JournalTOCs

Current Medical Science
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Hybrid journal (It can contain Open Access articles)
ISSN (Print) 2096-5230 - ISSN (Online) 2523-899X
Published by Springer-Verlag

[2468 journals]

Prediction of Tumor Microenvironment Characteristics and Treatment
Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related
Immune Genes
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  Abstract: Objective Pseudogenes are initially regarded as nonfunctional genomic sequences, but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities. Olfactory receptor family 7 subfamily E member 47 pseudogene (OR7E47P) is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma (LUSC). Methods Clinical and molecular information from The Cancer Genome Atlas (TCGA) LUSC cohort was used to identify OR7E47P-related immune genes (ORIGs) by weighted gene correlation network analysis (WGCNA). Based on the ORIGs, 2 OR7E47P clusters were identified using non-negative matrix factorization (NMF) clustering, and the stability of the clustering was tested by an extreme gradient boosting classifier (XGBoost). LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model (ORPScore) for immunotherapy. The Botling cohorts and 8 immunotherapy cohorts (the Samstein, Braun, Jung, Gide, IMvigor210, Lauss, Van Allen, and Cho cohorts) were included as independent validation cohorts. Results OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC. A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters (Cluster 1 and Cluster 2) with distinct immune, mutation, and stromal programs. Compared to Cluster 1, Cluster 2 had more infiltration by immune and stromal cells, lower mutation rates of driver genes, and higher expression of immune-related proteins. The clustering performed well in the internal and 5 external validation cohorts. Based on the 7 ORIGs (HOPX, STX2, WFS, DUSP22, SLFN13, GGCT, and CCSER2), the ORPScore was constructed to predict the prognosis and the treatment response. In addition, the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients. The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts. Conclusion Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC. ORIGs can be applied to molecularly stratify patients, and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.
  PubDate: 2023-11-28
Protein Disulfide Isomerase A2 Is Correlated with Immune Infiltrates and
Is a Novel Prognostic Biomarker in Glioma Patients
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  Abstract: Objective Protein disulfide isomerase A2 (PDIA2), a member of the protein disulfide isomerase family, plays a key role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds, together with enzymes such as thiol isomerase, oxidase, and reductase. This study investigated the clinical significance and potential functions of PDIA2 in glioma. Methods The expression of PDIA2 in gliomas was explored using The Cancer Genome Atlas and Gene Expression Omnibus databases. We analyzed the clinical characteristics of glioma patients and the prognostic and diagnostic value of PDIA2 expression. Kaplan-Meier and Cox regression analyses were used to examine the effect of PDIA2 expression on overall survival, progression-free interval, and disease-specific survival. Furthermore, we performed Gene Set Enrichment Analysis and immune infiltration analysis to investigate the functions of PDIA2. PDIA2 mRNA and protein expression was evaluated in cell lines and glioma tissues. Results PDIA2 was expressed at low levels in glioma patients. Kaplan-Meier survival analysis showed that glioma patients with low PDIA2 levels had a worse prognosis than those with high PDIA2 levels. Receiver operating characteristic curve analysis indicated the diagnostic and prognostic ability of PDIA2 (area under the curve = 0.918). Pathways associated with PD1, PI3K/AKT, cancer immunotherapy via PD1 blockade, Fceri-mediated NF-kB activation, FOXM1, and DNA repair were enriched in glioma patients with low levels of PDIA2. PDIA2 expression levels were negatively correlated with immune cell infiltrate levels. Conclusion PDIA2 levels are significantly downregulated in glioma. PDIA2 expression may be a potential biomarker for the diagnosis and prognosis of glioma patients.
  PubDate: 2023-11-18
Modified Glucose-insulin-potassium Therapy for Hemorrhage-induced
Traumatic Cardiac Arrest in Rabbits
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  Abstract: Objective Resuscitation with whole blood is known to be better than that with saline in attaining the return of spontaneous circulation (ROSC) and improving the short-term survival rate for hemorrhage-induced traumatic cardiac arrest (HiTCA). However, the resuscitation with whole blood alone fails to address the pathophysiological abnormalities, including hyperglycemia, hyperkalemia and coagulopathy, after HiTCA. The present study aimed to determine whether the modified glucose-insulin-potassium (GIK) therapy can ameliorate the above-mentioned pathophysiological abnormalities, enhance the ROSC, improve the function of key organs, and reduce the mortality after HiTCA. Methods HiTCA was induced in rabbits (n=36) by controlled hemorrhage. Following arrest, the rabbits were randomly divided into three groups (n=12 each): group A (no resuscitation), group B (resuscitation with whole blood), and group C (resuscitation with whole blood plus GIK). The GIK therapy was administered based on the actual concentration of glucose and potassium. The ROSC rate and survival rate were obtained. Hemodynamical and biochemical changes were detected. Thromboelastography (TEG) was used to measure coagulation parameters, and enzyme-linked immunosorbent assay to detect parameters related to inflammation, coagulation and the function of brain. Results All animals in groups B and C attained ROSC. Two rabbits died 24–48 h after HiTCA in group B, while no rabbits died in group C. The GIK therapy significantly reduced the levels of blood glucose, potassium, and biological markers for inflammatory reaction, and improved the heart, kidney, liver and brain function in group C when compared to group B. Furthermore, the R values of TEG were significantly lower in group C than in group B, and the maximum amplitude of TEG was slightly lower in group B than in group C, with no significant difference found. Conclusion Resuscitation with whole blood and modified GIK therapy combined can ameliorate the pathophysiological disorders, including hyperglycemia, hyperkalemia and coagulopathy, and may improve the function of key organs after HiTCA.
  PubDate: 2023-11-13
Rifaximin Prevents Intestinal Barrier Dysfunction and Alleviates Liver
Injury in MCT-induced HSOS Mice
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  Abstract: Objective Rifaximin is an effective component of treatment strategies for liver and intestinal diseases. However, the efficacy of rifaximin in hepatic sinusoidal obstruction syndrome (HSOS) has not been explored. The present study aimed to investigate the efficacy and mechanism of rifaximin in HSOS. Methods An HSOS model was established in mice through the administration of monocrotaline (MCT, 800 mg/kg), and part of the HSOS mice were intragastrically administered with rifaximin. Then, the efficacy of rifaximin in HSOS was evaluated based on the liver pathological findings, liver proinflammatory cytokines, and alanine aminotransferase and aspartate aminotransferase levels. The Ussing chamber was used to evaluate the intestinal permeability, and tight junction (TJ) proteins were measured by Western blotting and real-time polymerase chain reaction to evaluate the intestinal barrier integrity. Then, the serum proinflammatory cytokine levels were evaluated by enzyme-linked immunosorbent assay. Afterwards, an in vitro experiment was performed to determine the relationship between rifaximin and TJ proteins. Results Rifaximin effectively alleviated the MCT-induced HSOS liver injury, suppressed the expression of liver proinflammatory cytokines, and reduced the serum levels of tumor necrosis factor-alpha and interleukin-6. Furthermore, rifaximin reduced the intestinal permeability, improved the intestinal barrier integrity, and promoted the expression of TJ proteins. Conclusion The results revealed that the intestinal barrier integrity was destroyed in MCT-induced HSOS. The significant alleviation of MCT-induced HSOS induced by rifaximin might be correlated to the repairment of intestinal barrier integrity via the regulation of the TJ protein expression.
  PubDate: 2023-11-11
Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to
Clinical Practice
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  Abstract: Abstract Long COVID symptoms typically occur within 3 months of an initial COVID-19 infection, last for more than 2 months, and cannot be explained by other diagnoses. The most common symptoms include fatigue, dyspnea, coughing, and cognitive impairment. The mechanisms of long COVID are not fully understood, but several hypotheses have been put forth. These include coagulation and fibrosis pathway activation, inflammatory and autoimmune manifestations, persistent virus presence, and Epstein-Barr virus reactivation. Hyperbaric oxygen therapy (HBOT) is a therapeutic method in which a person inhales 100% oxygen under pressure greater than that of the atmosphere. HBOT has some therapeutic effects, including improvement of microcirculation, inhibition of cytokine release leading to a reduction in inflammatory responses, inhibition of autoimmune responses, and promotion of neurological repair. Several clinical trials have been carried out using HBOT to treat long COVID. The results suggest that HBOT helps to improve symptom severity, reduce symptom duration, and enhance patients’ quality of life. It is believed that HBOT is an effective option for patients with long COVID, which is worth actively promoting.
  PubDate: 2023-11-04
Resolvin D1 Induces mTOR-independent and ATG5-dependent Autophagy in BV-2
Microglial Cells
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  Abstract: Objective The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation. Autophagy is a catabolic process responsible for maintaining cellular homeostasis. In recent years, autophagy has been demonstrated to play an important role in neuroinflammation. Resolvin D1 (RvD1) is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities. However, whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation. The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways. Methods Mouse microglial cells (BV-2) were cultured, treated with RvD1, and examined by Western blotting, confocal immunofluorescence microscopy, transmission electron microscopy, and flow cytometry. Results RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes. Importantly, RvD1 had no significant effect on the activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II (CaMK II) activation. Moreover, by downregulating ATG5, the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy. Conclusion The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy, highlighting its therapeutic potential against neuroinflammation.
  PubDate: 2023-11-04
P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and
Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke
Mice
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  Abstract: Objective Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior. Methods Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3β inhibitor (LiCl) to the roles of CDK5 and GSK3β in mediating ischemia-reperfusion-induced tau phosphorylation. Results Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD. Conclusion These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.
  PubDate: 2023-11-04
LITAF Promotes Atherosclerotic Plaque Formation by Stimulating the
NF-κB Inflammatory Pathway
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  Abstract: Objective Lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) protein is a newly discovered inflammatory protein. This study aims to study the role of LITAF in the formation of atherosclerosis. Methods A total of 10 C57BL/6J mice and 10 C57BL/6J mice with knockout of LITAF gene (C57BL/6J–LITAF–) were divided into two groups: the control group and the LITAF−/− group. The animals were accommodated for 16 weeks and then euthanized with their hearts and aortas isolated thereafter. Next, the roots of the mouse aorta were cryosectioned and stained with Oil Red O staining and immunohistochemical staining (CD68, α-SMA, and Masson), respectively. The area of Oil Red O staining and the proportion of positive expression after immunohistochemical staining were then compared between the control and LITAF−/− groups. At the same time, the blood of mice was collected for the extraction of proteins and RNA. The proteins and RNA were used to detect the expression of major molecules of the NF-κB inflammatory pathway in mice in the control group and the LITAF−/− group by Western blotting and RT-PCR. Results Oil Red O staining of the aortic root sections of the mice in each group revealed that the area of atherosclerotic plaques in the LITAF−/− group was substantially lower than that in the control group (P<0.05). Moreover, immunohistochemical staining determined that the expression level of α-SMA and CD68 in the LITAF−/− group was significantly lower than that in the control group, whereas the results were reversed following Masson staining (P<0.05). The expression levels of P65 and caspase 3 were significantly lower in the LITAF−/− group than in the control group (P<0.05), whereas the expression level of IκB was higher in the LITAF−/− group. Conclusion LITAF might participate in the formation of atherosclerotic plaque through the NF-κB pathway and play a promoting role in the formation of atherosclerosis.
  PubDate: 2023-10-18
Clinical Characteristics, Diagnosis, and Therapeutics of COVID-19: A
Review
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  Abstract: Abstract The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that suddenly emerged at the end of December 2019 and caused coronavirus disease 2019 (COVID-19) continues to afflict humanity, not only seriously affecting healthcare systems but also leading to global social and economic imbalances. As of August 2022, there were approximately 580 million confirmed cases of COVID-19 and approximately 6.4 million confirmed deaths due to this disease. The data are sufficient to highlight the seriousness of SARS-CoV-2 infection. Although most patients with COVID-19 present primarily with respiratory symptoms, an increasing number of extrapulmonary systemic symptoms and manifestations have been associated with COVID-19. Since the outbreak of COVID-19, much has been learned about the disease and its causative agent. Therefore, great effort has been aimed at developing treatments and drug interventions to treat and reduce the incidence of COVID-19. In this narrative review, we provide a brief overview of the epidemiology, mechanisms, clinical manifestations, diagnosis, and therapeutics of COVID-19.
  PubDate: 2023-10-14
MicroRNA-409-5p Inhibits GIST Tumorigenesis and Improves Imatinib
Resistance by Targeting KDM4D Expression
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  Abstract: Objective Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST. Methods To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes. Results In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3′-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis. Conclusion This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.
  PubDate: 2023-10-13
Circular RNAs: Diagnostic and Therapeutic Perspectives in CNS Diseases
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  Abstract: Abstract Circular RNAs (circRNAs) are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends. A growing body of evidence suggests that circRNAs play important roles in physiology and pathology. In particular, accumulating data on circRNA functions in various central nervous system (CNS) diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders. In this review, we focus on the regulatory and functional roles of circRNAs in CNS diseases, highlighting their diagnostic and therapeutic potential, with the aim of providing new insights into CNS diseases.
  PubDate: 2023-10-10
Development and Validation of a Prediction Model on Adult Emergency
Department Patients for Early Identification of Fulminant Myocarditis
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  Abstract: Objective It is difficult to predict fulminant myocarditis at an early stage in the emergency department. The objective of this study was to construct and validate a simple prediction model for the early identification of fulminant myocarditis. Methods A total of 61 patients with fulminant myocarditis and 160 patients with acute myocarditis were enrolled in the training and internal validation cohorts. LASSO regression and multivariate logistic regression were selected to develop the prediction model. The selection of the model was based on overall performance and simplicity. A nomogram based on the optimal model was built, and its clinical usefulness was evaluated by decision curve analysis. The predictive model was further validated in an external validation group. Results The resulting prediction model was based on 4 factors: systolic blood pressure, troponin I, left ventricular ejection fraction, and ventricular wall motion abnormality. The Brier scores of the final model were 0.078 in the training data set and 0.061 in the internal testing data set, respectively. The C-indexes of the training data set and the testing data set were 0.952 and 0.968, respectively. Decision curve analysis showed that the nomogram model developed based on the 4 predictors above had a positive net benefit for predicting probability thresholds. In the external validation cohort, the model also showed good performance (Brier score=0.007, and C-index=0.989). Conclusion We developed and validated an early prediction model consisting of 4 clinical factors (systolic blood pressure, troponin I, left ventricular ejection fraction, and ventricular wall motion abnormality) to identify potential fulminant myocarditis patients in the emergency department.
  PubDate: 2023-10-01
Research Progress in Function and Regulation of E3 Ubiquitin Ligase SMURF1
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  Abstract: Abstract Smad ubiquitylation regulatory factor 1 (Smurf1) is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase. Initially, Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein (BMP) pathway. After further research, several studies have confirmed that Smurf1 is widely involved in various biological processes, such as bone homeostasis regulation, cell migration, apoptosis, and planar cell polarity. At the same time, recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression, activity, and substrate selectivity. In our review, a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.
  PubDate: 2023-10-01
Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib
Resistance in Gastric Cancer
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  Abstract: Objective Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance. Methods Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model. Results The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity. Conclusion These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
  PubDate: 2023-09-27
Causal Association Between Tea Consumption and Gout: A Mendelian
Randomization Study
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  Abstract: Objective Evidence from prospective studies on the consumption of tea and risk of gout is conflicting and limited. We aimed to investigate the potential causal effects of tea intake on gout using Mendelian randomization (MR). Methods Genome-wide association studies in UK Biobank included 349 376 individuals and successfully discovered single-nucleotide polymorphisms linked to consumption of one cup of tea per day. Summary statistics from the Chronic Kidney Disease Genetics consortium included 13 179 cases and 750 634 controls for gout. Two-sample MR analyses were used to evaluate the relationship between tea consumption and gout risk. The inverse-variance weighted (IVW) method was used for primary analysis, and sensitivity analyses were also conducted to validate the potential causal effect. Results In this study, the genetically predicted increase in tea consumption per cup was associated with a lower risk of gout in the IVW method (OR: 0.90; 95% CI: 0.82–0.98). Similar results were found in weighted median methods (OR: 0.88; 95% CI: 0.78–1.00), while no significant associations were found in MR-Egger (OR: 0.89; 95% CI: 0.71–1.11), weighted mode (OR: 0.80; 95% CI: 0.65–0.99), and simple mode (OR: 1.01; 95% CI: 0.75–1.36). In addition, no evidence of pleiotropy was detected by MR-Egger regression (P=0.95) or MR-PRESSO analysis (P=0.07). Conclusion This study provides evidence for the daily consumption of an extra cup of tea to reduce the risk of gout.
  PubDate: 2023-09-27
25-Hydroxyvitamin D Is Associated with Islet Homeostasis in Type-2
Diabetic Patients with Abdominal Obesity
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  Abstract: Objective Islet α cells input is essential for insulin secretion from β cells. The present study aims to investigate the association between 25-hydroxyvitamin D [25(OH)D] and islet function homeostasis in type-2 diabetes (T2D) patients. Methods A total of 4670 T2D patients from seven communities in Shanghai, China were enrolled. The anthropometric indices, biochemical parameters, serum 25(OH)D, and islet function [including C-peptide (C-p) and glucagon] were measured. Results The fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), glucagon, and C-p levels exhibited a significantly decreasing trend in T2D patients as the 25(OH)D levels increased. Next, the population was divided into two groups: abdominal obesity and non-abdominal obesity groups. After adjustment, the 25(OH)D level was found to be associated with HbA1c, glucagon, and homeostasis model assessment of β (HOMA-β) in the non-abdominal obesity group. There was a significant relationship between 25(OH)D and HbA1c, glucagon, HOMA-IR, baseline insulin or C-p in the abdominal obesity group. In the abdominal obesity group, the ordinary least squares (OLS) regression and quantile regression revealed that 25(OH) D was obviously associated with glucagon and fasting C-p levels. In the abdominal obesity group, the moderate analysis revealed a significant interaction effect of 25(OH)D and glucagon on C-p (P=0.0124). Furthermore, the conditional indirect effect of 25(OH)D on the glucagon/C-p ratio was significantly lower at 1 standard deviation (SD) below the mean (P=0.0002), and lower at the mean of the course of diabetes (P=0.0007). Conclusion 25(OH)D was found to be negatively correlated to glucagon and C-p in T2D patients with abdominal obesity. The 25(OH)D influenced C-p in part by influencing glucagon. The effect of 25(OH)D on the glucagon/C-p ratio in T2D patients with abdominal obesity, in terms of islet homeostasis, is influenced by the course of diabetes.
  PubDate: 2023-09-12
  DOI: 10.1007/s11596-023-2780-z
Roles of MT-ND1 in Cancer
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  Abstract: Abstract The energy shift toward glycolysis is one of the hallmarks of cancer. Complex I is a vital enzyme complex necessary for oxidative phosphorylation. The mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1 (MT-ND1) is the largest subunit coded by mitochondria of complex I. The present study summarizes the structure and biological function of MT-ND1. From databases and literature, the expressions and mutations of MT-ND1 in a variety of cancers have been reviewed. MT-ND1 may be a biomarker for cancer diagnosis and prognosis. It is also a potential target for cancer therapy.
  PubDate: 2023-08-29
  DOI: 10.1007/s11596-023-2771-0
Fluoxetine Ameliorates the Aggravation of UC Symptoms in C57BL/6 Mice
Induced by CUMS
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  Abstract: Objective Patients with chronic ulcerative colitis (UC) often have mental symptoms such as depression and anxiety, and stress can lead to gastrointestinal diseases. However, the correlation between mental stress and UC is unclear. In this paper, chronic unpredictable mild stress (CUMS) was utilized to evaluate the involvement of mental factors in the pathogenesis of UC. Methods The CUMS model was used to evaluate the direct/indirect involvement of mental factors in the pathogenesis of UC. The behavior was evaluated by the open field, forced swimming, and tail suspension tests. Body weight, the disease activity index (DAI) score, colon length, and HE staining of colon tissue were used to evaluate the action of CUMS and fluoxetine. Results The results showed that weight loss and the DAI score increased in CUMS mice, but they had no meaningful effect on colon length and morphological structure of colon tissue. However, CUMS aggravated dextran sulfate sodium (DSS)-induced colon length shortening and colon morphological structure damage. Fluoxetine significantly improved the DAI score, shortened colon length, and damaged morphology and structure of the colons induced by CUMS combined with DSS in mice. Fluoxetine also decreased the level of IL-6 in the serum and the TNF-α and IFN-γ levels of colon tissue. Fluoxetine simultaneously improved behavioral abnormalities induced by CUMS combined with DSS in mice. Conclusion CUMS aggravated the UC symptoms induced by DSS, and fluoxetine could improve the UC symptoms due to its improvement in the inflammatory level and behavioral abnormalities.
  PubDate: 2023-08-29
  DOI: 10.1007/s11596-023-2743-4
TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the
KEAP1-Nrf2 Pathway
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  Abstract: Objective Cisplatin is the first-line treatment for breast cancer, but it faces challenges of drug resistance. This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer. Methods We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2 (TMED2) and breast cancer. Western blotting, real-time PCR, CCK-8, and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines. Results TMED2 was overexpressed in breast cancer and associated with poor prognosis. TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1 (KEAP1), relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2 (Nrf2), and increasing expression of downstream drug resistance related genes, such as heme oxygenase 1 (HO-1) and NAD (P) H quinone oxidoreductase 1 (NQO1). Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer. Our results provide theoretical guidance for future clinical applications.
  PubDate: 2023-08-24
  DOI: 10.1007/s11596-023-2777-7
Inhibitory Effect of PPARδ Agonist GW501516 on Proliferation of
Hypoxia-induced Pulmonary Arterial Smooth Muscle Cells by Regulating the
mTOR Pathway
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  Abstract: Objective This study aimed to investigate the effects of the peroxisome proliferator-activated receptor δ (PPARδ) agonist GW501516 on the proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia, in order to search for new drugs for the treatment and prevention of pulmonary vascular remodeling. Methods PASMCs were incubated with different concentrations of GW501516 (10, 30, 100 nmol/L) under the hypoxic condition. The proliferation was determined by a CCK-8 assay. The cell cycle progression was analyzed by flow cytometry. The expression of PPARδ, S phase kinase-associated protein 2 (Skp2), and cell cycle-dependent kinase inhibitor p27 was detected by Western blotting. Then PASMCs were treated with 100 nmol/ L GW501516, 100 nmol/L mammalian target of rapamycin (mTOR) inhibitor rapamycin and/or 2 µmol/L mTOR activator MHY1485 to explore the molecular mechanisms by which GW501516 reduces the proliferation of PASMCs. Results The presented data demonstrated that hypoxia reduced the expression of PPARδ in an oxygen concentration- and time-dependent manner, and GW501516 decreased the proliferation of PASMCs induced by hypoxia by blocking the progression through the G0/G1 to S phase of the cell cycle. In accordance with these findings, GW501516 downregulated Skp2 and upregulated p27 in hypoxia-exposed PASMCs. Further experiments showed that rapamycin had similar effects as GW501516 in inhibiting cell proliferation, arresting the cell cycle, regulating the expression of Skp2 and p27, and inactivating mTOR in hypoxia-exposed PASMCs. Moreover, MHY1485 reversed all the beneficial effects of GW501516 on hypoxia-stimulated PASMCs. Conclusion GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway.
  PubDate: 2023-08-22
  DOI: 10.1007/s11596-023-2757-y