Search Results (268)

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent; however, its clinical application is limited by dose-dependent cardiotoxicity, which can result in progressive cardiac dysfunction and heart failure. Increasing evidence indicates that DOX-induced cardiotoxicity is closely associated with premature cardiac senescence, a pathological process distinct from physiological cardiac aging. DOX induces senescence-associated alterations in multiple cardiac cell populations, disrupting cardiac homeostasis and contributing to pathological remodeling. In this review, we summarize current advances in DOX-induced cardiac senescence, focusing on the contributions of different cardiac cell types, the underlying molecular mechanisms, and emerging therapeutic strategies. We further discuss the challenges and future perspectives for developing effective interventions that alleviate cardiac senescence while preserving the anticancer efficacy of DOX. Understanding the mechanisms driving DOX-induced cardiac senescence may provide new opportunities to develop effective cardioprotective strategies and improve long-term cardiac outcomes after chemotherapy. Full article

Background: As a common clinical anticancer drug, doxorubicin (DOX) easily triggers obvious doxorubicin-induced cardiotoxicity (DIC) during clinical application. Accumulating evidence has proven that ferroptosis dominates the pathological process of DIC yet efficient targeted treatment strategies remain scarce. The present work mainly focused on clarifying the protective role of quercetin (QUE) against DIC. Methods: In vivo rat models and in vitro cardiomyocyte injury models were constructed to mimic DIC. Echocardiographic detection and histological staining were adopted to observe overall cardiac function and myocardial fibrotic changes. Ultrastructural alterations of intracellular mitochondria were observed under a transmission electron microscope. Relevant ferroptosis and oxidative stress levels were further determined. Moreover, a Western blot assay and NRF2 gene transfection technique were applied to confirm the involvement of the NRF2 signaling pathway. Results: In vivo and in vitro experimental outcomes showed that QUE treatment effectively relieved abnormal cardiac function and myocardial fibrotic lesions and improved damaged mitochondrial morphology. It also markedly restrained excessive iron accumulation and abnormal lipid peroxidation and restored disturbed redox balance in cardiomyocytes. Further mechanism exploration revealed that QUE could facilitate NRF2 entry into the cell nucleus and activate downstream SLC7A11/GPX4 signaling to maintain cellular glutathione homeostasis. Silencing NRF2 expression could fully reverse the above beneficial influences of QUE. Conclusions: Collectively, our experimental data demonstrated that QUE confers cardioprotective effects against DIC within subacute rat models and cultured cardiomyocyte injury models. Further mechanistic observations revealed that this protective phenotype is closely linked to the activation of NRF2/SLC7A11/GPX4 signaling alongside obvious reductions in multiple characteristic ferroptosis markers. Full article

Doxorubicin-induced cardiotoxicity remains a major limitation of anthracycline chemotherapy and is closely associated with oxidative stress and mitochondrial dysfunction. Here, we investigated whether a commercial Codonopsis pilosula polysaccharide preparation (CPP) could attenuate Dox-induced cardiac injury in mice. The preparation was characterized as a glucose-dominant heteropolysaccharide with a broad and heterogeneous molecular-weight distribution dominated by a lower-molecular-weight fraction (89.25% of the integrated chromatographic area; Mw = 1.64 kDa). CPP administration improved ejection fraction and fractional shortening and attenuated myocardial fibrosis and serum markers of cardiac injury. Histological and ultrastructural analyses showed preservation of myocardial architecture and mitochondrial integrity. CPP treatment was accompanied by increased SOD and GSH-PX activities, reduced MDA accumulation, partial recovery of mitochondrial respiratory-chain-related transcripts, and restoration of cardiac ATP content. In addition, 16S rRNA gene sequencing showed that high-dose CPP treatment was associated with partial reversal of Dox-induced gut-microbiota alterations, including increased microbial diversity, reduced Escherichia-Shigella, and increased norank_f__Muribaculaceae and Ligilactobacillus. Collectively, the tested heterogeneous CPP preparation attenuated Dox-induced cardiac injury and was accompanied by improved oxidative-stress indices, preserved mitochondrial structure and function, and changes in gut-microbiota composition. Full article

Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies. Full article

The clinical use of doxorubicin (DOX), an effective chemotherapeutic drug for breast cancer, is limited by off-target nephrotoxicity, which is exacerbated in elderly patients. While excessive mitochondrial fission is known to contribute to DOX-induced cardiotoxicity, its role in DOX-induced nephrotoxicity, particularly in the context of renal aging, remains unclear. To explore this and investigate the therapeutic potential of the mitochondrial fission inhibitor Mdivi-1, female Wistar rats with D-galactose-induced accelerated renal aging were allocated into four groups: vehicle, DOX, DOX+Mdivi-1 co-treatment, and DOX+Mdivi-1 post-treatment. DOX administration resulted in significant renal dysfunction, oxidative stress, inflammation, and histopathological damage. Mitochondrial dysfunction along with the increased expression of fission protein, decreased fusion proteins, and activation of apoptotic markers and PINK1 expression were also evident. Remarkably, both co-treatment and post-treatment with Mdivi-1 comparably and significantly attenuated DOX-induced renal damage. This study suggests that Mdivi-1 mitigates DOX-induced nephrotoxicity in the aged kidney by modulating mitochondrial dynamics, suppressing oxidative stress and inflammation, and inhibiting apoptosis. These findings highlight mitochondrial fission as a promising therapeutic target for the treatment of doxorubicin toxicity and provide further support for the possible use of Mdivi-1 as a therapeutic strategy to protect the kidneys of elderly breast cancer patients undergoing chemotherapy. Full article

Doxorubicin-induced cardiotoxicity is an important concern in veterinary oncology, and early detection of myocardial injury remains clinically challenging. This exploratory pilot study described changes in cardiac fatty acid-binding protein (h-FABP), cardiac troponin I (cTnI), NT-proBNP, conventional echocardiographic variables, and 24-h Holter-derived heart rate variability parameters in dogs with hemangiosarcoma treated with doxorubicin. Fourteen dogs were prospectively evaluated before treatment initiation and one week after the third doxorubicin dose, corresponding to a cumulative dose of 90 mg/m². The study did not include a control group, a predefined cardiotoxicity endpoint, or diagnostic-performance analysis. Plasma biomarkers, echocardiographic parameters, ventricular arrhythmic events, and Holter-derived time- and frequency-domain heart rate variability variables were compared between both time points. Cardiac troponin I increased significantly after three doxorubicin doses, from a median of 0.05 ng/mL to 0.15 ng/mL (p = 0.002). In contrast, h-FABP did not change significantly, with median values of 2.43 ng/mL at baseline and 2.62 ng/mL after treatment (p = 0.27). NT-proBNP also showed no significant change (p = 0.87). Among echocardiographic variables, E-point septal separation, fractional shortening, ejection fraction, LA/Ao, and LVDd index did not change significantly. Ventricular arrhythmic events were infrequent and were described descriptively, whereas Holter-derived HRV variables did not show statistically significant differences between time points. In this exploratory cohort, cTnI increased after three doxorubicin doses, whereas h-FABP and NT-proBNP did not change significantly at the evaluated time point. Because h-FABP was measured one week after treatment, its potential short-term post-infusion release cannot be assessed. Larger studies with serial early sampling, predefined cardiotoxicity endpoints, appropriate control groups, and adjusted statistical analyses are required. Full article

Anthracycline cardiotoxicity involves early oxidative–inflammatory injury to the myocardium and vasculature. Repurposing anti-inflammatory agents may offer pragmatic cardioprotection. The purpose of this study is to evaluate whether sulfasalazine (SSZ) mitigates doxorubicin (DOX)-induced myocardial and aortic injury in rats. Twenty-eight male Wistar albino rats were randomized to: Control (vehicle, n = 8), DOX (20 mg/kg i.p., single dose; n = 10), and SSZ + DOX (SSZ 300 mg/kg i.p. once daily for 3 days, then DOX 20 mg/kg i.p.; n = 10). At 24 h post-DOX, ECG and invasive blood pressure (BP) were recorded. The heart and thoracic aorta were harvested for histopathology and oxidative stress assays (MDA, SOD, GSH, CAT; composite indices where applicable). Compared with SSZ + DOX, the DOX group exhibited higher BP and greater arrhythmic burden. In the aorta, DOX elevated MDA and reduced SOD, GSH, and CAT versus the control, whereas SSZ + DOX shifted these toward control values. In the myocardium, DOX decreased SOD and increased oxidative index; SSZ + DOX attenuated histological injury (edema, hemorrhage, cardiomyocyte degeneration) and restored aortic intima–media thickness toward control. Heart rate was lower in SSZ + DOX than other groups. Short-course SSZ pretreatment alleviated early DOX-induced oxidative stress and structural damage in myocardial and aortic tissues, with concurrent improvement in hemodynamic and ECG profiles. These data support further dose–timing optimization and longer-term functional studies to define SSZ’s translational potential as an adjunct cardioprotective strategy during anthracycline exposure. Full article

Anthracycline agents, principally doxorubicin and daunorubicin, are widely used in oncology yet carry a narrow therapeutic index and pronounced interindividual pharmacokinetic variability that exposes patients simultaneously to the risk of subtherapeutic dosing and cumulative cardiotoxicity. Conventional therapeutic drug monitoring (TDM) based on periodic venous sampling and offline high-performance liquid chromatography cannot resolve the sub-minute concentration dynamics that determine organ-specific drug exposure. Electrochemical aptamer-based (EAB) sensors couple nucleic-acid aptamers, self-assembled monolayers, and methylene blue redox reporters on gold microelectrodes to convert binding-induced conformational changes into real-time, reagent-free electrochemical signals. Recent advances in this field fall into five areas: signal interrogation strategies, from kinetic differential measurement to calibration-free Fourier-transform impedance spectroscopy (FFT-EIS); interface engineering including nanostructured electrodes and AI-guided aptamer design; in vivo multi-compartment pharmacokinetic monitoring and closed-loop feedback drug delivery; the mechanisms of in vivo signal drift alongside antifouling countermeasures spanning hydrogel barriers, zwitterionic brushes, and xenonucleic acid backbone substitution; and FDA premarket pathways and clinical translation, including Premarket Approval requirements and the emerging Real-Time Clinical Trial (RTCT) framework. In live rodents, dual-compartment monitoring has resolved a reproducible 30–60 min plasma-to-ISF lag for doxorubicin at 12 s temporal resolution; calibration-free FFT-EIS interrogation achieves inter-animal coefficients of variation below 12% without individual pre-calibration; and xenonucleic acid backbone substitution has extended continuous in vivo operation to seven consecutive days. Unlike prior EAB reviews that survey general molecular targets or benchtop aptasensors, this review uniquely integrates anthracycline-specific in vivo pharmacokinetics, multi-compartment plasma–ISF monitoring, calibration-free interrogation, XNA-enabled long-term stability, and FDA/RTCT regulatory translation into a single clinical roadmap. Three gaps still separate rodent proof-of-concept work from chemotherapy patients: clinical-context validation, tumor microenvironment calibration, and anthracycline-specific XNA aptamer design. Full article

Doxorubicin (DOX) remains an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Mitochondrial dysfunction and metabolic remodeling are central features of DOX-induced cardiac injury. ATP synthase inhibitory factor-1 (IF1) is an endogenous inhibitor of the hydrolytic activity of mitochondrial ATP synthase and has emerged as an important regulator of cellular bioenergetics. Cardiac IF1 expression is increased in multiple pathological conditions; however, its role in chemotherapy-induced cardiotoxicity remains unclear. Here, we investigated the contribution of IF1 to DOX-induced cardiotoxicity using male C57BL/6J wild-type (WT) and IF1 knockout (IF1KO) mice, isolated cardiac mitochondria, cultured neonatal cardiomyocytes, and AC16 human cardiomyocytes. Cardiac function was assessed by echocardiography, mitochondrial function by high-resolution respirometry and Seahorse metabolic flux analysis, and myocardial injury by histological and ultrastructural analyses. DOX treatment markedly increased cardiac IF1 protein levels despite reduced IF1 mRNA expression. IF1 deficiency enhanced mitochondrial respiration in isolated cardiac mitochondria and cultured cardiomyocytes under both basal and DOX-stressed conditions. IF1KO mice exhibited attenuated cardiac dysfunction and improved myocardial ultrastructure following DOX treatment compared with WT mice. In AC16 cardiomyocytes exposed to DOX, overexpression of WT IF1 improved cellular metabolic activity but provided only limited preservation of mitochondrial respiratory capacity. In contrast, overexpression of the dominant-negative IF1 mutant (IF1E30A) not only improved metabolic activity but also preserved mitochondrial respiration. These findings identify IF1 as a key regulator of metabolic adaptation during DOX stress. Upregulation of functional IF1 may represent an adaptive response that promotes glycolytic ATP production during mitochondrial stress, whereas inhibition of IF1 activity preserves metabolic activity primarily through maintenance of mitochondrial function. Collectively, these findings provide new insights into the role of IF1 in DOX-induced cardiomyopathy and highlight IF1 as a potential therapeutic target in cardio-oncology. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence suggests that epigenetic dysregulation, particularly altered DNA methylation, contributes to DOX-induced cardiac injury. Metformin has been reported to exert cardiometabolic and epigenetic regulatory effects. This study investigated genome-wide DNA methylation changes induced by chronic metformin exposure and their effects on doxorubicin sensitivity in H9c2 cardiomyoblast cells. Methods: Genome-wide DNA methylation changes induced by chronic metformin exposure were investigated in H9c2 cardiomyoblast cells using whole-genome bisulfite sequencing (WGBS). Cells were treated with metformin (0.7–2.8 mM) for four months prior to DOX exposure. Cellular sensitivity to DOX was evaluated using MTT-based dose–response analysis and IC₅₀ estimation. Results: DOX reduced cell viability (IC₅₀ = 0.164 µM). Chronic metformin pre-treatment produced a dose-dependent rightward shift in DOX dose–response curves, increasing IC₅₀ values to 0.21, 0.289, and 0.51 µM at 0.7, 1.4, and 2.8 mM metformin, respectively. WGBS revealed distinct separation between treatment groups in principal component analysis. Significant methylation changes (adjusted p-value < 0.05) were identified in genes related to oxidative stress, mitochondrial function, apoptosis, and chromatin regulation. Conclusions: Chronic metformin exposure induces dose-dependent genome-wide DNA methylation remodeling in cardiac cells and is associated with altered cellular sensitivity to doxorubicin. These findings suggest that metabolic modulation by metformin may influence epigenetic regulation and cellular stress responses relevant to chemotherapy-induced cardiotoxicity. Full article

The mechanisms underlying doxorubicin (DOX) cardiotoxicity include activation of the renin–angiotensin–aldosterone system (RAAS), oxidative stress, mitochondrial dysfunction, calcium overload, and cardiomyocyte apoptosis. Cortisol plays a key role in regulating multiple metabolic, immunological, cardiovascular, and neuroendocrine processes and may additionally influence drug pharmacokinetics by modulating the activity of P-glycoprotein (P-gp). The peptide apelin, through its specific target, angiotensin II protein J receptor (APJ), exerts cardioprotective, antifibrotic, and anti-inflammatory effects. The available data demonstrate that apelin signaling protects against DOX-induced cardiotoxicity, impacts cortisol secretion, and inhibits RAAS. Short-term elevation in cortisol levels, caused by apelin, may reduce inflammation and thus have cardioprotective properties. However, through chronically elevated cortisol levels, apelin may indirectly contribute to peripheral resistance, cardiac remodeling, and myocardial damage, especially when cortisol metabolism by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is altered. This narrative review explores the potential molecular and cellular mechanisms shaping the outcome of apelin–cortisol interplay, offering a potential foundation for developing cardioprotective strategies during anticancer therapy. Future studies should be aimed at assessing the complex interactions between cortisol, apelin, and the RAAS regarding DOX-induced cardiotoxicity. Full article

Doxorubicin (DOX), an effective chemotherapeutic agent for many types of cancer, is known for significant cardiotoxic side effects, which largely limit its clinical usage. A 3 h treatment of cardiomyoblast H9C2 cells with a low concentration of DOX (100 nM) can induce senescence-associated β-galactosidase (SA β-gal) staining, a gold standard of cell senescence. In the current study, we comprehensively characterized the phenotype of the DOX-induced senescent cardiomyocytes for the first time. Establishing this in vitro model will facilitate an expanded capacity for searching for effective treatments for DOX-induced cell senescence. Using SA β-gal staining and cell growth rate as readouts, we assessed the concentration-dependent effect of DOX on H9C2 cell senescence. The cells were treated with DOX for 3 h and subsequently cultured for 3 days. We found that a 50 nM concentration of DOX induced ~50% SA β-gal staining and completely inhibited cell growth. The DOX-induced H9C2 cell senescence was further confirmed by several well-accepted senescence markers, including cell hypertrophy, increased p16 and p21 expression, increased Senescence Associated Secretory Phenotype (SASP) markers, arrested cell cycle, and increased ROS production. Interestingly, we found that 50 nM DOX increased mitochondrial respiration. Translationally, we found that mitochondrial-targeted tetrapeptide SS-31 (elamipretide, 1 µM) partially attenuated 50 nM DOX-induced SA β-gal staining from 51.4% to 35.8%. SS-31 also prevented increases in the p16, p21, and SASP markers and mitigated mitochondrial ROS production. Additionally, SS-31 reversed the 50 nM DOX-induced elevation of mitochondrial respiration. However, 1 µM SS-31 failed to prevent the cell cycle arrest induced by 50 nM DOX. Using a 3 h treatment of 50 nM DOX, we established an H9C2 cell senescence model. Treatment with SS-31 attenuates this DOX-induced cell senescence but not the cell cycle arrest. These data suggest that SS-31 is a promising drug to treat DOX-induced cardiomyocyte senescence. Full article

Objectives: An ideal cardiotoxicity inhibitor targeting the angiotensin (Ang) II type 1 (AT₁) receptor would be a β-arrestin-biased orthostatic ligand, which inhibits the G protein pathway and activates the β-arrestin pathway. Therefore, this study examined seven Ang II mimetic peptides (MP1–7), Ang A and TRV027 as potential β-arrestin-biased AT₁ receptor ligands to prevent doxorubicin (Dox)-induced cardiotoxicity. Methods: Competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) 1/2 activation were performed using COS7 cells. Changes in phosphorylated Akt (Ser473), c-Jun N-terminal kinase (JNK) (Thr183/Tyr185), Bad (Ser112), Bcl-2 (Ser70), p53 (Ser46), active caspase-8 (Asp384) and active caspase-9 (Asp315) in cell lysates were measured using AT₁ receptor-transfected H9C2 cells. Results: Binding assays showed Ang II and Ang A had the highest affinity, with MP2 and MP7 similar to TRV027. IP production was strong for Ang II and Ang A, minimal for MP1 and MP7, and no stimulation for MP2 and TRV027. Ang II and Ang A significantly activated ERK1/2 in this cell system. MP2 and MP7 in addition to TRV027 also significantly activated ERK1/2, whereas MP1 did not activate it. Dox-activated JNK and Bad, while Ang A, TRV027, MP2, and MP7 inhibited JNK activation without affecting Bad or Akt. Conclusions: MP2, which is a candidate biased ligand for the AT₁ receptor and has similar amino acid sequence to TRV027, along with TRV027, attenuated Dox-induced JNK activation while avoiding excessive G protein-mediated activation. Interestingly, MP7, which showed minimal G protein-mediated activation with β-arrestin-mediated ERK activation, also attenuated Dox-induced JNK activation, a marker of pro-apoptotic stress signaling. Full article

Background/Objectives: Anthracycline-induced cardiotoxicity remains a major challenge in cancer treatment, and researchers are showing interest in artificial intelligence (AI) to improve the prediction and detection of cancer therapy-related cardiac dysfunction (CTRCD). Current surveillance strategies rely mainly on left ventricular ejection fraction and, more recently, global longitudinal strain. Methods: The present study was designed to evaluate cardiac performance in a rat model of doxorubicin-induced cardiotoxicity and empagliflozin-mediated cardioprotection using a machine learning-based analytical framework. Eighteen adult male Sprague–Dawley rats were assigned to five experimental groups. We aimed to quantify ventricular wall dynamics and contractility using an advanced image-processing and object-detection model that has not been previously used to distinguish normal from impaired cardiac kinetics. During real-time recording, simultaneous electrocardiogram monitoring was performed, enabling direct correlation between deep learning-based ventricular wall motion metrics and cardiac electrical activity. The cardioprotective effects of empagliflozin were further validated by immunofluorescence staining (cTnI, vimentin, α-SMA, and Cx43) of rat cardiomyocytes and paraffin-embedded cardiac tissue, demonstrating attenuation of cellular injury and structural remodeling. Results: The integrated analysis of cardiac kinetic patterns derived via machine learning distinguishes not only extreme cardiotoxicity, but also tracks a graded pattern consistent with ECG-derived severity and treatment-related functional preservation. These findings indicate that the algorithm captures the gradient of empagliflozin’s cardioprotective effect within this internally validated preclinical setting. Additionally, immunofluorescence results validated the benefits of SGLT2 inhibition on myocardial integrity. Conclusions: The novelty of the present work lies at the intersection of advanced cardiac kinetic analysis using AI, preclinical modeling, and SGLT2-mediated cardioprotection in cardio-oncology. Full article

Doxorubicin (DOX) is a potent chemotherapeutic drug, whose clinical application is largely restricted by dose-dependent cardiotoxicity (DIC). Dracocephalum moldavica L. is a classic medicinal and edible plant with obvious cardiovascular protective effects; however, the role of its total flavonoids (TFDM) in DIC remains unclear. This study explored the cardioprotective effect of TFDM on DOX-induced myocardial injury and its mechanism related to mitochondrial quality control. We established in vivo and in vitro DIC models and adopted echocardiography, detection of cardiac injury and oxidative stress indicators, transmission electron microscopy, mitochondrial functional assessment and Western blotting, with AMPK knockdown performed for mechanism verification. Results showed that TFDM effectively improved cardiac function, reduced myocardial oxidative stress and apoptosis, and maintained mitochondrial ultrastructure and energy metabolism. TFDM activated the AMPK/PGC1α signaling axis to facilitate mitochondrial biogenesis, and AMPK silencing eliminated the protective effect of TFDM. In conclusion, AMPK/PGC-1α pathway is a primary key pathway involved in TFDM’s protective effects, which provides an experimental basis for the development of Dracocephalum moldavica L. as a functional food and adjuvant agent against DIC. Full article