Search Results (697)

Background: The specific mechanisms underlying the antihypertensive actions of corosolic acid (CA) have not been systematically elucidated. Methods: Evidence was categorized according to major signaling and physiological pathways, including the renin–angiotensin system (RAS), oxidative and inflammatory responses, endothelial and smooth muscle regulation (NO/cGMP and H₂S/K_ATP), and kinase-mediated signaling (AMPK, NF-κB, JAK/STAT, PKC). Results: Consistent with in vitro and animal studies, CA has been reported to attenuate pro-hypertensive signaling through multiple pathways: (i) downregulating renin–angiotensin system-related cascades; (ii) reduction in reactive oxygen species and inflammatory mediators through activation of AMPK and inhibition of NF-κB and JAK/STAT pathways; (iii) improved vascular tone by enhancing NO/cGMP signaling, partly involving the H₂S/K_ATP pathway, and inhibiting PKC. CA may indirectly contribute to blood pressure reduction by improving glucose and lipid metabolism and adipose tissue inflammation, thereby affecting metabolic risk factors. The existing evidence gaps include: lack of direct studies on voltage-gated, receptor-gated and store-regulated calcium channels; the specific effects on the isoforms of nitric oxide synthase (eNOS/iNOS/nNOS) and PKC are not known; limited human data on the antihypertensive efficacy, dose effect and safety of CA in humans are available. Conclusions: CA may have multi-targeted blood-pressure-lowering potential. Its clinical efficacy and safety require further confirmation. Full article

The renin–angiotensin–aldosterone system (RAAS) is a fundamental regulator of blood pressure, electrolyte balance, fluid homeostasis, and tissue remodeling. The discovery of the prorenin receptor (PRR), the protein encoded by the ATP6AP2 gene, has substantially expanded the classical RAAS paradigm by demonstrating that prorenin possesses biological activity beyond its proteolytic conversion to renin. Binding of renin or prorenin to PRR enhances local angiotensin II (Ang II) generation while simultaneously initiating Ang II-independent intracellular signaling pathways, including ERK1/2, mitogen-activated protein kinases, PI3K/Akt, transforming growth factor-β, and nuclear factor-κB, thereby promoting inflammation, oxidative stress, fibrosis, cellular proliferation, and extracellular matrix accumulation. Beyond its receptor function, PRR serves as an essential accessory component of the vacuolar H+-ATPase (V-ATPase) complex, regulating vesicular acidification, lysosomal function, autophagy, protein trafficking, cellular metabolism, and Wnt/β-catenin signaling. These diverse functions explain its indispensable role in embryonic development, cell differentiation, and tissue homeostasis, as evidenced by the embryonic lethality associated with ATP6AP2 gene deficiency. PRR is predominantly localized to intracellular organelles, including the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, and autophagic vesicles, although membrane-bound and soluble forms also contribute to physiological and pathological processes. Increasing evidence implies dysregulated PRR signaling in the development and progression of hypertension, cardiovascular disease, chronic kidney disease, diabetes, obesity, and other metabolic disorders. This review summarizes current advances in PRR and soluble PRR biology, discusses unresolved mechanistic and translational questions, and evaluates the potential of PRR as a biomarker and therapeutic target for cardiovascular, renal, and metabolic diseases. Full article

Obesity is an increasingly important and modifiable driver of chronic kidney disease (CKD), with effects that extend well beyond its associations with type 2 diabetes, hypertension, and dyslipidemia. To synthesize the evidence that excess adiposity is a causal and modifiable determinant of kidney disease, and to examine how specific adipose depots injure the glomerulus and the tubulointerstitium, and then map these mechanisms onto established and emerging therapies. Throughout, obesity-related kidney disease (ORKD) denotes the full spectrum of diposity-driven renal injury, whereas obesity-related glomerulopathy (ORG) is reserved for the biopsy-defined glomerular lesion. Central, visceral, perirenal and renal-sinus adiposity act first through structural and haemodynamic mechanisms, promoting glomerular hyperfiltration, mechanical renal compression and activation of the adipose-derived renin–angiotensin–aldosterone system (RAAS). In parallel, these depots drive cellular and metabolic injury through lipotoxicity, adipokine imbalance, sterile inflammation, oxidative stress, gut dysbiosis, mitochondrial dysfunction, epigenetic remodelling and cellular senescence. Ectopic lipid accumulation within the renal parenchyma—fatty kidney—offers a unifying description of these changes and is most marked in type 2 diabetes mellitus. These interacting processes converge on podocyte stress, tubular metabolic failure, endothelial dysfunction and interstitial fibrosis, producing a phenotypic continuum that ranges from early albuminuria to obesity-related glomerulopathy and progressive CKD. Within the RAAS limb we highlight two comparatively underappreciated, adiposity-linked routes to injury: adipocyte-derived leptin directly upregulates adrenal aldosterone synthase (CYP11B2), and mast-cell chymase generates angiotensin II independently of angiotensin-converting enzyme, together reinforcing aldosterone- and angiotensin II–mediated damage that conventional RAAS blockade only partially interrupts. We further consider the counter-regulatory ghrelin–leptin axis, in which the suppression of ghrelin that accompanies obesity may withdraw an antioxidant, anti-inflammatory and podocyte-protective signal precisely as leptin-driven glomerular injury intensifies, positioning ghrelin as a plausible modulator and candidate biomarker of obesity-related kidney injury. We also examine how obesity complicates renal risk assessment, drug dosing, dialysis delivery and transplant access. Emerging, mechanism-matched therapies—SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, structured lifestyle intervention, metabolic-bariatric surgery and, most recently, aldosterone synthase inhibitors that suppress the chymase- and leptin-driven aldosterone escaping receptor blockade—now enable a precision cardiovascular-kidney-metabolic framework that aligns adipose-depot biology, biomarkers, histology and treatment response to guide mechanism-based care in ORKD. Full article

Vascular smooth muscle cells (VSMCs), the contractile cells in the tunica media of blood vessels, maintain vascular tone. The proliferation of VSMCs is an important feature of vascular remodeling that contributes to the regulation of blood pressure. Autophagy, an intracellular self-degrading process that delivers cytoplasmic constituents to lysosomes, plays a vital role in VSMC proliferation. This is regulated by the dopaminergic and renin–angiotensin systems but their interplay in their regulation of autophagy in VSMCs is not well-understood. In rat VSMCs, fenoldopam (Fen), a dopamine D1-like receptor agonist, increased autophagy, as determined by the increase in the protein expressions of microtubule-associated protein 1 light chain (LC)3-II and beclin-1 (BECN1), in a time- and concentration-dependent manner. Conversely, angiotensin II (Ang II), the endogenous Ang II type 1 receptor (AT₁R) agonist, decreased the protein expression of LC3-II and BECN1, also in a time- and concentration-dependent manner. The production of cyclic adenosine monophosphate (cAMP) and autophagic LC3-II puncta in VSMCs were increased by Fen and decreased by Ang II. Pre-treatment of VSMCs with Rp-cAMPS, a protein kinase A inhibitor, prevented the Fen-mediated increase and the Ang II-mediated decrease in LC3-II protein expression. Fen decreased, whereas Ang II increased the phosphorylation of P70S6K, a direct downstream mammalian target of rapamycin (mTOR). The inhibitory effect of Fen and stimulatory effect of Ang II on P70S6K phosphorylation were prevented by Rp-cAMPS. Ang II also decreased the Fen-mediated increase in cAMP production, while Fen attenuated the Ang II-mediated increase in cell proliferation, a response that occurs downstream of autophagy. Moreover, Ang II prevented the Fen-mediated inhibition of cell proliferation, an effect that was blocked by losartan, an AT₁R antagonist. These results demonstrate that Fen and Ang II counter-regulate autophagy and proliferation of VSMCs via the mTOR pathway, which is cAMP-dependent. Full article

Background/Objectives: Esaxerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) with potent cardiorenal protective effects. However, the clinical effects of switching from eplerenone to esaxerenone in patients with chronic heart failure complicated by hypertension remain unclear. This study investigated the effects of switching from eplerenone to esaxerenone on blood pressure, heart failure biomarkers, renal function, and the renin–angiotensin–aldosterone system (RAAS). Methods: A total of 156 patients with chronic heart failure and hypertension who had been receiving eplerenone for more than one year were prospectively enrolled. Eplerenone was switched to esaxerenone, and the patients were followed for 6 months. Blood pressure, heart rate, brain natriuretic peptide (BNP), renal function, urinary albumin-to-creatinine ratio (UACR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary osmolality (U-OSM) were evaluated. Results: Following the switch to esaxerenone, systolic and diastolic blood pressure significantly decreased (both p < 0.001), whereas heart rate remained unchanged. BNP levels significantly decreased at 3 and 6 months (p = 0.008 and p = 0.002, respectively). Serum creatinine decreased (p = 0.017), estimated glomerular filtration rate increased (p = 0.028), and UACR significantly decreased at both time points (both p < 0.001). PRA and PAC significantly increased after switching (both p < 0.05), whereas angiotensin II levels remained unchanged. U-OSM significantly decreased (p = 0.01 and p = 0.002 at 3 and 6 months, respectively). No major cardiovascular events or severe adverse events were observed. Conclusions: In patients with chronic heart failure and hypertension, switching from eplerenone to esaxerenone was associated with reductions in blood pressure, BNP, UACR, and urinary osmolality, together with improvements in renal function. These findings suggest favorable physiological changes following the switch from a steroidal to a non-steroidal mineralocorticoid receptor antagonist, although confirmation in randomized controlled studies with clinical outcome measures is warranted. Full article

Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac remodelling in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by metabolic and hypertensive stress (MHS). Methods: Male and female C57BL/6J mice were exposed to MHS (angiotensin II + high-fat diet) for 28 days, with or without mirabegron treatment (2 mg/kg/day). Cardiac structure and function were assessed by echocardiography, and molecular and histological analyses were performed on cardiac and BATs. Results: Mirabegron attenuated several features of cardiac remodelling in males, including cardiac hypertrophy, left atrial enlargement, and left ventricular dilation. These effects were associated with reduced expression of genes related to hypertrophy and fibrosis. In contrast, it was shown that females exhibited a less pronounced response pattern. BAT mass and thermogenic gene expression (Ucp1) increased more markedly in males than in females, suggesting differential BAT responsiveness between sexes. Conclusions: β3-AR activation is associated with sex-dependent cardiac responses in this HFpEF model, with more pronounced protective effects in males. These findings are consistent with a potential contribution of BAT activation to cardiac remodelling, although causality was not directly demonstrated in the present study. Full article

Ischemia–reperfusion injury (IRI) of the kidney represents a serious medical issue with complex pathological mechanisms that remain poorly elucidated. The development of ischemic acute kidney injury (AKI) may be mediated by NADPH oxidase and angiotensin II type 2 receptors. The aim of our study was to explore the effects of novokinin (NOV), angiotensin II type 2 receptor (AT2R) agonist and apocynin (APO), an NADPH oxidase inhibitor, on kidney structure and function, as well as the level of oxidative stress in spontaneously hypertensive rats (SHR) with induced IRI. Animals were randomly assigned into five experimental groups: the Sham-operated animals (SHAM) group, the AKI group, and AKI groups receiving APO, NOV, or their combination. Slight improvements in renal function were noted across all treated groups; however, only the combined action of APO + NOV led to a significant decrease in kidney injury molecule-1 (KIM-1) levels and markedly reduced oxidative stress compared with the control AKI group. Our results demonstrate that additively targeting NADPH oxidase and AT2R provides new insights in comparison to individual treatments. These findings suggest a potentially promising new therapeutic strategy for managing IRI and improving outcomes in critically ill patients with AKI. Full article

Cancer therapy-related cardiac dysfunction (CTRCD) is a significant complication of anthracycline-based regimens and anti-HER2 agents. Global longitudinal strain (GLS) detects subclinical dysfunction before ejection fraction decline and is recommended by the 2022 ESC guidelines for surveillance. Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has shown cardioprotective potential in recent trials. Following PRISMA 2020 guidelines, we searched PubMed, EMBASE, and Cochrane CENTRAL through February 2026. Three RCTs met eligibility criteria (n= 350; PROSPERO: CRD420261383124): Hsu 2025 (n = 100, 12 months), PRADA II 2025 (n = 138, 18 months), and SARAH 2025 (n = 112, 6 months). Random-effects meta-analysis used REML with Hartung–Knapp–Sidik–Jonkman adjustment. The pooled mean difference in final GLS significantly favored sacubitril/valsartan (MD −0.95%; 95% CI −1.40 to −0.50; p = 0.012; I² = 0%). Final LVEF showed a consistent trend (MD +1.53%; 95% CI −0.47 to 3.52; p = 0.082; I² = 0%). Hypotension was numerically more frequent with sacubitril/valsartan (OR 5.10; 95% CI 0.52–49.50; p = 0.091). Sacubitril/valsartan initiated during anthracycline therapy was associated with significant GLS preservation. However, GLS is a surrogate imaging marker and hard clinical events were rare or absent, so the modest effect magnitude and limited number of trials warrant cautious interpretation; the clinical benefit remains uncertain and requires confirmation in adequately powered trials with hard clinical endpoints. Full article

Background: Heart transplantation (HT) remains the definitive therapy for end-stage heart failure, yet rejection and cardiac allograft vasculopathy (CAV) continue to limit long-term outcomes. Beyond donor-specific HLA antibodies, non-HLA antibodies, particularly anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), have been implicated in allograft injury, but published findings are heterogeneous. Aim: The aim of this study is to systematically evaluate the evidence linking AT1R gene expression and anti-AT1R antibodies with key post-heart transplant outcomes. Methods: We conducted a systematic review in accordance with PRISMA guidelines. Scopus, PubMed, Web of Science, and the Cochrane Library were searched (December 2025) for cohort and case–control studies evaluating AT1R gene expression and/or AT1R-Ab status in HT recipients and their association with post-transplant outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the NIH Quality Assessment Tool. Results: Twelve studies encompassing 951 recipients met the inclusion criteria. Five studies evaluated AT1R mRNA expression, reporting variable patterns: several observed reduced AT1R/AT2R transcription after transplantation without clear clinical correlation, whereas others associated higher donor or recipient AT1R expression with transplant coronary artery disease and recurrent rejection. AT1R-Ab prevalence varied widely and appeared to increase after mechanical circulatory support, with substantial seroconversion reported during LVAD support in initially antibody-negative patients. Associations between AT1R-Ab and acute cellular rejection and antibody-mediated rejection were inconsistent across studies, and survival findings were inconclusive; however, some reports linked elevated AT1R-Abs to poorer long-term freedom from adverse events. Evidence regarding CAV was mixed, with signals of increased vasculopathy risk in some cohorts but not others. Conclusions: Current evidence suggests a potential role for AT1R expression and AT1R-Abs in cardiac allograft dysfunction, including rejection phenotypes and vasculopathy. Larger prospective studies with harmonized testing strategies are needed to define clinically meaningful AT1R-Ab cutoffs and clarify their utility in risk stratification and targeted therapeutic trials. Full article

The carotid body (CB) is an interoceptive organ that transmits afferent information to the brain via the carotid sinus nerve (CSN) to maintain homeostasis, i.e., the regulation of internal equilibrium despite external changes. It functions as a complex polymodal receptor capable of sensing multiple stimuli, including blood flow, osmolarity, pO₂, pH, pCO₂, CO₂/H⁺, and temperature. In addition, the CB responds to a wide range of circulating molecules such as angiotensin II, endothelin-1, aldosterone, insulin, histamine, and leptin, and expresses receptors for interleukins (ILs) and tumor necrosis factor-α (TNF-α) (1). CB dysfunction has been associated with conditions such as obstructive sleep apnea (OSA), in which intermittent hypoxemia induces an inflammatory response mediated, among other mechanisms, by reactive oxygen species (ROS). This process contributes to alterations in respiratory drive and enhanced sympathetic nervous system activity. Following streptococcal toxic shock syndrome due to Streptococcus Pyogenes, severe abdominal septic shock, and multiple infectious complications, our patient developed an altered respiratory pattern and a hypercatabolic state that precluded weaning from mechanical ventilation (MV) despite respiratory physiotherapy. Given treatment failure, we hypothesized underlying carotid body (CB) hyperexcitability, likely pre-existing due to obstructive sleep apnea (OSA) and exacerbated by cytokine storm and severe systemic inflammation related to Strept. Pyogenes toxins and subsequent abdominal sepsis from colonic perforation. This may have contributed to sustained sympathetic overactivation and immune dysregulation. Clinically, the patient exhibited increased respiratory drive (30–35 breaths/min), excessive inspiratory effort, and marked patient–ventilator asynchrony in the absence of hypoxemia. Non-targeted physiotherapy may have acted as a second inflammatory hit, perpetuating the inflammatory cycle. Full article

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca²+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS. Full article

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). The remission rate of MN remains limited, and effective strategies for refractory MN are not established. We present the case of a 49-year-old Japanese woman with severe NS caused by MN. Kidney biopsy revealed glomerular basement membrane thickening with granular deposition of immunoglobulin G (IgG) and complement component 3. IgG subclass analysis showed predominant IgG1 deposition, with weak IgG2 and IgG3 deposition. Phospholipase A2 receptor (PLA2R) deposition was equivocal in the first kidney biopsy and negative in the second. Serum anti-PLA2R antibody was not detected. Electron microscopy revealed subepithelial, subendothelial, and mesangial electron-dense deposits. Detailed screening revealed no significant abnormalities other than appendiceal findings, suggesting secondary MN associated with appendiceal infection. Although combined therapy with prednisolone, cyclosporine, rituximab, and low-density lipoprotein apheresis was administered during the first 6 months, remission of MN was not achieved. During dialysis, initiated because of kidney failure, long-term multidisciplinary management, including control of appendiceal infection and inflammation and initiation of angiotensin II receptor blocker therapy, ultimately led to remission of MN and discontinuation of dialysis. Overall, even refractory MN requiring dialysis may have a reversible clinical course with careful conservative management and long-term follow-up. 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

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

Hypertension is one major risk factor of cardiovascular diseases, and RAS plays vital role during the development of hypertension. To obtain a novel antihypertensive peptide, Coix glutelin was hydrolyzed by trypsin and further separated by Sephadex G10. Based on 751 identified sequences, pharmacophore mapping, molecular docking, and in silico proteolysis were applied to screen and optimize the candidate sequence. Finally, a novel peptide, ENWAAL, was generated with IC₅₀ of 210.57 μM, which acted with ACE in a competitively inhibitory pattern. The in vivo antihypertensive effect was evaluated in SHRs. Significant improvements were observed in hypertension-related characteristics, including blood pressure, cardiac structure and function, and serum angiotensin II (Ang II) level. In the brain, quantitative real-time PCR analysis revealed significant downregulation of angiotensin II type 1 receptor (AT1R) mRNA expression, concomitant with upregulation of angiotensin-converting enzyme 2 (ACE2) and MAS receptor. The protein expression of ACE and AT1R in the ENWAAL group also significantly decreased. This study can provide a candidate antihypertensive drug targeting RAS. Full article