Interplay of ferroptosis, cuproptosis, and PANoptosis in cancer treatment-induced cardiotoxicity: Mechanisms and therapeutic implications.

With the prolonged survival of individuals with cancer, the emergence of cardiovascular diseases (CVD) induced by cancer treatment has become a significant concern, ranking as the second leading cause of death among cancer survivors. This review explores three distinct types of programmed cell death (PCD): ferroptosis, cuproptosis, and PANoptosis, focusing on their roles in chemotherapy-induced cardiotoxicity. While ferroptosis and cuproptosis are triggered by excess iron and copper (Cu), PANoptosis is an inflammatory PCD with features of pyroptosis, apoptosis, and necroptosis. Recent studies reveal intricate connections among these PCD types, emphasizing the interplay between cuproptosis and ferroptosis. Notably, the role of intracellular Cu in promoting ferroptosis through GPX4 is highlighted. Additionally, ROS-induced PANoptosis is influenced by ferroptosis and cuproptosis, suggesting a complex interrelationship. This review provides insights into the molecular mechanisms of these PCD modalities and their distinct contributions to chemotherapy-induced cardiotoxicity. Furthermore, we discuss the potential application of cardioprotective drugs in managing these PCD types. This comprehensive analysis aims to advance the understanding, diagnosis, and therapeutic strategies for cardiotoxicity associated with cancer treatment.

Advances in the application of nanotechnology in reducing cardiotoxicity induced by cancer chemotherapy.

Advances in the development of anti-tumour drugs and related technologies have resulted in a significant increase in the number of cancer survivors. However, the incidence of chemotherapy-induced cardiotoxicity (CIC) has been rising continuously, threatening their long-term survival. The integration of nanotechnology and biomedicine has brought about an unprecedented technological revolution and has promoted the progress of anti-tumour therapy. In this review, we summarised the possible mechanisms of CIC, evaluated the role of nanoparticles (including liposomes, polymeric micelles, dendrimers, and hydrogels) as drug carriers in preventing cardiotoxicity and proposed five advantages of nanotechnology in reducing cardiotoxicity: Liposomes cannot easily penetrate the heart's endothelial barrier; optimized delivery strategies reduce distribution in important organs, such as the heart; targeting the tumour microenvironment and niche; stimulus-responsive polymer nano-drug carriers rapidly iterate; better economic benefits were obtained. Nanoparticles can effectively deliver chemotherapeutic drugs to tumour tissues, while reducing the toxicity to heart tissues, and break through the dilemma of existing chemotherapy to a certain extent. It is important to explore the interactions between the physicochemical properties of nanoparticles and optimize the highly specific tumour targeting strategy in the future.

Relevance of mitochondrial oxidative stress to arrhythmias: Innovative concepts to target treatments.

Cardiac arrhythmia occurs frequently worldwide, and in severe cases can be fatal. Mitochondria are the power plants of cardiomyocytes. In recent studies, mitochondria under certain stimuli produced excessive reactive oxygen species (ROS), which affect the normal function of cardiomyocytes through ion channels and related proteins. Mitochondrial oxidative stress (MOS) plays a key role in diseases with multifactorial etiopathogenesis, such as arrhythmia; MOS can lead to arrhythmias such as atrial fibrillation and ventricular tachycardia. This review discusses the mechanisms of arrhythmias caused by MOS, particularly of ROS produced by mitochondria. MOS can cause arrhythmias by affecting the activities of Ca2+-related proteins, the mitochondrial permeability transition pore protein, connexin 43, hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, and ion channels. Based on these mechanisms, we discuss possible new treatments for arrhythmia. Targeted treatments focusing on mitochondria may reduce the progression of arrhythmias, as well as the occurrence of severe arrhythmias, and may be effective for personalized disease prevention.

Soy isoflavone genistein inhibits hsa_circ_0031250/miR-873-5p/FOXM1 axis to suppress non-small-cell lung cancer progression.

The foods of plants provide the rich nutrition and have protective function in human diseases, including cancers. Genistein is a major isoflavone constituent in soybeans, which has an anti-cancer role in non-small-cell lung cancer (NSCLC). Nevertheless, the mechanism underlying the anti-cancer function of genistein in NSCLC remains largely unknown. NSCLC cells (H292 and A549) were exposed to genistein. Circular RNA hsa_circ_0031250 (circ_0031250), microRNA (miR)-873-5p and forkhead box M1 (FOXM1) abundances were examined via quantitative reverse transcription polymerase chain reaction and Western blotting. The function of genistein, circ_0031250, miR-873-5p, and FOXM1 on NSCLC progression was investigated via Cell Counting Kit-8, colony formation, transwell well, wound healing, flow cytometry, Western blotting and xenograft model. The target relationship was analyzed by dual-luciferase reporter analysis and RNA immunoprecipitation. Results showed that genistein inhibited NSCLC cell viability in dose-time-dependent patterns. circ_0031250 abundance was elevated in NSCLC samples and cell lines, and it was reduced via genistein exposure. circ_0031250 knockdown aggravated genistein-caused suppression of cell proliferation, migration and invasion and elevation of apoptosis. miR-873-5p expression was decreased in NSCLC samples and cells. miR-873-5p was targeted via circ_0031250, and miR-873-5p knockdown attenuated the influence of circ_0031250 silence on NSCLC progression in the presence of genistein. FOXM1 was regulated via circ_0031250/miR-873-5p axis. miR-873-5p constrained cell proliferation, migration and invasion and increased apoptosis via regulating FOXM1 in genistein-treated cells. circ_0031250 knockdown enhanced the inhibitive function of genistein on NSCLC cell growth in xenograft model. Collectively, genistein repressed NSCLC progression by modulating circ_0031250/miR-873-5p/FOXM1 axis.

Does heart failure increase the risk of incident cancer? A meta-analysis and systematic review.

Recently, several studies have demonstrated that heart failure (HF) may increase the risk of incident cancer. However, this association has not been statistically and systematically verified by any comprehensive pooled analyses. We performed a meta-analysis on cancer morbidity and co-mortality of adults with HF in a large sample size to explore the relationship between HF and the risk of developing cancer. From inception to April 2019, we searched PubMed and EMBASE for published relevant articles on patients with HF diagnosed with cancer afterwards, with reported outcomes of morbidity and mortality. Two investigators independently reviewed these included studies. Study data were independently extracted using predefined data extraction forms. Random and fixed-effects models were fit for the study duration. This analysis consisted of 4 cohort studies comprising 5,004,251 participants. The relative risk (RR) for incident cancer was 1.22 (95% confidence interval (CI), 1.13-1.33) indicating that patients with HF may have a higher risk of developing cancer. The pooled RR of co-mortality was 2.03 (95% CI, 1.13-3.65), indicating that HF associated with cancer increases the risk of mortality. In this meta-analysis and systematic review, our results demonstrated that heart failure may increase the risk of incident cancer and that HF associated with cancer increases the risk of mortality.

Chinese herbal medicine for coronavirus disease 2019: A systematic review and meta-analysis.

Currently, coronavirus disease 2019 (COVID-19), which can lead to severe respiratory failure and death, is now a global pandemic with no specific anti-viral drugs or vaccines. However, It is worth noting that traditional Chinese medicine (TCM), especially Chinese herbal medicine (CHM), has been widely applied in mainland China since outbreak, bringing new hope for the prevention and control of COVID-19. A comprehensive literature searching was conducted in 7 electronic databases from their inception up to June 21, 2020 to evaluate the efficacy and safety of CHM for COVID-19. Eighteen randomized controlled trials (RCTs) involving 2275 patients were enrolled. Most of CHMs were originated from classical Chinese herbal formulas. Liquoric Root (Gancao, Radix Glycyrrhizae), Baical Skullcap Root (Huangqin, Radix Scutellariae Baicalensis), Pinellia Rhizome (Banxia, Rhizoma Pinelliae Tematae), Forsythia Fruit (Lianqiao, Fructus Forsythiae Suspensae), and Bitter Apricot Seed (Kuxingren, Semen Armeniacae Amarum) were most frequently used Chinese herbs. The most commonly used dosage formulation was decoction. Our meta-analyses found that comparing CHM group and conventional western medicine group, CHM group has improvements in several clinical parameters including lung CT, clinical cure rate, ranging from mild to critical cases, length of hospital stay, total score of clinical symptoms, fever reduction time, symptom score of fever, number of cough reduction cases, symptom score of cough, number of fatigue reduction cases, symptom score of fatigue, disappearing time of fatigue, TCM syndrome, viral nucleic acid testing, and inflammatory biomarkers (C-reactive protein). Besides, no severe adverse effects was identified by CHM. CHM, especially classical Chinese herbal formulas, could be used as potential candidates for COVID-19 in this battle.

Role of cardioprotective agents on chemotherapy-induced heart failure: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Although previous clinical randomized controlled trials (RCTs) have tested the effect of a variety of cardioprotective agents on cancer therapy-induced cardiotoxicity, the number of included patients was limited, and the results remained controversial. In this study, we aimed to evaluate the preventive or therapeutic effects of cardioprotective agents on heart failure (HF) caused by cardiotoxicity induced by cancer therapy. METHODS: We included trials of the following cardioprotective drugs: Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists and stains. We extracted the relevant information with predefined data extraction forms, and assessed the risk of bias in randomized controlled trials with the Cochrane risk of bias tool. The primary outcome was the left ventricular ejection fraction of patients after chemotherapy. We used the random-effects model to carry out pair-wise meta-analysis, and then carry out the random-effects network meta-analysis within the Bayesian framework. RESULTS: Twenty-two relevant RCTs, including 1 916 patients (79.6 % women) with a mean age of 48.4 years, were included. Based on the evaluation of all drug species from 20 studies (26 comparisons), the analysis found that 4 therapies, aldosterone antagonists (MD, 12.78 [95 % CI, 2.87-22.69] and MD, 13.75 [95 % CI, 2.21-25.30]), ACEIs (MD, 6.79 [95 % CI, 2.11-11.48] and MD, 7.76 [95 % CI, 2.64-12.88]), statin (MD, 8.35 [95 % CI, 1.11-15.59]), and beta-blockers (MD, 4.00 [95 % CI, 0.87-7.14]), had a higher efficacy than placebo and/or control, suggesting an LVEF protective effect of cardioprotective therapy. In the analysis classified by single drug or drug combination, based on 22 studies (31 comparisons), spironolactone (MD, 12.77 [95 % CI, 1.76-23.79] and MD, 14.62 [95 % CI, 1.70-27.55]), a combination of candesartan and carvedilol (MD, 12.40 [95 % CI, 0.99-23.81]), enalapril (MD, 7.35 [95 % CI, 1.16-13.54] and MD, 9.20 [95 % CI, 2.61-15.79]), and statin (MD, 8.36 [95 % CI, 0.36-16.36]) showed significant benefits in protecting left ventricular (LV) systolic function compared with the placebo and/or control. CONCLUSION: When classified according to drug type, aldosterone antagonists, ACEIs, statins, and beta-blockers could substantially improve the LV systolic function. In the analysis classified by single drug or drug combination, spironolactone, enalapril, and statin have a significant cardioprotective effect. However, ARBs have no cardioprotective effect and fail to improve the LVEF.

Cardiac injury associated with severe disease or ICU admission and death in hospitalized patients with COVID-19: a meta-analysis and systematic review.

BACKGROUND: Cardiac injury is now a common complication of coronavirus disease (COVID-19), but it remains unclear whether cardiac injury-related biomarkers can be independent predictors of mortality and severe disease development or intensive care unit (ICU) admission. METHODS: Two investigators searched the PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI), Wanfang, MedRxiv, and ChinaXiv databases for articles published through March 30, 2020. Retrospective studies assessing the relationship between the prognosis of COVID-19 patients and levels of troponin I (TnI) and other cardiac injury biomarkers (creatine kinase [CK], CK myocardial band [CK-MB], lactate dehydrogenase [LDH], and interleukin-6 [IL-6]) were included. The data were extracted independently by two investigators. RESULTS: The analysis included 23 studies with 4631 total individuals. The proportions of severe disease, ICU admission, or death among patients with non-elevated TnI (or troponin T [TnT]), and those with elevated TnI (or TnT) were 12.0% and 64.5%, 11.8% and 56.0%, and 8.2% and. 59.3%, respectively. Patients with elevated TnI levels had significantly higher risks of severe disease, ICU admission, and death (RR 5.57, 95% CI 3.04 to 10.22, P < 0.001; RR 6.20, 95% CI 2.52 to 15.29, P < 0.001; RR 5.64, 95% CI 2.69 to 11.83, P < 0.001). Patients with an elevated CK level were at significantly increased risk of severe disease or ICU admission (RR 1.98, 95% CI 1.50 to 2.61, P < 0.001). Patients with elevated CK-MB levels were at a higher risk of developing severe disease or requiring ICU admission (RR 3.24, 95% CI 1.66 to 6.34, P = 0.001). Patients with newly occurring arrhythmias were at higher risk of developing severe disease or requiring ICU admission (RR 13.09, 95% CI 7.00 to 24.47, P < 0.001). An elevated IL-6 level was associated with a higher risk of developing severe disease, requiring ICU admission, or death. CONCLUSIONS: COVID-19 patients with elevated TnI levels are at significantly higher risk of severe disease, ICU admission, and death. Elevated CK, CK-MB, LDH, and IL-6 levels and emerging arrhythmia are associated with the development of severe disease and need for ICU admission, and the mortality is significantly higher in patients with elevated LDH and IL-6 levels.

AEBP1, a prognostic indicator, promotes colon adenocarcinoma cell growth and metastasis through the NF-κB pathway.

The abnormal expression of adipocyte enhancer binding protein 1 (AEBP1) has been implicated in the carcinogenesis and progression of various types of human tumors. However, the role of AEBP1 in colon adenocarcinoma (COAD) remains largely unelucidated. In this study, we explored the clinical significance and biological function of AEBP1 in COAD. We observed that AEBP1 was overexpressed in COAD tissues and cells and that the expression of AEBP1 was correlated with tumor size, the level of histologic differentiation, lymph node metastasis, and cancer stage in COAD patients. In addition, univariate and multivariate Cox regression analyses revealed that high AEBP1 expression suggested poor prognosis in COAD. Moreover, AEBP1 silencing suppressed COAD cell proliferation, migration, and invasion, whereas the upregulation of AEBP1 promoted these behaviors. Additionally, mechanistic studies further demonstrated that AEBP1 promoted COAD cell proliferation, migration, and invasion by upregulating the expression of matrix metalloproteinase-2, vimentin, and TWIST whereas downregulating that of E-cadherin through the nuclear factor-κB pathway. Collectively, these data indicated that AEBP1 may be a new prognostic factor and a potential gene therapy target in COAD.

Efficacy and safety of Chinese herbal medicine for patients with postmenopausal hypertension: A systematic review and meta-analysis.

Chinese herbal medicine has been increasingly used for patients with postmenopausal hypertension in China. A comprehensive literature search was performed in 7 electronic databases from their inception up to December 17, 2017 to examine the efficacy and safety of Chinese herbal medicine for postmenopausal hypertension. Thirty-nine randomized controlled trials involving 3, 823 participants were included. Meta-analyses favored Chinese herbal medicine plus antihypertensive drugs on blood pressure, blood pressure variability, postmenopausal symptoms, quality of life, and hormone levels compared with antihypertensive drugs. No severe adverse effects were identified. Er-xian decoction was the most frequently prescribed herbal formula, while Rehmannia glutinosa Libosch. was the most commonly used single herb. Chinese herbal medicine as complementary therapy maybe beneficial for postmenopausal hypertension. However, the effectiveness and safety of the decoction are still uncertain due to methodological shortcomings. Well-conducted trials are warranted to resolve the issue.