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Pistacia lentiscus L. var. Chia is an endemic tree cultivated in the Southern part of Chios Greek Island. Chios mastiha, the aromatic resin secreted from this tree, has been used as traditional remedy since ancient times to cure many peptic system diseases and as a nutritional agent. Nowadays, Chios mastiha has been widely investigated for its biological activities and its chemical composition. A major part of Chios mastiha’s bioactive compounds are triterpenoids, which are proposed to interfere with glucocorticoid receptor (GR) signaling, acting as selective GR agonists. In this study a specific “neutral fraction” of Chios mastiha resin, a portion devoid of acidic triterpenoids, was investigated regarding its biological potential and chemical composition. The study aimed to determine if the neutral triterpenoids, the non-carboxylic ones, within this fraction drive Chios mastiha’s interference with GR signaling and whether it exhibits anti-inflammatory, apoptotic, and potential antilipidemic activities. The phytochemical characterization of this specific resin portion, applying ¹H NMR and HPLC-QTOF-MS/MS analysis, identified novel unidentified Chios mastiha’s phenolic components (apigenin, astragalin, diosmetin, flavidin, genistein), a complex mixture of fatty acids (palmitic, stearic, oleic), non-carboxylic triterpenoids (lupeol, β-amyrin, keto-oleanolic aldehyde), and a trace of terpenoids. Biological assessment of DEX-induced GR transcriptional activation revealed that neutral triterpenoid fractions only minimally contribute to GR transcriptional activation while positively regulating GR and its target, phosphoenolpyruvate carboxykinase (PEPCK), protein levels. Additionally, negative regulation of the peroxisome proliferator-activated receptor alpha (PPARα) protein levels as well as inhibition of the TNFα-induced NF-κΒ activity and reduction in the p65 subunit of NF-κΒ protein levels, were observed, indicating potential antilipidemic and anti-inflammatory Chios mastiha’s neutral fraction activities, which were attributed to its composition in triterpenoids, fatty acids, and novel phenolic compounds. Moreover, mitochondrial-dependent induction of apoptosis accompanied by reduction in cell viability was observed in lupeol, β-amyrin, and fatty acids-enriched fractions. The plethora of bioactive compounds associated with a variety of Chios mastiha’s neutral fraction render Chios mastiha a valuable food additive and nutritional agent. Full article

Chronic inflammatory skin diseases, including psoriasis, hidradenitis suppurativa (HS), and atopic dermatitis (AD), are increasingly recognized as systemic disorders associated with chronic immune dysregulation. Growing evidence supports their links with metabolic disorders, reflected in heightened interest in therapeutic strategies targeting the immunometabolic axis. This review summarizes current knowledge on the role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the regulation of immune and metabolic processes in chronic inflammatory skin diseases, with particular emphasis on molecular mechanisms and available experimental and clinical data. GLP-1RAs, widely used in the treatment of type 2 diabetes and obesity, may also exhibit anti-inflammatory and immunomodulatory properties beyond their classical metabolic effects. GLP-1 signalling can influence keratinocyte function, immune cell activity, and wound healing. Furthermore, it modulates multiple intracellular signalling pathways, including cAMP/PKA, AMPK, PI3K/Akt, and NF-κB, as well as immune axes such as IL-23/Th17/IL-17 and inflammasome-related signalling. Available evidence suggests that GLP-1RAs may reduce inflammation and disease activity in selected inflammatory dermatoses. However, current evidence remains limited and is based primarily on experimental studies, case reports, and small-scale observational studies. Further well-designed clinical trials are needed to better define the therapeutic potential of GLP-1RAs and their role in dermatological practice. Full article

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2− metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28–82); all 110 patients (100.0%) were female; the median BSA was 1.56 m² (range, 1.29–2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3–498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2− metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life. Full article

Background: Metabolic syndrome is characterized by dysregulated glucose metabolism and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Although glucose-lowering therapies such as glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, their use may be limited by cost, administration route, side effects and tolerability. Bergamot (Citrus bergamia Risso et Poiteau) extract, rich in flavanones, has shown favorable metabolic effects in clinical studies, although its mechanisms of action remain insufficiently defined. This study aimed to investigate the potential glucose-modulating mechanisms of a standardized phospholipid-formulated bergamot extract (BP) (Vazguard™) in vitro. Methods: GLP-1R activation was assessed in a U2OS cell line expressing cyclic adenosine monophosphate (cAMP)-sensitive Nomad Biosensors™. Dipeptidyl peptidase-4 (DPP4) activity was evaluated using a cell-free enzymatic assay, while Glucose transporter type 4 (GLUT4)-mediated glucose uptake was assessed in CHO-K1 cells stably expressing human GLUT4 using an adenosine triphosphate (ATP)-based readout. Cytotoxicity was also using lactate dehydrogenase (LDH), MTT, and nuclei count assays. Results: BP exhibited a dose-dependent (0.31–5 mg/mL) increase in cAMP biosensor fluorescence, consistent with GLP-1R-associated signaling and a maximal response of approximately 60% relative to the positive control (GLP-1R agonist II). No cytotoxic effects were observed. In contrast, BP showed no inhibitory effect on DPP4 activity and did not alter GLUT4-mediated glucose uptake under the experimental conditions tested. Conclusions: These findings provide novel mechanistic evidence that phospholipid-formulated bergamot extract suggests a possible involvement in GLP-1R-associated signaling in vitro, without detectable effects on DPP4 or GLUT4 pathways under the conditions tested. This suggests a mechanism consistent with weak agonist or allosteric modulation of GLP-1R and supports further investigation of bergamot formulated with phospholipids as potential natural adjuncts in metabolic health management. Full article

Background: Glucagon-like peptide-1 (GLP-1)-based therapies offer significant cardiometabolic benefits. Obesity-related heart failure with preserved ejection fraction (HFpEF) arises from a complex interplay of increased lipids, chronic inflammation, and metabolic disturbances. These factors not only exacerbate the disease but also affect GLP-1 pathways, supporting the potential role of GLP-1-based therapies in targeting this condition. Objective: This review aimed to synthesize the current evidence on GLP-1-based therapy in HFpEF, focusing on mechanisms of action, clinical outcomes, and practical significance. Methodology: A narrative review using PubMed and Scopus was conducted, including studies published between January 2020 and March 2026. Evidence from randomized trials, pooled analyses, mechanistic studies, and observational data was incorporated. Results: GLP-1-based therapies, including semaglutide and tirzepatide, demonstrated significant improvements in symptoms, exercise capacity, and quality of life. These benefits are closely linked to weight loss, reduced inflammation, and improved congestion indices. Tirzepatide use has also been associated with a reduction in heart failure-related complications. The underlying mechanisms likely involve coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. Current evidence suggests that its efficacy in improving morbidity rates is stronger than its efficacy in reducing mortality rates. Conclusions: GLP-1-based therapies offer a promising, phenotypically targeted approach to managing obesity-associated HFpEF. However, their long-term effects on mortality remain unclear, highlighting the need for further research. Further studies should refine patient selection and define optimal clinical integration. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and newer dual-incretin therapies have become central to the treatment of diabetes mellitus and obesity, with benefits extending beyond glycemic control. Their expanding use has prompted growing interest in their potential ocular effects. Experimental data support plausible protective mechanisms, including reduction in oxidative stress and neuroprotective effects on retinal and optic nerve tissues. Clinical evidence, however, remains heterogeneous. In diabetic retinopathy, the main concern appears to be transient early worsening associated with rapid glycemic improvement rather than direct retinal toxicity. A potential semaglutide-associated signal for non-arteritic anterior ischemic optic neuropathy has raised concern, although the absolute risk appears low and causality remains unproven. Emerging studies also suggest possible beneficial associations with glaucoma, ocular surface diseases, and certain retinal vascular outcomes, whereas the evidence regarding age-related macular degeneration and cataract remains conflicting or preliminary. Overall, ocular outcomes associated with incretin-based therapies seem to reflect a complex interplay among drug-specific pharmacology, systemic metabolic changes, and individual patient susceptibility rather than a class effect. Baseline ophthalmic assessment and individualized follow-up may be advisable in selected high-risk patients. Further prospective ophthalmology-focused studies are needed to clarify long-term safety and identify the patients most likely to benefit or develop adverse events. Full article

Background/Objectives: The aim of this study was to investigate the effects of intraocular pressure (IOP)-lowering drops on the sublayers of the human tear film as assessed by a novel nanometer-resolution Tear Film Imager (TFI, AdOM, Israel). Methods: In a prospective, cross-sectional study, 98 eyes from 56 adult human subjects were imaged using the TFI. The dataset included data from 18 eyes from 12 subjects treated with preserved IOP-lowering drops and 80 eyes from 44 control subjects not under ocular hypotensive therapy. Subjects in the IOP treatment group used a variety of IOP-lowering medications, including prostaglandin analogs, beta-blockers, carbonic anhydrase inhibitors, alpha agonists, and combination drops. A linear mixed effects model was used to assess the association between IOP-lowering therapy and tear film (TF) metrics, controlling for age and intra-individual correlation. The following parameters were measured: muco-aqueous layer thickness (MALT), muco-aqueous layer thinning rate (MALTR), lipid layer thickness (LLT), lipid map uniformity (LMU), inter-blink intervals (IBI), and lipid break-up time (LBUT). Results: Average ages significantly differed (p = 0.013) between the treatment group (66.5 years) and control group (average age 51.5 years), and thus results were adjusted for age accordingly. IOP was 17.1 mmHg in the treatment group and 16.1 mmHg in the control group. When analyzing the sublayers of the TF, MALTR had a significant association with IOP-lowering therapy after adjusting for age, with a difference of −52.68 nm/s; 95% confidence interval [−96.87, −8.48]; p-value = 0.020. Additionally, IBI was significantly associated with IOP-lowering therapy after log transformation (p = 0.049), with shorter IBI in the treatment group. All other metrics (MALT, LLT, LMU, and LBUT) were statistically insignificant (p > 0.05). Conclusions: These pilot results suggest that IOP-lowering drops may accelerate thinning of the TF, specifically the muco-aqueous layer. Longitudinal studies with significantly larger samples are needed to specify the differential impact of various ocular hypotensive therapies on the human TF and the clinical implications of these findings. Full article

Severe aplastic anemia (SAA) in pregnancy represents a rare but life-threatening clinical challenge. Standard therapies such as hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy are limited during pregnancy due to safety concerns, leaving supportive care as the mainstay. Thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag have emerged as promising agents in refractory SAA, though evidence of their safety in pregnancy remains scarce. We present the case of a 27-year-old woman with SAA post-allogeneic bone marrow transplant who relapsed during subsequent pregnancies. Her disease course was characterized by recurrent pancytopenia, mixed chimerism, and repeated need for stem cell boosts. During pregnancy in 2023, discontinuation of cyclosporine led to worsening cytopenias, prompting reintroduction of cyclosporine and the continuation of eltrombopag. This combined approach, alongside G-CSF and stem cell boosts, contributed to favorable hematologic stabilization. She successfully delivered a healthy infant and achieved hematologic recovery following a third stem cell boost postpartum. This report highlights the potential utility of TPO-RAs during pregnancy when conventional therapy is limited, while emphasizing the need for vigilant monitoring of maternal–fetal outcomes. A review of the literature suggests that although routine use of eltrombopag in pregnancy is not recommended, it may be considered in refractory SAA cases with careful risk–benefit assessment. The case underscores the role of multidisciplinary care, individualized therapeutic planning, and the need for further studies on TPO-RAs in pregnancy-associated bone marrow failure syndromes. Full article

The direct involvement of the phosphatidylinositol 3-kinase (PI3K)/serine threonine kinase (AKT) signaling pathway in the alleviation of the heat stress (HS)-induced damage to the integrity and barrier function of broiler jejunal organoids (JOs) by supplemental zinc (Zn) has not been confirmed. To verify it, two experiments were conducted in the present study. In experiment 1, the optimal concentrations of PI3K/AKT inhibitor (PI3K-IN-1) or agonist (YS-49) were screened. In experiment 2, the role of PI3K/AKT in Zn alleviation of HS-induced damage to JOs was evaluated with three JO types as control groups under baseline incubation temperature (40 °C) plus a 3 (JOs types) × 3 (Zn sources) factorial design under high temperature (44 °C). The results showed that the optimal concentrations of the PI3K-IN-1 and YS-49 for effectively inhibiting and promoting (p < 0.001) phosphorylation of PI3K and AKT were 16 μmol/L and 9 μmol/L, respectively. Adding Zn, especially Zn proteinate with moderate chelation strength (Zn-Prot M), alleviated (p < 0.001) the HS-induced increases in diamine oxidase content and lactate dehydrogenase activity in the media and the HS-induced decreases in JOs budding percentage, proportions of 5-ethynyl-2′-deoxyuridine and proliferating cell nuclear antigen positive cells, and the phosphorylation of PI3K and AKT. PI3K/AKT inhibition or activation reduced or enhanced (p < 0.05) the above alleviating effect of Zn, especially Zn-Prot M. These results indicate that the PI3K/AKT signaling pathway mediated the alleviation of HS-induced damage to integrity and barrier function of broiler JOs by supplemental Zn, particularly Zn-Prot M via promotion of cell proliferation. Full article

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a prevalent condition with a significant annual incidence, particularly increasing with age. Its pathophysiology is explained by Virchow’s triad (venous stasis, vascular injury, and hypercoagulability). Tirzepatide, a dual receptor agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is approved for type 2 diabetes mellitus (T2DM) and obesity, showing efficacy in lowering HbA_1c and promoting weight loss. Recent case reports have linked tirzepatide to VTE events, particularly in patients experiencing significant weight loss, raising concerns about its safety profile. We present a case of a male T2DM subject who developed PE after five injections of tirzepatide in a patient with grade I obesity. We also review emerging literature on VTE associated with tirzepatide, emphasizing the need for further research to clarify the drug’s risk and underlying mechanisms. Full article

Background/Objectives: Long-acting lipid-lowering injectable therapies, including PCSK9 monoclonal antibodies, inclisiran, and selected glucagon-like peptide-1 receptor agonists, represent a structural innovation in chronic disease management. By reducing dosing frequency and embedding pharmacologic persistence within healthcare delivery systems, these therapies address persistent challenges of long-term statin non-adherence. However, from a health economics perspective, such innovations may also alter incentive structures related to preventive behaviors. This study examines whether outcome measurement in the long-acting injectable literature reflects shifts in the balance between pharmacologic adherence and lifestyle-related prevention. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. Eligible studies included adult populations receiving PCSK9 monoclonal antibodies, inclisiran, or GLP-1 receptor agonists that reported pharmacologic adherence or persistence and/or lifestyle-related measures. Studies were categorized by therapy class and design. The prevalence of adherence and lifestyle outcome measurement was calculated, and a descriptive Measurement Asymmetry Index was defined as the difference between adherence measurement prevalence and lifestyle measurement prevalence. Results: Four studies met the inclusion criteria, comprising randomized controlled trials. Pharmacologic adherence or persistence was measured in all included studies (100%), whereas lifestyle-related outcomes were assessed in only one study (25%), limited to a GLP-1 receptor agonist trial. No study explicitly evaluated behavioral substitution, risk compensation, or changes in patient responsibility. The Measurement Asymmetry Index was 75 percentage points, indicating a pronounced imbalance between pharmacologic and behavioral outcome domains. Conclusions: The findings do not provide evidence of behavioral moral hazard at the individual level but reveal a structural asymmetry in how prevention is assessed within the injectable therapy evidence base. This pattern may reflect an emphasis on drug-attributable and measurable outcomes, with comparatively limited attention to lifestyle engagement. As long-acting therapies become more integrated into chronic disease management, incorporating standardized lifestyle metrics into cardiovascular research may be necessary to support a more balanced framework of preventive responsibility. Full article

Obesity resulting from melanocortin-4 receptor (MC4R) dysfunction is characterized by combined metabolic dysregulation and maladaptive reward-related behaviors that limit the durability of existing therapies. The endocannabinoid system is a central regulator of appetite, lipid metabolism, and reward processing; however, first-generation cannabinoid receptor 1 (CB1) antagonists were limited by adverse neuropsychiatric effects. SKNY-1 is an orally active tetrahydrocannabivarin (THCV) analog designed to engage pathway-biased CB1 signaling, modulate cannabinoid receptor 2 (CB2), and selectively inhibit monoamine oxidase B (MAO-B), with the objective of addressing both metabolic and behavioral components of obesity while minimizing central nervous system liability through biased CB1 signaling, CB2 modulation, and potential complementary MAO-B inhibition. Here, we integrated in vitro pharmacological profiling of SKNY-1 with in vivo evaluation in an adult mc4r(G894C) zebrafish model exhibiting obesity-associated metabolic and reward-related phenotypes. In vitro, SKNY-1 displayed low-potency modulation of CB1 cyclic AMP signaling (EC₅₀ ~30 µM) but more potent antagonism of the CB1 β-arrestin pathway (IC₅₀ ~6 µM), consistent with differential CB1 pathway modulation. SKNY-1 acted as a CB2 partial agonist (EC₅₀ ~0.1 µM), with antagonist activity emerging at higher concentrations, and selectively inhibited MAO-B at low affinity with no activity against MAO-A. In vivo, mc4r(G894C) zebrafish mutants exhibited dyslipidemia, hepatic triglyceride accumulation, altered appetite-regulatory gene expression, increased metabolic rate, and enhanced compulsive high-calorie feeding and nicotine-seeking behaviors. Oral administration of SKNY-1 for six days produced dose-dependent effects. Both doses normalized total cholesterol and low-density lipoprotein levels and reduced hepatic triglycerides toward wild-type values without affecting circulating triglycerides. The higher dose (200 ng per fish per day) induced significant body weight reduction while preserving body density and attenuated reward-associated feeding and nicotine-seeking behaviors. The lower dose (20 ng per fish per day) more effectively normalized the leptin a-to-ghrelin expression ratio. Collectively, these findings demonstrate that SKNY-1 engages integrated endocannabinoid and potential dopaminergic mechanisms to improve metabolic parameters and attenuate maladaptive reward-related behaviors in an MC4R-deficient vertebrate model, supporting its further translational investigation for obesity complicated by compulsive eating and substance-seeking behaviors. Full article

Background and Objectives: Sevoflurane, a widely used volatile anesthetic, can induce oxidative stress and apoptosis, but the underlying mechanisms in human cardiomyocytes remain unclear. This study investigated the role of transient receptor potential vanilloid 1 (TRPV1) channels in sevoflurane-induced cardiotoxicity and the potential mitigating effect of ascorbic acid. Materials and Methods: Human cardiomyocytes were exposed to sevoflurane (5.1%, 6 h) and/or ascorbic acid (1 mM, 30 min), with or without the TRPV1 channel antagonist capsazepine and with the TRPV1 channel agonist Capsaicin. Intracellular calcium, reactive oxygen species (ROS), apoptosis, mitochondrial membrane potential, and caspase-3/9 activities were assessed. Results: Sevoflurane significantly increased intracellular calcium levels, ROS production, mitochondrial depolarization, apoptosis, and caspase-3/9 activity compared with controls (p < 0.001). These effects were attenuated by capsazepine, suggesting a role for TRPV1 involvement. Ascorbic acid pretreatment significantly reduced sevoflurane-induced elevations in all parameters (p < 0.001). Combined ascorbic acid and capsazepine treatment yielded further reductions in calcium, ROS, apoptosis, and caspase activities compared to ascorbic acid alone (p < 0.05). Conclusions: Sevoflurane induces apoptosis in human cardiomyocytes via ROS-mediated activation of the TRPV1 channel, leading to calcium overload, mitochondrial dysfunction, and caspase-dependent cell death. Ascorbic acid exerts mitigating effects by reducing oxidative stress and modulating TRPV1 channel activity, suggesting a potential therapeutic strategy for myocardial protection during sevoflurane anesthesia. Full article

Signal transducers and activators of transcription (STAT) proteins, which operate via canonical and non-canonical mechanisms, are critically implicated in thyroid tumorigenesis. This review integrates their multifaceted roles in thyroid cancer. STAT3 acts as a “double-edged sword”: hyperactive STAT3 drives metastasis and BRAF inhibitor resistance in advanced carcinomas, yet paradoxically acts as a tumor suppressor by restraining the Warburg effect via non-canonical mitochondrial localization. Clinically, preserved nuclear STAT3 independently predicts a favorable prognosis and is inversely correlated with TERT promoter mutations, offering a biological modifier for clinical risk stratification. Furthermore, STAT1 regulates differentiation via the IGF2BP2-m⁶A axis, STAT5 drives proliferation upon release from TRβ suppression, and STAT6 confers chemoresistance. While novel direct STAT3 inhibitors (e.g., TTI-101) and rational combinations with immune checkpoint inhibitors or STING agonists show promise in overcoming refractory disease, the intricate dual functionality of STAT family proteins demands rigorous biomarker-guided precision medicine approaches. Full article

Objective: Peripheral arterial occlusive disease (PAOD) is characterized by impaired tissue perfusion, chronic ischemia, and increased platelet reactivity. Hyperbaric oxygen therapy (HBOT) is used as adjunctive treatment in advanced PAOD, but its effect on platelet function remains insufficiently studied. This study examined the association between HBOT and platelet aggregation. Methods: This prospective observational study included 90 patients with Fontaine stage IV PAOD and chronic ulceration, assigned to an HBOT group (n = 60) or waiting-list control group (n = 30). Patients were predominantly male; mean age was 66.82 ± 9.42 years in the study group and 63.00 ± 8.31 years in controls, and diabetes mellitus was present in 55.0% and 63.3%, respectively. Prior revascularization included open surgery in 33.3% and 30.0%, endovascular treatment in 36.7% and 43.3%, and no option for revascularization in 30.0% and 26.7%, respectively. HBOT was administered over 4 weeks (20 sessions, 2.0–2.5 ATA). Platelet aggregation was measured by impedance aggregometry using arachidonic-acid-induced aggregation (ASPI), adenosine-diphosphate-induced aggregation (ADP), and thrombin-receptor-activating peptide-induced aggregation (TRAP) agonists. Changes were analyzed using generalized estimating equation models adjusted for antiplatelet therapy, diabetes mellitus, smoking, and C-reactive protein (CRP). Results: Significant group × time interactions were observed for all platelet activation pathways, indicating greater reductions in the HBOT group than controls: ASPI (β = −290.5; p < 0.001), ADP (β = −243.6; p < 0.001), and TRAP (β = −330.9; p < 0.001). No significant change was observed in controls. HBOT was associated with reduced pain intensity, while CRP and platelet-to-lymphocyte ratio (PLR) remained stable. Ulcer size showed no significant change after 4 weeks. Conclusions: In patients with PAOD, HBOT was associated with reduced platelet reactivity independent of antiplatelet therapy. Further randomized studies are needed to determine its clinical significance. Full article