Search Results (1,831)

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders. Full article

Human skin remains difficult to model in vitro because it brings together stratified epidermal, dermal, hypodermal, vascular, immune, appendageal, neural, and microbial elements within a single tissue. Traditional two-dimensional cultures and animal models still offer useful insight, but both have clear translational limits. Three-dimensional (3D) human skin models have therefore become increasingly valuable for mechanistic, pharmacologic, and regenerative research. This narrative review followed a fit-for-purpose literature selection framework. Priority was given to primary studies and reviews published between 2019 and 2025 that reported major advances in model architecture, biomaterials, vascularization, immune integration, appendage formation, sensorization, or translational application. Greater weight was given to studies that linked added complexity to measurable functional outputs. Current platforms include organotypic human skin equivalents, bioprinted constructs, microfluidic skin-on-a-chip systems, and pluripotent stem cell-derived organoids. Important advances include self-assembled or decellularized matrices that more closely reflect native extracellular matrix composition, perfusable microvasculature, hypodermal incorporation, immune cell integration, and real time sensing. These systems now support work in barrier testing, safety testing, dermal drug development, inflammatory dermatoses, melanoma, wound healing, aging, and regenerative transplantation. No single platform fully reproduces native human skin. The more relevant question is not how much complexity can be added, but which added features meaningfully improve performance for a defined endpoint. A fit-for-purpose framework may offer a better basis for model selection, benchmarking, standardization, and translational adoption. Future progress will depend on application specific validation, clearer performance benchmarks, scalable manufacturing, and closer alignment with regulatory and clinical needs. From that perspective, 3D skin models are best understood as complementary platforms for translational dermatology research. Full article

Osteoporosis is one of the most prevalent metabolic bone diseases worldwide, and current pharmacological options are limited by adverse effects and are poorly suited to long-term use, underscoring the need for novel therapeutic targets. Bifidobacterium, one of the most representative beneficial bacterial genera in the human gut, has been linked to bone mineral density, and supplementation with specific strains improves bone metabolic parameters in animal models of osteoporosis. This narrative review examines the molecular mechanisms through which Bifidobacterium may protect bone via the gut–bone axis, encompassing four interconnected dimensions: reinforcement of the intestinal barrier, modulation of the immune network, remodeling of the gut microbiota, and production of bone-protective metabolites. The review makes three principal contributions. First, it establishes a four-tier mechanistic framework of Bifidobacterium-mediated regulation of osteoporosis in which the evidence is stratified into three categories—direct evidence from Bifidobacterium-specific studies, indirect evidence from other probiotics, and general mechanisms of gut microbiota-regulated bone metabolism—thereby strengthening the rigor of each argument and explicitly distinguishing evidence derived from Bifidobacterium-specific studies from that based on other probiotics or general gut-microbiota mechanisms throughout the review. Second, it systematically compares the osteoprotective efficacy of different Bifidobacterium strains (Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium adolescentis, etc.), highlighting the central importance of strain specificity. Third, it evaluates the strength of the evidence and identifies knowledge gaps for each mechanistic pathway. Most current evidence derives from cross-sectional studies and animal models; causal relationships await validation in large-scale prospective cohort studies and randomized controlled trials. In addition, functional disparities among strains and heterogeneity across clinical studies remain the core bottleneck in translating these fundamental findings into clinical practice. Full article

Natural product (NP)-based neuroregeneration research has generated extensive preclinical evidence over the past five decades. Pharmacological activity across core processes of central nervous system (CNS) repair including neurogenesis, axonal regeneration, and neuroplasticity have been documented. Despite consistent observations of neurite outgrowth, neuroprotection, and partial functional recovery in cellular and animal models, translation into durable clinical therapies has remained limited. Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) similarly exhibit strong regenerative effects in experimental systems, but even direct central administration has failed to produce sustained long-distance axonal regeneration or stable circuit reconstruction. This suggests that delivery constraints alone do not explain the failure to achieve clinically-relevant functional repair. It is proposed herein that this limitation reflects intrinsic constraints in how regenerative signalling is organised across multiple biological scales. Integrating evidence from in vitro and in vivo injury models, we can introduce a Target–Mechanism–Network (T-M-N) approach that systematically maps NPs activity onto a hierarchical regulatory architecture. Across diverse NPs classes, ~55 recurrent molecular targets cluster into 10 functional mechanisms, which converge into four higher-order network control regimes governing energetic competence, regenerative signalling capacity, redox-immune balance, and structural plasticity. This analysis reveals that NPs converge on shared regenerative networks but rarely coordinate all required domains within a unified pharmacological programme. They can thus be seen to represent a pre-organised source of evolutionarily selected pharmacophores encoding discrete elements of neuroregenerative network control. On this basis, pseudo-natural product (PNP) design enabled by computational chemistry and phenotypic screening may provide a strategy to recombine these fragments into engineered scaffolds with improved functional selectivity and regenerative coherence. The need to shift drug discovery from optimisation of individual NPs toward architecture-driven design of multi-functional molecules that address the integrated demands of neuroregeneration is discussed. Full article

Thyroid hormone physiology has traditionally been understood through the hypothalamic–pituitary–thyroid (HPT) axis and the genomic actions of triiodothyronine (T3). However, advances in thyroid hormone biology have expanded this classical paradigm, demonstrating that thyroid hormone signaling is regulated through a coordinated network involving tissue-specific deiodination, specialized membrane transporters, genomic and non-genomic signaling pathways, and mitochondrial regulation of cellular bioenergetics. Among the iodothyronine metabolites generated through thyroid hormone metabolism, 3,5-diiodothyronine (3,5-T₂) has emerged as one of the most extensively investigated because of its reported ability to rapidly influence mitochondrial respiration, oxidative metabolism, and energy expenditure. Experimental studies suggest that 3,5-T₂ enhances mitochondrial respiration, fatty acid oxidation, oxidative phosphorylation, and metabolic efficiency, particularly in metabolically active tissues such as liver and skeletal muscle. These findings have generated considerable interest in the potential role of 3,5-T₂ in metabolic disorders characterized by mitochondrial dysfunction, including metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. However, important translational challenges remain. Most available data derive from animal studies using pharmacologic doses, while the endogenous physiology of 3,5-T₂ in humans, its molecular targets, tissue-specific regulation, and long-term endocrine effects remain incompletely understood. In addition, evidence of hypothalamic–pituitary–thyroid axis suppression following exogenous 3,5-T₂ administration and limitations in accurately measuring circulating 3,5-T₂ continue to complicate clinical translation. This review critically evaluates the emerging biology of 3,5-diiodothyronine, integrating current evidence regarding its biosynthesis, mechanisms of thyroid hormone signaling, mitochondrial actions, metabolic effects, translational challenges, and future research priorities. By synthesizing findings from primary experimental studies and emerging translational investigations, this review places 3,5-T₂ within the broader framework of contemporary thyroid hormone biology while highlighting key knowledge gaps that must be addressed before its physiological and therapeutic significance can be fully established. Full article

Over the years, metabolic syndrome (MetS) has emerged as one of the most significant public health challenges, driven by the global increase in obesity, physical inactivity, unhealthy dietary patterns, and population aging. Ellagitannins are a class of hydrolysable tannins that have emerged as promising natural bioactive compounds, owing to their broad spectrum of biological activities. Increasing evidence suggests that some ellagitannins and their metabolites modulate several pathogenic mechanisms underlying metabolic syndrome, including oxidative stress, chronic inflammation, insulin resistance, endothelial dysfunction, and dysregulated lipid metabolism. This work reviews the pharmacological activities and therapeutic prospects of ellagitannins in the management of metabolic syndrome-related disorders. It further provides a critical and comparative analysis of the pharmacological profiles of reported ellagitannins, offering insights into their therapeutic efficacy and potential synergistic applications in the management of MetS-related disorders. Overall, Punicalagin and Geraniin currently possess the strongest preclinical evidence, supported by multiple independent studies employing both cellular and animal models that consistently demonstrate beneficial effects across several components of MetS. Chebulagic acid, Corilagin, Chebulinic acid, and Punicalin also show considerable promise but require further validation in diverse experimental systems. Potential synergistic interactions among ellagitannins when administered in combination should be investigated for enhanced therapeutic efficacy and broader multifaceted pharmacological effects. Full article

Background/Objectives: Recent evidence has suggested a transcriptional reduction in Kv7 potassium channels in the CA1 area of acquired experimental epilepsy, but presynaptic Kv7 channels might be spared. Here, we tested the influence of the Kv7 channel blocker XE991 on two forms of short-term plasticity, which are supposed to be presynaptic in nature: post-tetanic potentiation and paired-pulse ratio. Methods: Systemic pilocarpine was administered to induce status epilepticus and chronic epilepsy in the rat. In the chronically epileptic CA1 area, extracellular electrophysiological experiments were performed to analyze paired-pulse ratio before and after tetanic stimulation (100 Hz, 1 s). Results: Both the post-tetanic potentiation and the paired-pulse ratio were significantly higher in the epileptic CA1 as compared to control tissue (Cohen’s d > 3; n = 10–11 slices from 3–4 animals per group). While pharmacological inhibition of Kv7 channels with XE991 had no effect on these measures in control CA1, it significantly reversed both forms of enhanced short-term plasticity in the epileptic CA1 to control levels (Cohen’s d > 3; n = 10–11 slices from 3 animals per group). Conclusions: The epileptic CA1 showed enhanced short-term plasticity, which was not due to the loss of Kv7 channels in the epileptic CA1 subfield, since it was reversed by XE991. Therefore, our findings provide indirect evidence that the presynaptic Kv7 channel function may be at least partially intact in the epileptic CA1. It may be speculated whether potassium channel activators could pose a risk to enhance rather than depress short-term plasticity at Schaffer collateral–CA1 synapses in epilepsy. Full article

Feline intestinal inflammation is a common gastrointestinal disorder in cats and is associated with immune dysregulation, epithelial barrier injury, microbial imbalance, and persistent inflammatory signaling. This entirely in silico study investigated predicted molecular associations between vine tea (Ampelopsis grossedentata) constituents and feline intestinal inflammation using network pharmacology, molecular docking, and molecular dynamics simulation. No feline cells, tissues, animals, or clinical samples were used. Candidate compounds were screened and evaluated with SwissADME as a computational prioritization step, and potential targets were predicted using multiple databases. Human-centric database-derived genes associated with the broad intestinal-inflammation phenotype were subjected to feline ortholog mapping/verification and intersected with predicted vine tea targets. Protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed, followed by construction of a compound-target-pathway-disease network. Ten representative compounds were cross-docked against six core targets, producing 60 docking combinations, and the lowest-energy complex was subjected to a 100 ns molecular dynamics simulation. Seventeen candidate compounds, 966 predicted vine tea targets, and 102 candidate shared targets were retained in the archived workflow. IL6, TNF, IL1B, STAT3, CASP3, and TLR4 were prioritized as core targets. Enrichment analysis linked the shared-target set to inflammatory responses, innate immunity, cytokine activity, Th17 cell differentiation, and the IL-17, Toll-like receptor, NOD-like receptor, NF-kappa B, TNF, JAK-STAT, and PI3K-Akt signaling pathways. Molecular docking predicted favorable interactions between several compounds and the core targets, particularly IL6, and the IL6-cianidanol complex showed the lowest docking energy and relative stability during simulation. Overall, the analyses prioritize candidate compounds, targets, and pathways for subsequent feline-specific validation; they do not demonstrate therapeutic efficacy, target regulation, or biologically relevant exposure in cats. Full article

Angiotensin-converting enzyme (ACE) inhibitory peptides are promising bioactive components for developing blood pressure-regulating functional foods. Idesia polycarpa meal (IPM), an underutilized protein-rich byproduct from oil processing, is currently restricted to low-value applications such as animal feed, and systematic research on its ACE inhibitory peptides remains largely absent. This study hypothesized that controlled enzymatic hydrolysis of IPM protein could release novel ACE inhibitory peptide candidates with high activity. Fourier-transform infrared spectroscopy and differential scanning calorimetry (DSC) confirmed that ultrasonic treatment induced moderate conformational loosening of IPM protein, with thermal denaturation temperature decreasing from 162.20 °C to 158.79 °C, while the core secondary structure remained intact, thereby improving enzymatic hydrolysis efficiency. After sequential purification via ultrafiltration and gel filtration chromatography, the CP3-H3 fraction (molecular weight < 3 kDa) exhibited the highest ACE inhibitory rate of 95.39% at 1.0 mg/mL. Amino acid analysis showed that the active fraction contained 48.92% hydrophobic amino acids and 11.55% aromatic amino acids, which matched the structural requirements for potent ACE inhibition. Eight novel ACE inhibitory peptides were identified via LC-MS/MS combined with multi-round in silico screening, all of which were not recorded in the Database of Food-derived Bioactive Peptides (DFBP). Molecular docking analysis revealed that all eight peptides could stably bind to the active pocket of ACE, among which WDW showed the strongest binding affinity to PTGS2 with a binding free energy of −10.7 kcal/mol. Network pharmacology analysis demonstrated that these peptides exerted antihypertensive effects through synergistic regulation of 142 core blood pressure homeostasis-related targets and multiple key pathways. The core peptide WNWD was chemically synthesized and verified to have an ACE inhibitory IC₅₀ value of 3.529 mM. This study demonstrates that IPM is a promising food-derived source of ACE inhibitory peptides, and provides a theoretical basis for the high-value utilization of Idesia polycarpa processing byproducts. Full article

Background/Objectives: Behavioral and psychological symptoms of dementia (BPSD) are common and represent major drivers of caregiver burden and healthcare utilization. Animal-assisted therapy (AAT) is used as a non-pharmacological intervention in dementia care, yet quantitative evidence of its efficacy remains inconsistent. We systematically evaluated the effects of AAT on cognitive, affective, and behavioral outcomes in individuals with dementia. Methods: Following PRISMA 2020 guidelines, we searched seven electronic databases from inception through 27 September 2025 for studies evaluating AAT in dementia. Randomized and non-randomized controlled studies were included in quantitative synthesis. Risk of bias was assessed with the Cochrane Risk of Bias 2 and ROBINS-I tools. Random-effects meta-analyses used standardized mean differences (SMDs), with sensitivity, influence, subgroup, and publication bias analyses conducted where appropriate. Results: Fifty-nine studies met inclusion criteria, including 24 controlled studies with 1881 participants. AAT was associated with reduced overall BPSD severity, although this effect was sensitive to study quality and was not retained after excluding high-risk studies. AAT significantly improved depressive symptoms (SMD, −0.79, 95%CI, −1.33 to −0.26) and cognitive performance (SMD, 1.17; 95%CI, 0.31 to 1.79), with substantial heterogeneity; both effects persisted after excluding studies at high or serious risk of bias. No significant effects were observed for agitation, quality of life, or activities of daily living. Benefits were observed primarily in live animal interventions; robotic subgroups comprised a few studies and were underpowered to detect an effect. Conclusions: AAT may confer meaningful benefits for mood and cognitive engagement in dementia, particularly with live animals, but confidence is limited by methodological heterogeneity and the predominance of studies at moderate to serious risk of bias. Full article

Alpha-1 adrenergic receptor antagonists are widely used in the management of lower urinary tract symptoms, where they can induce ejaculatory dysfunction as a pharmacodynamic effect, particularly with α1A-selective agents. This observation has led to growing interest in their potential role as non-hormonal male contraceptives. This narrative review evaluates current clinical and preclinical evidence regarding the impact of α-blockers on the ejaculatory mechanism, with a focus on their potential application in male contraception. Both human and animal data were examined to contextualize the mechanistic basis for contraceptive potential. Evidence from clinical and pharmacological studies indicates that inhibition of α1-adrenoceptor-mediated smooth-muscle contraction in tissues involved in seminal emission, including the vas deferens, seminal vesicles, and prostate, can impair the emission phase of ejaculation. Agents such as tamsulosin and silodosin have been reported to induce anejaculation or markedly reduce semen volume, providing pharmacodynamic evidence of impaired seminal emission; however, these effects should not be considered equivalent to demonstrated contraceptive efficacy. Prospective clinical evidence currently includes one prospective pilot study and one randomized placebo-controlled clinical trial evaluating silodosin as a potential reversible non-hormonal male contraceptive. The prospective evidence includes marked and progressive suppression of sperm output and semen volume with repeated silodosin administration; at week 12, 94% of participants achieved a total sperm count ≤ 1 × 10⁶ per ejaculate, while the observed pregnancy incidence was 4% versus 17% with placebo. However, the available evidence remains insufficient to establish reliable contraceptive effectiveness for individual sexual exposures. Safety considerations, including cardiovascular effects and sexual dysfunction, also remain insufficiently characterized in healthy men. α1-adrenoceptor antagonists represent a biologically plausible pharmacologic strategy for male non-hormonal contraception by interfering with seminal emission and sperm delivery without directly suppressing spermatogenesis. Further pharmacokinetic–pharmacodynamic studies and rigorously designed multicentre clinical trials are required to determine the optimal dosing strategy, completeness and consistency of seminal emission suppression, contraceptive effectiveness, safety, acceptability, and reversibility of this approach. Full article

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the central nervous system. Nevertheless, their functional effects on peripheral neuronal populations, including enteric and dorsal root ganglion (DRG) neurons, remain incompletely characterized at a comparative pharmacological level. This study aimed to perform a comparative functional neuropharmacological profiling of commonly used ASDs in primary cultured myenteric and DRG neurons. Methods: Changes in neuronal activity were assessed in primary cultured guinea pig myenteric and DRG neurons using voltage-sensitive dye imaging with Di-8-ANEPPS following direct ASD application under standardized in vitro conditions. Results: ASDs exerted distinct drug- and neuron-type-specific effects on peripheral neuronal excitability. Topiramate induced the most pronounced reduction in neuronal excitability in myenteric neurons, whereas phenobarbital and levetiracetam produced only minor changes compared with buffer control. Potassium bromide induced mainly excitatory effects in both enteric and DRG neurons. Overall, most ASDs predominantly increased neuronal excitability in DRG neurons. Conclusions: These findings demonstrate distinct functional response profiles of ASDs in enteric and sensory neuronal populations. This comparative in vitro approach may provide a basis for future studies investigating peripheral neuronal drug effects and may help relate experimental pharmacological profiling to clinically relevant challenges associated with ASD treatment across different disorders. Full article

Hedera helix L. leaf extracts are regulated expectorants for productive cough, yet their evidence is dispersed across pharmaceutical quality, nonclinical pharmacology, disposition, toxicology, clinical pharmacology, efficacy, safety, and regulatory assessment. This review integrates those domains in a single study-level account and explicitly distinguishes isolated constituents, incompletely specified extracts, defined monograph preparations, proprietary extracts, and combination products. Hederacoside C is the pharmacopoeial marker, while α-hederin is the constituent most extensively examined in β2-adrenergic receptor models. Cell studies documented reduced agonist-induced receptor internalisation, greater ligand binding and cAMP responsiveness, and altered GRK2/β-arrestin signalling. Isolated tissue and animal studies reported antispasmodic, anti-inflammatory, antitussive, and tracheobronchial secretory effects. Rat studies showed low, matrix-dependent oral exposure to hederacoside C and α-hederin. Small exploratory human studies detected no or only trace α-hederin and did not permit conventional pharmacokinetic analysis. Clinical evidence includes placebo-controlled adult trials, active comparator studies, paediatric investigations, postmarketing cohorts, systematic reviews, and pharmacovigilance reports. Controlled adult trials of EA 575 reported greater short-term improvement in cough or Bronchitis Severity Score than placebo; paediatric efficacy evidence is dominated by observational studies and small airway function trials. Short-term tolerability was generally favourable, with gastrointestinal and hypersensitivity reactions as the principal recognised adverse effects. The European Union monograph recognises specified extracts for productive cough, contraindicates use below two years, and does not recommend use during pregnancy or lactation. The distinctive contribution of this review is the complete quality-to-clinic evidence map, including dose, model, endpoint, study design, extract identity, and unresolved evidence domain for each major dataset. Full article

Citrullus colocynthis (L.) Schrad., a drought-tolerant member of the Cucurbitaceae family, has been used in traditional medicine for centuries and has recently attracted increasing interest because of its potential pharmacological, agricultural, and ecological applications. This review examines current information on the plant’s distribution, ethnomedicinal uses, phytochemical composition, biological activities, applications in poultry, and ecological significance. Its bioactive constituents include cucurbitacins, flavonoids, phenolic compounds, alkaloids, glycosides, fatty acids, and tocopherols. These compounds have been associated with anticancer, antidiabetic, antimicrobial, antioxidant, anti-inflammatory, neuroprotective, hepatoprotective, and other biological activities, although most of the available evidence comes from in-vitro and preclinical studies. Initial findings also indicate that the plant may have value as a phytogenic feed additive in poultry and as a drought-tolerant species for soil stabilization, rangeland rehabilitation, and desertification control. However, the practical application of these findings is still constrained by differences in research methods, variation in phytochemical composition, limited clinical evidence, and the plant’s narrow therapeutic window and dose-dependent toxicity. Consequently, its therapeutic effectiveness and suitability for routine agricultural use cannot yet be established with certainty. Future research should focus on phytochemical standardization, quality control, thorough toxicological assessment, mechanistic studies, and well-designed clinical and animal trials using standardized preparations. Collectively, the available evidence indicates that C. colocynthis is a promising source of bioactive compounds with potential pharmaceutical, veterinary, and ecological applications, although rigorous scientific validation is required before its safe and effective utilization can be recommended. Full article

Marked interindividual variability in drug response remains a major challenge in clinical pharmacology and cannot be fully explained by host genetics alone. Increasing evidence indicates that the gut microbiota constitutes an additional determinant of drug efficacy and toxicity through bidirectional interactions with pharmacological therapies. This recognition has led to the emergence of pharmacomicrobiomics, a field that investigates how microbial communities influence drug disposition and response, and how drugs, in turn, alter the microbiome. Microbiome-mediated effects on drug efficacy and toxicity have been described across several therapeutic areas, including oncology, multiple sclerosis, and type 2 diabetes mellitus. Although these findings are promising, most mechanistic evidence derives from preclinical and animal studies, with relatively limited validation in controlled clinical trials. Strategies to modulate the gut microbiota, including prebiotics, probiotics, and faecal microbiota transplantation, have shown preliminary promise in optimising drug efficacy and reducing adverse effects, although methodological heterogeneity and incomplete mechanistic understanding limit their current clinical application. The identification of robust microbiome-derived biomarkers and the integration of multi-omics approaches, particularly metabolomics, are expected to accelerate the translation of pharmacomicrobiomics into precision medicine. This review summarises current evidence regarding microbiome–drug interactions, the mechanisms underlying microbiome-mediated modulation of pharmacokinetics and pharmacodynamics, emerging therapeutic strategies, and the challenges that remain before pharmacomicrobiomics can be implemented in clinical practice. Full article