Disproportional signal of pericarditis with biological diseasemodifying antirheumatic drugs (bDMARDs) in patients with ankylosing spondylitis: a disproportionality analysis in the FAERS database.

Objective: This study aimed to investigate the potential association between biological disease-modifying antirheumatic drugs (bDMARDs) and pericarditis and uncover relevant clinical characteristics in ankylosing spondylitis (AS). Methods: Reports of pericarditis recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004-December 2022) were identified through the preferred term "pericarditis." Demographic and clinical characteristics were described, and disproportionality signals were assessed through the reporting odds ratio (ROR) and information component (IC). A significant signal was detected if the lower bound of IC (IC025) was more than zero. Results: We found 1,874 reports of pericarditis with bDMARDs (11.3% of cases with fatal outcomes). Adalimumab (IC025 3.24), infliximab (IC025 4.90), golimumab (IC025 5.40), certolizumab (IC025 5.43), etanercept (IC025 3.24), secukinumab (IC025 3.97), and ustekinumab (IC025 7.61) exhibit significant disproportionality signals compared to other medications in the FAERS database. After excluding pre-existing diseases and co-treated drugs that may increase the susceptibility of pericarditis, the disproportionality signal associated with infliximab, certolizumab, etanercept, secukinumab, and ustekinumab remained strong. Pericarditis cases associated with all bDMARDs were predominantly recorded in women aged 25-65 years. Conclusion: More reports of pericarditis were detected with AS patients on bDMARDs than with other drugs in the overall database. Further studies are warranted to investigate the underlying mechanisms and identify patient-related susceptibility factors, thus supporting timely diagnosis and safe(r) prescribing of bDMARDs.

Recent progress in the role of endogenous metal ions in doxorubicin-induced cardiotoxicity.

Doxorubicin is a widely used anticancer drug in clinical practice for the treatment of various human tumors. However, its administration is associated with cardiotoxicity. Administration of doxorubicin with low side effects for cancer treatment and prevention are, accordingly, urgently required. The human body harbors various endogenous metal ions that exert substantial influences. Consequently, extensive research has been conducted over several decades to investigate the potential of targeting endogenous metal ions to mitigate doxorubicin's side effects and impede tumor progression. In recent years, there has been a growing body of research indicating the potential efficacy of metal ion-associated therapeutic strategies in inhibiting doxorubicin-induced cardiotoxicity (DIC). These strategies offer a combination of favorable safety profiles and potential clinical utility. Alterations in intracellular levels of metal ions have been found to either facilitate or mitigate the development of DIC. For instance, ferroptosis, a cellular death mechanism, and metal ions such as copper, zinc, and calcium have been identified as significant contributors to DIC. This understanding can contribute to advancements in cancer treatment and provide valuable insights for mitigating the cardiotoxic effects of other therapeutic drugs. Furthermore, potential therapeutic strategies have been investigated to alleviate DIC in clinical settings. The ultimate goal is to improve the efficacy and safety of Dox and offer valuable insights for future research in this field.

Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease.

Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.

Hyperoside Protects Trastuzumab-Induced Cardiotoxicity via Activating the PI3K/Akt Signaling Pathway.

PURPOSE: Trastuzumab is a landmark agent in the treatment of human epidermal growth factor receptor-2(HER2)-positive breast cancer. Nevertheless, trastuzumab also comes with unexpected cardiac side effects. Hyperoside is a natural product that serves beneficial roles in cardiovascular disease. This study aimed to explore the effect and mechanism of hyperoside in trastuzumab-induced cardiotoxicity. METHODS: A female C57BL/6 mice cardiotoxicity model was established via intraperitoneally injecting with trastuzumab (10 mg/kg/day, once every other day, cumulative dosage to 40 mg/kg) with or without hyperoside (15 or 30 mg/kg/day) administration. In vitro, the H9c2 cells were exposed to 1 µM trastuzumab with or without hyperoside (100 or 200 µM) administration. Cardiac function was evaluated by echocardiographic, myocardial enzymes levels, and pathological section examinations. TUNEL staining and Annexin V-FITC/ propidium iodide flow cytometry were used to analyze the cardiomyocyte apoptosis. RESULTS: Compared to the control group, the LVEF, LVFS was decreased and the concentrations of cTnT, CK, CK-MB and LDH in mice were significantly increased after treatment with trastuzumab. Collagen deposition and cardiomyocyte hypertrophy were observed in the myocardium of the trastuzumab group. However, these changes were all reversed by different doses of hyperoside. In addition, hyperoside attenuated trastuzumab-induced myocardium apoptosis and H9c2 cells apoptosis through inhibiting the expressions of cleaved caspase-3 and Bax. Trastuzumab abolished the PI3K/Akt signaling pathway in mice and H9c2 cells, while co-treatment of hyperoside effectively increased the ratio of p-Akt/Akt. CONCLUSION: Hyperoside inhibited trastuzumab-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Hyperoside may be a promising therapeutic approach to trastuzumab-induced cardiotoxicity.

The Involvement of PGRMC1 Signaling in Cognitive Impairment Induced by Long-Term Clozapine Treatment in Rats.

INTRODUCTION: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. METHODS: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. RESULTS: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. CONCLUSION: PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.

Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System.

BACKGROUND AND OBJECTIVE: Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear. METHODS: A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship. RESULTS: From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria. CONCLUSIONS: This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.

Trastuzumab potentiates doxorubicin-induced cardiotoxicity via activating the NLRP3 inflammasome in vivo and in vitro.

Trastuzumab (Tra), the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), is commonly used alongside doxorubicin (Dox) as a combination therapy in HER2-positive breast cancer. Unfortunately, this leads to a more severe cardiotoxicity than Dox alone. NLRP3 inflammasome is known to be involved in Dox-induced cardiotoxicity and multiple cardiovascular diseases. However, whether the NLRP3 inflammasome contributes to the synergistic cardiotoxicity of Tra has not been elucidated. In this study, primary neonatal rat cardiomyocyte (PNRC), H9c2 cells and mice were treated with Dox (15 mg/kg in mice or 1 µM in cardiomyocyte) or Tra (15.75 mg/kg in mice or 1 µM in cardiomyocyte), or Dox combined Tra as cardiotoxicity models to investigate this question. Our results demonstrated that Tra significantly potentiated Dox-induced cardiomyocyte apoptosis and cardiac dysfunction. These were accompanied by the increased expressions of NLRP3 inflammasome components (NLRP3, ASC and cleaved caspase-1), the secretion of IL-ß and the pronounced production of ROS. Inhibiting the activation of NLRP3 inflammasome by NLRP3 silencing significantly reduced cell apoptosis and ROS production in Dox combined Tra-treated PNRC. Compared with the wild type mice, the systolic dysfunction, myocardial hypertrophy, cardiomyocyte apoptosis and oxidative stress induced by Dox combined Tra were alleviated in NLRP3 gene knockout mice. Our data revealed that the co-activation of NLRP3 inflammasome by Tra promoted the inflammation, oxidative stress and cardiomyocytes apoptosis in Dox combined Tra-induced cardiotoxicity model both in vivo and in vitro. Our results suggest that NLRP3 inhibition is a promising cardioprotective strategy in Dox/Tra combination therapy.

Hyperoside prevents doxorubicin-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway.

Clinical application of doxorubicin (Dox) in cancer chemotherapy is limited by its cardiotoxicity. Present study aimed to demonstrate the effect and mechanism of hyperoside in Dox-induced cardiotoxicity. C57BL/6 mice were injected with 12 mg/kg of Dox, and 1 µM Dox was exposed to primary cardiomyocytes. Cardiac function was evaluated by echocardiographic and myocardial enzyme levels. Cardiomyocyts apoptosis was analyzed by TUNEL staining and flow cytometry. Network pharmacology and molecular docking were utilized to explore potential targets of hyperoside. Protein expressions were detected by western blot and enzyme activities were determined by colorimetry. Cardiac dysfunction and cardiomyocyte apoptosis induced by Dox were attenuated by hyperoside. Mechanism of hyperoside was mainly related to "oxidative stress" pathway. Hyperoside exhibited strong binding activities with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs, the main source of ROS in cardiomyocytes) and cyclooxygenases (COXs). Experiments proved that hyperoside suppressed the ROS generation and the elevated activities of NOXs and COXs induced by Dox. Dox also triggered the activation of NLRP3 inflammasome, which was reversed by hyperoside. Hyperoside bound to NOXs and COXs, which prevents Dox-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway. Hyperoside holds promise as a therapeutic strategy for Dox-induced cardiotoxicity.

Tumor Lysis Syndrome Associated with Monoclonal Antibodies in Patients with Multiple Myeloma: A Pharmacovigilance Study Based on the FAERS Database.

Although some tumor lysis syndrome (TLS) cases have been reported with patients with multiple myeloma (MM) taking monoclonal antibodies (mAbs), the association between TLS and mAbs remains mostly unknown. We aim to investigate the association between TLS and mAbs and describe clinical features. We conducted a disproportionality analysis to investigate the link between mAbs and TLS by excluding known confounders and compared with other anticancer drugs. The association between mAbs and TLS was evaluated using information component (IC). Drug-drug interaction signals were calculated based on the Ω shrinkage measure. Parametric distribution with the goodness-of-fit test was used for the reported time-to-onset analysis. From 2016 Q1, to 2022 Q4, a total of 274 TLS with mAbs were reported in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. There were 27% of patients with TLS with mAbs who died and 20.1% occurred a life-threatening situation. Daratumumab, elotuzumab, and belantamab mafodotin presented a robust disproportionate signal of TLS after excluding known confounders (IC025 > 0). Daratumumab had the highest disproportionate signal of TLS among all anticancer drugs for MM. Reported time-to-onset analysis showed the median days for TLS with daratumumab, isatuximab, elotuzumab, and belantamab mafodotin were 1.5, 14.5, 5.5, and 5.5 days, respectively. The drug-drug interaction analysis showed the co-administration of drugs known to increase urate, induce hyperkalemia, or hypocalcemia elevated the reporting frequency for TLS with mAbs (Ω025 > 0). Our postmarketing pharmacovigilance analysis detected the reporting association of TLS and mAbs in patients with MM. Additional studies with robust epidemiological study designs that can validate these findings are warranted.

Insight into mitochondrial dysfunction mediated by clozapine-induced inhibition of PGRMC1 in PC12 cells.

Clozapine is usually considered as the last resort for treatment-resistant schizophrenia (TRS). However, it shows limited efficacy in cognition improvement. Moreover, the metabolic side effects induced by clozapine can aggravate cognitive impairment, which is closely related to its neurotoxicity. Nevertheless, the mechanisms underlying clozapine's neurotoxicity remain largely elusive. In this study, PC12 cells were simultaneously treated with different concentrations (0 µM, 10 µM, 20 µM, 40 µM and 80 µM) of clozapine and AG205 which functions as a blocking reagent of progesterone receptor membrane component 1 (PGRMC1). In addition, we examined the effect of PGRMC1 in clozapine-induced neurotoxicity through overexpressing or downregulating PGRMC1. Molecular docking and surface plasmon resonance (SPR) analysis indicated that clozapine and AG205 inhibited the binding of endogenous progesterone to PGRMC1. The results showed that high concentration of clozapine and AG205 induced a significant increase in cytotoxicity, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse, all of which were worsened as concentration increases, while overexpression of PGRMC1 reverted the above toxic effect of clozapine on PC12 cells. Furthermore, clozapine and AG205 also downregulated the expression of PGRMC1, glucagon-like peptide-1 receptor (GLP-1R) and mitofusin2 (Mfn2). Interestingly, overexpression of PGRMC1 could revert these effects. Our data suggest that overexpression of PGRMC1 in PC12 cells prevents and restores clozapine-induced oxidative and mitochondrial damage. We propose PGRMC1 activation as a promising therapeutic strategy for clozapine-induced neurotoxicity to facilitate the relief of neuronal damage.

Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features. Methods: Reports of PJP recorded in FAERS (January 2004-December 2022) were identified through the preferred term "Pneumocystis jirovecii pneumonia". Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence. Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed. Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

A rapid and sensitive LC-MS/MS method for simultaneous determination of melphalan and its monohydroxy and dihydroxy metabolites in human plasma.

As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the concentrations of melphalan and its hydrolyzed metabolites in plasma. The aim of this study was to develop a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of melphalan and its hydrolyzed metabolites, monohydroxy melphalan (MOH melphalan) and dihydroxy melphalan (DOH melphalan). A simple protein precipitation was employed for sample preparation and melphalan-d8 was used as internal standard. Baseline separation of target analytes was achieved using an XSelect HSS T3 column (2.1 × 50 mm, 5 µm) with a gradient elution at a flow rate of 0.5 mL/min in 5 min. The monitored transitions were m/z 305.1 â†’ 287.7 for melphalan, m/z 287.1 â†’ 228.0 for MOH melphalan, m/z 269.3 â†’ 251.8 for DOH melphalan, and m/z 313.1 â†’ 295.7 for melphalan-d8. The method was fully validated in accordance with the FDA guideline. The calibration curves were established over the range of 5.22-5220 ng/mL for melphalan, 7.94-1588 ng/mL for MOH-melphalan, and 15.0-3000 ng/mL for DOH-melphalan with the regression coefficients greater than 0.99. The intra- and inter-day coefficients of variation for the analytes were ≤11.0% and all the biases were less than 8.3%. The method has been successfully applied to the quantification of melphalan and its metabolites in clinical plasma samples obtained from hematopoietic stem cell transplantation patients who received a dose of melphalan for pre-transplant conditioning.

Variable p53/Nrf2 crosstalk contributes to triptolide-induced hepatotoxic process.

This study was to investigate the potential mechanism of triptolide-induced hepatotoxicity. We found a novel and variable role of p53/Nrf2 crosstalk in triptolide-induced hepatotoxic process. Low doses of triptolide led to adaptive stress response without obvious toxicity, while high levels of triptolide caused severe adversity. Correspondingly, at the lower levels of triptolide treatment, nuclear translocation of Nrf2 as well as its downstream efflux transporters multidrug resistance proteins and bile salt export pump expressions were significantly enhanced, so did p53 pathways that also increased; at a toxic concentration, total and nuclear accumulations of Nrf2 decreased, while p53 showed an obvious nuclear translocation. Further studies showed the cross-regulation between p53 and Nrf2 after different concentrations of triptolide treatment. Under mild stress conditions, Nrf2 induced p53 highly expression to maintain the pro-survival outcome, while p53 showed no obvious effect on Nrf2 expression and transcriptional activity. Under high stress conditions, the remaining Nrf2 as well as the largely induced p53 mutually inhibited each other, leading to a hepatotoxic result. Nrf2 and p53 could physically and dynamically interact. Low levels of triptolide enhanced the interaction between Nrf2 and p53. Reversely, p53/Nrf2 complex dissociated at high levels of triptolide treatment. Altogether, variable p53/Nrf2 crosstalk contributes to triptolide-induced self-protection and hepatotoxicity, modulation of which may be a potential strategy for triptolide-induced hepatotoxicity intervention.

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice.

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study.

Introduction: Antibody-drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies. Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis. Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses. Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p <0.001); however, age did not exert influence on the risk of sepsis. We identified that 973 of 2,441 (39.9%) cases had acute myeloid leukemia (AML), and 766 of 2613 (29.3%) cases on ADCs died during therapy. Time-to-onset analysis indicated ADC-related sepsis is prone to occur within a month after administration. Co-administration of ADCs with colony-stimulating factors, proton pump inhibitors, H2-receptor antagonists, or CYP3A4/5 inhibitors showed to synergistically increase the risk of sepsis-related toxicities. Conclusion: Antibody-drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway.

Sunitinib is a multi-targeted tyrosine kinase inhibitor with remarkable anticancer activity, while hepatotoxicity is a potentially fatal adverse effect of its administration. The aim of this study was to elucidate the mechanism of hepatotoxicity induced by Sunitinib and the protective effect of glycyrrhetinic acid (GA). Sunitinib significantly reduced the survival of human normal hepatocytes (L02 cells), induced the increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Chloroquine (CQ) and Z-VAD-FMK were applied to clarify the cell death patterns induced by Sunitinib. Sunitinib significantly induced L02 cells death by triggering apoptosis and autophagy acted as a self-defense mechanism to promote survival. Sunitinib exposure caused excessive ROS generation which activated mitogen-activated protein kinases (MAPKs) signaling. Mechanistically, SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor) respectively blocked apoptosis and autophagy induced by Sunitinib. And inhibition of ROS by NAC pretreatment ameliorated the effect of Sunitinib on MAPKs phosphorylation. GA alleviated Sunitinib-induced cell damage by inhibiting apoptosis and autophagy. These results suggested ROS/MAPKs signaling pathway was responsible for Sunitinib-induced hepatotoxicity and GA could be a preventive strategy to alleviate liver injury caused by Sunitinib.

Dissecting the molecular mechanism of cepharanthine against COVID-19, based on a network pharmacology strategy combined with RNA-sequencing analysis, molecular docking, and molecular dynamics simulation.

OBJECTIVES: Recently, it has been reported that cepharanthine (CEP) is highly likely to be an agent against Coronavirus disease 2019 (COVID-19). In the present study, a network pharmacology-based approach combined with RNA-sequencing (RNA-seq), molecular docking, and molecular dynamics (MD) simulation was performed to determine hub targets and potential pharmacological mechanism of CEP against COVID-19. METHODS: Targets of CEP were retrieved from public databases. COVID-19-related targets were acquired from databases and RNA-seq datasets GSE157103 and GSE155249. The potential targets of CEP and COVID-19 were then validated by GSE158050. Hub targets and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI) network analysis and enrichment analysis. Subsequently, molecular docking was carried out to predict the combination of CEP with hub targets. Lastly, MD simulation was conducted to further verify the findings. RESULTS: A total of 700 proteins were identified as CEP-COVID-19-related targets. After the validation by GSE158050, 97 validated targets were retained. Enrichment results indicated that CEP acts on COVID-19 through multiple pathways, multiple targets, and overall cooperation. Specifically, PI3K-Akt signaling pathway is the most important pathway. Based on PPI network analysis, 9 central hub genes were obtained (ACE2, STAT1, SRC, PIK3R1, HIF1A, ESR1, ERBB2, CDC42, and BCL2L1). Molecular docking suggested that the combination between CEP and 9 central hub genes is extremely strong. Noteworthy, ACE2, considered the most important gene in CEP against COVID-19, binds to CEP most stably, which was further validated by MD simulation. CONCLUSION: Our study comprehensively illustrated the potential targets and underlying molecular mechanism of CEP against COVID-19, which further provided the theoretical basis for exploring the potential protective mechanism of CEP against COVID-19.

Role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity: A systematic review.

Cardiotoxicity induced by anticancer drugs interferes with the continuation of optimal treatment, inducing life-threatening risks or leading to long-term morbidity. The heart is a complex pluricellular organ comprised of cardiomyocytes and non-cardiomyocytes. Although the study of these cell populations has been often focusing on cardiomyocytes, the contributions of non-cardiomyocytes to development and disease are increasingly being appreciated as both dynamic and essential. This review summarized the role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity, including the mechanism of direct damage to resident non-cardiomyocytes, cardiomyocytes injury caused by paracrine modality, myocardial inflammation induced by transient cell populations and the protective agents that focused on non-cardiomyocytes.

Ferroptosis in inflammatory arthritis: A promising future.

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which is characterized by mitochondrial morphological changes and has a complex regulatory network. Ferroptosis has been gradually emphasized in the pathogenesis of inflammatory arthritis. In this review, we summarized the relevant research on ferroptosis in various inflammatory arthritis including rheumatoid arthritis (RA), osteoarthritis, gout arthritis, and ankylosing spondylitis, and focused on the relationship between RA and ferroptosis. In patients with RA and animal models of RA, there was evidence of iron overload and lipid peroxidation, as well as mitochondrial dysfunction that may be associated with ferroptosis. Ferroptosis inducers have shown good application prospects in tumor therapy, and some anti-rheumatic drugs such as methotrexate and sulfasalazine have been shown to have ferroptosis modulating effects. These phenomena suggest that the role of ferroptosis in the pathogenesis of inflammatory arthritis will be worth further study. The development of therapeutic strategies targeting ferroptosis for patients with inflammatory arthritis may be a promising future.

Olanzapine-induced lipid disturbances: A potential mechanism through the gut microbiota-brain axis.

Objective: Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis plays an important role in lipid metabolism, and may be related to the metabolic side effects of olanzapine. Therefore, we explored the mechanism by which olanzapine-induced lipid disturbances through the gut microbiota-brain axis. Methods: Sprague Dawley rats were randomly divided into two groups, which underwent subphrenic vagotomy and sham surgery. Then the two groups were further randomly divided into two subgroups, one was administered olanzapine (10 mg/kg/day) by intragastric administration, and the other was administered normal saline by intragastric administration (4 ml/kg/day) for 2 weeks. The final changes in lipid parameters, gut microbes and their metabolites, and orexin-related neuropeptides in the hypothalamus were investigated among the different groups. Results: Olanzapine induced lipid disturbances as indicated by increased weight gain, elevated ratio of white adipose tissue to brown adipose tissue, as well as increased triglyceride and total cholesterol. Olanzapine also increased the Firmicutes/Bacteroides (F/B) ratio in the gut, which was even aggravated by subphrenic vagotomy. In addition, olanzapine reduced the abundance of short-chain fatty acids (SCFAs) metabolism related microbiome and 5-hydroxytryptamine (5-HT) levels in the rat cecum, and increased the gene and protein expression of the appetite-related neuropeptide Y/agouti-related peptide (NPY/AgRP) in the hypothalamus. Conclusion: The abnormal lipid metabolism caused by olanzapine may be closely related to the vagus nerve-mediated gut microbiota-brain axis.