Marios Papadakis

Desmoid tumors (DTs) are rare, benign, locally aggressive myofibroblastic neoplasms. Complete resection with negative margins remains the standard treatment despite their lack of metastatic potential. As DT commonly involve the anterior abdominal wall, their excision may result in complex defects requiring advanced reconstruction. We herein present the first functional single‐stage reconstruction of an abdominal wall defect with the use of a free innervated gracilis muscle flap transfer. A 29‐year‐old woman, presented with a palpable tumor on the left‐side of her abdominal wall. She underwent surgery and on biopsy, the tumor was diagnosed as a DT. The patient underwent wide resection through an abdominoplasty approach, which resulted in a rectus abdominis defect involving the anterior rectus abdominis sheath. The 8 × 7cm‐sized defect was reconstructed with free transfer of a neurotized gracilis muscle flap, anastomosed to the deep inferior epigastric vessels, whereas, the anterior branch of the obturator nerve was coapted to the ninth intercostal nerve. Finally, a monofilament polypropylene mesh was used for reconstruction of the missing anterior rectus sheath. Ever since and during a follow‐up of 5 years, electromyographic examinations have demonstrated excellent re‐innervation of the gracilis muscle flap. The patient underwent regular follow‐up examinations, including CT imaging at 1, 2, and 5 years postoperatively, with no evidence of abdominal wall protrusion or tumor recurrence. This case demonstrates that the free innervated gracilis flap can provide a safe and reliable reconstructive option for complex abdominal wall defects following oncologic resection.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, neuroinflammation, and metabolic impairment. Increasing evidence suggests that bile acids, traditionally recognized for their roles in lipid digestion and hepatic metabolism, act as endocrine signaling molecules that influence central nervous system (CNS) homeostasis. Through enterohepatic circulation and microbiota-dependent biotransformation, bile acid composition is dynamically regulated and can modulate peripheral metabolic and immune pathways with downstream effects on the brain. Notably, bile acid signaling via key receptors such as the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 and G-protein-coupled bile acid receptor 1 (TGR5/GPBAR1) has emerged as a mechanistic bridge linking liver–gut physiology to neuroinflammatory and neurodegenerative processes. Altered bile acid profiles have been reported in AD and mild cognitive impairment, with accumulating findings suggesting that hydrophobic secondary bile acids may contribute to blood–brain barrier (BBB) disruption and neurotoxicity. In contrast, hydrophilic bile acids may exert neuroprotective and anti-inflammatory effects. In addition, bile acids drive the release of gut hormones such as glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 19 (FGF19), highlighting indirect neurometabolic pathways relevant to cognition and neurodegeneration. This narrative review synthesizes current biochemical, experimental, and clinical evidence supporting a role for bile acid signaling in AD pathogenesis and progression. We discuss receptor-mediated pathways, microbiota-bile acid interactions, neuroimmune modulation, and translational perspectives, proposing that bile acid–based biomarkers and therapeutic strategies targeting FXR/TGR5 signaling may represent promising avenues for future AD intervention.

Background and Aims: Fluconazole (FZL) is a broad‐spectrum antifungal drug associated with certain serious adverse effects such as polymorphic ventricular arrhythmia due to QT prolongation. Torsade de Pointes (TdP) is a unique type of polymorphic ventricular arrhythmia due to QT prolongation. It has been shown that the calcium‐channel blocker verapamil is effective in the management of TdP. Therefore, the present critical review aims to discuss and explain the possible role of verapamil in the prevention of FZL‐induced TdP. Methods: Databases of Scopus, Cochran, Embase, PubMed, and CENTRAL were examined to recognize suitable publications. Screened articles were designated rendering to exact eligibility criteria including original articles such as prospective and retrospective studies recognizing the role verapamil in the prevention of FZL‐induced TdP. Results: The use of FZL is linked with the development of TdP and prolongation of QT, and verapamil use could be effective in the management of TdP. In addition, verapamil has antifungal effects, affects the pharmacokinetics and pharmacodynamics of FZL. Verapamil inhibits the propagation of TdP by inhibiting the deregulation of repolarization early after depolarization in the heart. Conclusions: This critical review suggests that combination of verapamil with FZL leads to more beneficial effects by increasing the antifungal activity of FZL with a significant reduction the development of TdP which is a serious adverse effect of FZL.

Asthma is a heterogeneous chronic inflammatory airway disease characterized by persistent inflammation, dysregulated immune signaling, and progressive airway remodeling. It has been shown that asthma pathogenesis involves multiple signaling pathways. It has been illustrated that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) cascade, which emerges as a central regulator linking immune activation, epithelial dysfunction, and structural remodeling of the airway, is implicated in the pathogenesis of asthma. Sustained ERK1/2 activation is consistently demonstrated in human asthmatic airways and experimental models, correlating with disease severity, inflammatory cell infiltration, and corticosteroid resistance. This review provides a comprehensive and critical discussion of the ERK1/2 signaling in asthma, spanning immune cells, airway epithelium, and airway smooth muscle. We evaluate preclinical and translational evidence supporting ERK1/2 as a therapeutic target and examine emerging pharmacological strategies, including indirect pathway modulation via AMP-activated protein kinase (AMPK) activation and drug repositioning with the anti-diabetic metformin. By integrating mechanistic insights with therapeutic implications, this review positions ERK1/2 as a pivotal signaling node for precision targeting in severe, treatment-refractory asthma.

The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD ⁺ -dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.

Parkinson’s disease (PD) is a systemic neurodegenerative disease, and is mainly related to the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Despite extensive research regarding PD neuropathology, there are no active drugs to avert this disease. It has been described that the adenosine pathway, which is expressed centrally and peripherally, is involved in the pathogenesis of PD and other neurodegenerative diseases. Adenosine acts on adenosine receptors (ARs), including A1R, A2AR, A2BR, and A3R. Both A1R and A3R are neuroprotective, while A2AR and A2BR are neurotoxic for the brain. A2AR, in the SNpc, mediates the neurotoxicity of adenosine in PD. In addition, data from epidemiological studies highlighted controversial findings in PD and other neurodegenerative diseases. Therefore, the present review aims to revise from published articles the potential role of the adenosine pathway in PD neuropathology, and how methylxanthines affect the dopaminergic neurotransmission in the SNpc. This review highlighted that selective A2AR antagonists could be more effective than non-selective AR antagonists in the management of motor and non-motor symptoms of PD.

Asthma is a clinically and biologically heterogeneous disease for which current anti-inflammatory therapies, including inhaled corticosteroids, remain insufficient for many patients. Therefore, repurposing other FDA-approved drugs, such as phosphodiesterase (PDE) inhibitors, may be beneficial in the management of asthma. PDEs are central regulators of cyclic nucleotide signaling, modulating airway smooth-muscle tone, mucociliary function, and immune-cell activity by compartmentalizing the control of cAMP and cGMP. Although PDE4 inhibitors have shown strong pre-clinical efficacy, their translation into clinical practice has been hindered by dose-limiting systemic toxicities, revealing a persistent gap between mechanistic promise and therapeutic utility. This review synthesizes emerging insights into PDE isoenzyme selectivity, spatial localization, and cross-regulatory interactions across structural and immunocompetent airway cells. We outline how isoform- and splice-variant–specific functions contribute to key asthmatic phenotypes and evaluate innovative therapeutic strategies, including dual PDE3/4 inhibition, inhaled delivery approaches, and next-generation selective modulators designed to overcome historical limitations. By integrating these advances within an endotype-driven precision-medicine framework, this review provides a path toward unlocking the full therapeutic potential of PDE-targeted interventions in asthma.

Background Epilepsy is a neurological condition characterized by recurrent, spontaneous seizures stemming from sudden, abnormal synchronization of neuronal activity in specific brain regions, driven by structural or functional alterations. This disorder is preceded by epileptogenesis, a dynamic process marked by cellular and molecular changes that heighten brain excitability. Although anti-seizure medications (ASMs) remain the cornerstone of treatment, roughly 30% of patients develop refractory epilepsy, which resists ASMs therapy. Critically, ASMs do not prevent epileptogenesis, implying divergent mechanisms govern disease progression. Methods This review evaluates the pathway’s contributions to neuroinflammation, epileptogenesis, and epilepsy, and explores the promise of COX-2 inhibitors in managing refractory epilepsy. Results Epileptogenesis continues even after seizures manifest and is strongly associated with drug-resistant forms such as temporal lobe epilepsy (TLE). Neuroinflammation, which develops subsequent to the epileptic seizure, aggravates refractory epilepsy by enhancing the extrusion of ASMs across the blood-brain barrier (BBB), reducing their therapeutic efficacy. Following epileptic seizures, cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin (PG) synthesis, is upregulated and activates the COX-2/PG pathway, leading to exacerbation of neuroinflammation and acceleration of epilepsy progression. Furthermore, by inducing neuronal hyperexcitability and epileptogenesis, elevated COX-2 and PG levels correlate with increased seizure severity and frequency. Conclusion Consequently, targeting of the COX-2/PG axis has emerged as a potential therapeutic strategy.