Pneumatosis intestinalis post steroid use in a patient with immune-related adverse events: Case report, literature review and FAERS analysis.

Introduction: The accurate diagnosis of pneumatosis intestinalis (PI) is increasing despite patients' limited identification of etiologic factors. Recently a patient with lung squamous carcinoma who developed pneumatosis intestinalis following methylprednisolone administration for immune-related adverse events was treated at our hospital. Subsequent a literature review and an analysis of the FDA Adverse Event Reporting System (FAERS) database enabled the identification of additional cases of pneumatosis intestinalis. Methods: A literature review of the MEDLINE/PubMed and Web of Science Core Collection databases using standard pneumatosis intestinalis search terms to identify published cases of immune checkpoint inhibitors (ICIs) or steroids causing pneumatosis intestinalis were performed. A separate retrospective pharmacovigilance study of FAERS enabled the extraction of unpublished cases of pneumatosis intestinalis between the first quarter of 2005 and the third quarter of 2022. Disproportionality and Bayesian analyses were performed to identify signal detection in reported odds ratios, proportional reporting ratios, information components, and empirical Bayesian geometric means. Results: Ten case reports of steroid-related pneumatosis intestinalis were retrieved from six published studies. The implicated drug therapies included pre-treatment with steroids before chemotherapy, combination therapy with cytotoxic agents and steroids, and monotherapy with steroids. In the FAERS pharmacovigilance study, 1,272 cases of immune checkpoint inhibitors or steroid-related pneumatosis intestinalis were incidentally reported. The signal detected in five kinds of immune checkpoint inhibitors and six kinds of steroids implied a positive correlation between the drugs and adverse events. Conclusion: Steroids might be the etiologic factors in the current case of pneumatosis intestinalis. Reports supporting the role of steroids in suspected cases of pneumatosis intestinalis can be found in literature databases and the FAERS database. Even so, as documented in FAERS, immune checkpoint inhibitors-induced pneumatosis intestinalis should not be excluded.

Glucagon-like peptide 1 receptor agonists and the potential risk of pancreatic carcinoma: a pharmacovigilance study using the FDA Adverse Event Reporting System and literature visualization analysis.

BACKGROUND: There are increasing data on the potential risk of pancreatic carcinoma associated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). AIM: The study aimed to determine whether GLP-1RAs are associated with increased detection of pancreatic carcinoma based on the FDA Adverse Events Reporting System and clarify its potential mechanisms through keyword co-occurrence analysis from literature database. METHOD: Disproportionality and Bayesian analyses were used for signal detection using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Mortality, life-threatening events, and hospitalizations were also investigated. VOSviewer was adopted to generate visual analysis of keyword hotspots. RESULTS: A total of 3073 pancreatic carcinoma cases were related to GLP-1RAs. Five GLP-1RAs were detected with signals for pancreatic carcinoma. Liraglutide had the strongest signal detection (ROR 54.45, 95% CI 51.21-57.90; PRR 52.52, 95% CI 49.49-55.73; IC 5.59; EBGM 48.30). The signals of exenatide (ROR 37.32, 95% CI 35.47-39.28; PRR 36.45, 95% CI 34.67-38.32; IC 5.00; EBGM 32.10) and lixisenatide (ROR 37.07, 95% CI 9.09-151.09; PRR 36.09; 95% CI 9.20-141.64; IC 5.17, EBGM 36.09) were stronger than those of semaglutide (ROR 7.43, 95% CI 5.22-10.57; PRR 7.39; 95% CI 5.20-10.50; IC 2.88, EBGM 7.38) and dulaglutide (ROR 6.47, 95% CI 5.56-7.54; PRR 6.45; 95% CI 5.54-7.51; IC 2.67, EBGM 6.38). The highest mortality rate occurred in exenatide (63.6%). Based on the bibliometric investigation, cAMP/protein-kinase, Ca2+ channel, endoplasmic-reticulum stress, and oxidative stress are potential pathogenesis of pancreatic carcinoma resulting from GLP-1RAs. CONCLUSION: Based on this pharmacovigilance study, GLP-1RAs, except albiglutide, are associated with pancreatic carcinoma.

Drug-Induced Cardiotoxicity in Children During the Past 30 Years: A Bibliometric Study and Visualization Analysis.

BACKGROUND Drug-induced cardiotoxicity (DICT) is one of the most serious adverse drug reactions, which is an important safety issue in drug development and clinical practice. This study aimed to summarize the knowledge structure and to detect emerging trends, and provide ideas for future research on DICT in children using bibliometric methods. MATERIAL AND METHODS All publications on DICT in children were retrieved through the Web of Science Core Collection up to April 20, 2022. The document type was restricted to articles with the language set to English. CiteSpace and VOSviewer were used to conduct this bibliometric analysis. RESULTS A total of 298 articles were included, and the annual publications decreased since 2021. The United States was the leading country with the most publications (117), the highest centrality (0.39), and total citations (4055). The most influential institution was the University of British Columbia, while Carleton BC and Rassekh SR, both from Canada, were the most productive authors, but there was no leader in this field. The keywords with both high frequency and high centrality after excluding "cardiotoxicity" and "children" were acute lymphoblastic leukemia (Freq=43, Central=0.15), childhood cancer (Freq=42, Central=0.13), toxicity (Freq=33, Central=0.16), and breast cancer (Freq=29, Central=0.19). "Adriamycin cardiotoxicity" was the first burst keyword, while "childhood cancer", "oxidative stress", and "cardiac dysfunction" were emerging research hotspots. CONCLUSIONS Attention to DICT in children was insufficient. This study serves as a breakthrough point, providing a comprehensive overview of the knowledge structure, development landscape, and future opportunities in this field.

Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.

Background: Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. Since Warburg O first observed alterations in cancer metabolism in the 1950s, people gradually found tumor metabolism pathways play a fundamental role in regulating the response to chemotherapeutic drugs, and the attempts of targeting tumor energetics have shown promising preclinical outcomes in recent years. This study aimed to summarize the knowledge structure and identify emerging trends and potential hotspots in metabolic signaling pathways of tumor drug resistance research. Methods: Publications related to metabolic signaling pathways of tumor drug resistance published from 1992 to 2022 were retrieved from the Web of Science Core Collection database. The document type was set to articles or reviews with language restriction to English. Two different scientometric software including Citespace and VOS viewer were used to conduct this scientometric analysis. Results: A total of 2,537 publications including 1,704 articles and 833 reviews were retrieved in the final analysis. The USA made the most contributions to this field. The leading institution was the University of Texas MD Anderson Cancer Center. Avan A was the most productive author, and Hanahan D was the key researcher with the most co-citations, but there is no leader in this field yet. Cancers was the most influential academic journal, and Oncology was the most popular research field. Based on keywords occurrence analysis, these selected keywords could be roughly divided into five main topics: cluster 1 (study of cancer cell apoptosis pathway); cluster 2 (study of resistance mechanisms of different cancer types); cluster 3 (study of cancer stem cells); cluster 4 (study of tumor oxidative stress and inflammation signaling pathways); and cluster 5 (study of autophagy). The keywords burst detection identified several keywords as new research hotspots, including "tumor microenvironment," "invasion," and "target". Conclusion: Tumor metabolic reprogramming of drug resistance research is advancing rapidly. This study serves as a starting point, providing a thorough overview, the development landscape, and future opportunities in this field.

The potential roles of Nrf2/Keap1 signaling in anticancer drug interactions.

Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), together with its suppressive binding partner Kelch-like ECH-associated protein 1 (Keap1), regulates cellular antioxidant response and drug metabolism. The roles of Nrf2/Keap1 signaling in the pathology of many diseases have been extensively investigated, and small molecules targeting Nrf2/Keap1 signaling have been developed to prevent or treat diseases such as multiple sclerosis, chronic kidney disease and cancer. Notably, Nrf2 plays dual roles in cancer development and treatment. Activation of Nrf2/Keap1 signaling in cancer cells has been reported to promote cancer progression and result in therapy resistance. Since cancer patients are often suffering comorbidities of other chronic diseases, anticancer drugs could be co-administrated with other drugs and herbs. Nrf2/Keap1 signaling modulators, especially activators, are common in drugs, herbs and dietary ingredients, even they are developed for other targets. Therefore, drug-drug or herb-drug interactions due to modulation of Nrf2/Keap1 signaling should be considered in cancer therapies. Here we briefly summarize basic biochemistry and physiology functions of Nrf2/Keap1 signaling, Nrf2/Keap1 signaling modulators that cancer patients could be exposed to, and anticancer drugs that are sensitive to Nrf2/Keap1 signaling, aiming to call attention to the potential drug-drug or herb-drug interactions between anticancer drugs and these Nrf2/Keap1 signaling modulators.

Predicting 1-Hour Thrombolysis Effect of r-tPA in Patients With Acute Ischemic Stroke Using Machine Learning Algorithm.

Background: Thrombolysis with r-tPA is recommended for patients after acute ischemic stroke (AIS) within 4.5 h of symptom onset. However, only a few patients benefit from this therapeutic regimen. Thus, we aimed to develop an interpretable machine learning (ML)-based model to predict the thrombolysis effect of r-tPA at the super-early stage. Methods: A total of 353 patients with AIS were divided into training and test data sets. We then used six ML algorithms and a recursive feature elimination (RFE) method to explore the relationship among the clinical variables along with the NIH stroke scale score 1 h after thrombolysis treatment. Shapley additive explanations and local interpretable model-agnostic explanation algorithms were applied to interpret the ML models and determine the importance of the selected features. Results: Altogether, 353 patients with an average age of 63.0 (56.0-71.0) years were enrolled in the study. Of these patients, 156 showed a favorable thrombolysis effect and 197 showed an unfavorable effect. A total of 14 variables were enrolled in the modeling, and 6 ML algorithms were used to predict the thrombolysis effect. After RFE screening, seven variables under the gradient boosting decision tree (GBDT) model (area under the curve = 0.81, specificity = 0.61, sensitivity = 0.9, and F1 score = 0.79) demonstrated the best performance. Of the seven variables, activated partial thromboplastin clotting time (time), B-type natriuretic peptide, and fibrin degradation products were the three most important clinical characteristics that might influence r-tPA efficiency. Conclusion: This study demonstrated that the GBDT model with the seven variables could better predict the early thrombolysis effect of r-tPA.

Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells.

Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA-induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention.

Dibenzoylmethane Protects Against CCl4-Induced Acute Liver Injury by Activating Nrf2 via JNK, AMPK, and Calcium Signaling.

Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl4)-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl4-induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.

Biotransformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis.

Microbial transformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis CICC 3043 yielded seven metabolites. Their structures were elucidated on the basis of extensive spectroscopic analyses. R. chinensis could catalyze hydroxylation and further dehydrogenation at C-24 of 20(R)-panaxadiol, as well as hydroxylation at C-7, C-15, C-16, and C-29. Three of these compounds at 10µM could moderately inhibit growth of HepG2 human hepatocellular carcinoma cells with an inhibition rate of about 40%. Three compounds (also at 10µM) showed approximately 30% inhibition on NF-κB transcriptional activity in SW480 human colon carcinoma cells stably transfected with NF-κB luciferase reporter and induced by LPS.