MDR inhibition via decreased Akt activity and reduced protein expression level of the MDR proteins P-glycoprotein, multidrug resistance protein 1 and ATP-binding cassette G2. These observations indicated that inhibition of p38 MAPK increased the sensitivity of the SW480/5-FU cells to noscapine by suppressing proliferation, induction of cell cycle arrest and apoptosis, and reversal of MDR in the SW480/5-FU cells.

BACKGROUNDPatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), have fever, dry cough, dyspnea, and fatigue. The disease has now become a global pandemic. The purpose of this study was to explore the relationship between COVID-19 and gastrointestinal (GI) symptoms.METHODSWe collected and analyzed data on patients with laboratory-confirmed COVID-19 by high-throughput sequencing or reverse transcription-polymerase chain reaction. We reviewed electronic medical records of 405 hospitalized COVID-19 patients in the Third Hospital of Wuhan.RESULTSAmong the 405 confirmed patients, 210 had no GI symptoms, 195 had GI symptoms, and the first symptom of 155 patients was GI. The prevalence of vascular and digestive diseases in the group with GI symptoms was significantly higher than in the group without GI symptoms. In patients with GI symptoms, the proportion with fever, cough, dysphoria, chest tightness, poor appetite, chest pain, and pharyngeal pain was significantly higher than in those without GI symptoms. There was no significant difference in imaging between the 2 groups. In patients with GI symptoms, the proportion with increased procalcitonin (PCT) level and decreased lymphocyte count was significantly higher than in those without GI symptoms.CONCLUSIONCOVID-19 patients with GI symptoms had significantly more vascular and digestive system diseases and were more likely to have clinical manifestations of fever, cough, poor appetite, chest tightness, chest pain, insomnia, and pharyngeal pain. There were more patients with diarrhea, nausea, and vomiting. Patients with GI symptoms were more likely to have increased PCT and decreased lymphocyte count.

Background Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. Materials and Methods In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot. Results We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling. Conclusion These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.

口腔微生态环境错综复杂,多种致病菌可导致根管内感染、牙周病、根尖周病的发作.而上述疾病的发生与牙齿和牙周组织结构有关,它们会吸引不同种类的致病菌在相应部位聚集,为有效应对这类疾病,抗生素组合的应用显得尤为重要.三联抗生素糊剂(TAP)是环丙沙星、甲硝唑和米诺环素3种抗生素的组合,具有良好的抗菌作用,可以有效控制根管内感染、促进牙髓血运重建.本文主要回顾和总结TAP在牙髓病和牙周病治疗中的应用.

It can get better effect to perform tooth demineralization for tough tissue in multitudinous oral disease during clinical therapy. Demineralization of tooth is needed in many simulated experiments in vitro. Demineralization is not only essential measure of tooth treatment, but also the progress of part of tooth diseases. This paper summarized the current methods of demineralization for tooth hard tissue.