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Overcoming Gastric Barriers for Oral Peptide Delivery: QbD-Based Development of Sodium Caprate-Enabled Tirzepatide Tablets.
Pharmaceutics
Seokhyun Im, Ji-Yoon Lee, Joo-Eun Kim
Background/Objectives: Tirzepatide is a dual GIP and GLP-1 receptor agonist indicated for the treatment of type 2 diabetes and obesity. Oral delivery of tirzepatide is limited by poor gastrointestinal permeability, pH-dependent solubility, and manufacturing challenges associated with high-dose absorption enhancers. Methods: This study developed an immediate-release oral tirzepatide tablet using a Quality by Design (QbD) approach. Sodium caprate (C10) was selected as the absorption enhancer based on acid-neutralizing capacity, Caco-2 permeability enhancement, and preliminary rat pharmacokinetic screening. Quality target product profile, critical quality attributes, preliminary hazard analysis, and failure mode and effects analysis identified binder/disintegrant ratios as critical material attributes and hammer milling conditions as critical process parameters. Face-centered central composite designs and multiple-response optimization (MRO) were applied to optimize dissolution, flowability, and tablet mechanical integrity. Results: The optimized binder/disintegrant composition produced benchmark-comparable dissolution profiles against oral semaglutide tablets in pH 1.2, 4.0, and 6.8 media, with f2 values exceeding 50 for both C10 300 mg and 500 mg formulations. The optimized process yielded tablets with low friability (0.58%) and acceptable flowability (Carr's index, 24). In beagle dogs, the C10 300 mg formulation achieved higher systemic exposure than the C10 500 mg formulation, with a Cmax of 46.49 ± 23.79 ng/mL and AUClast of 1261.03 ± 690.44 h·ng/mL. Conclusions: These results support C10-mediated oral tirzepatide delivery and QbD-based optimization for oral peptide tablets.
Trends in publicly subsidized and private access to GLP-1 medicines indicated for type 2 diabetes in Australia, 2020-2025.
Br J Clin Pharmacol
Michael O Falster, Juliana de Oliveira Costa, Tamara Y Milder +8 more
GLP-1 medicines provide substantial cardio-renal benefits for type 2 diabetes (T2D) and are increasingly used for weight loss. Most high-income countries subsidize access for T2D with restrictions; use outside of these restrictions occurs through private prescriptions. Despite strong consumer demand, the extent of private access to GLP-1 medicines remains poorly quantified.
Tirzepatide and metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity: a real-world multicenter study.
Front Endocrinol (Lausanne)
Martina Galasso, Ludovica Verde, Renato Patrone +5 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and is strongly associated with obesity, insulin resistance, and systemic inflammation. Tirzepatide, a dual GIP and GLP-1 receptor agonist, has shown significant effects on weight loss and metabolic control. However, real-world evidence on hepatic steatosis remains limited. The aim of this study was to evaluate the effect of tirzepatide treatment in patients with obesity and MASLD and to identify the clinical predictors of its hepatic effect.
Relationship Between GLP-1-Based Therapies and Periodontal Health: A Systematic Review of Current Evidence and Future Perspectives.
Int J Mol Sci
Kacper Nijakowski, Dawid Gruszczyński, Szymon Łacinik +3 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes mellitus and obesity, have recently attracted attention for their potential effects on periodontal tissues. This systematic review aimed to evaluate the current evidence regarding the relationship between GLP-1-based therapies and periodontal health, with particular emphasis on anti-inflammatory, osteogenic, and regenerative mechanisms. A comprehensive literature search of PubMed, Web of Science, and Embase databases identified 22 eligible studies, including in vitro, animal, and human investigations. The available evidence suggests that GLP-1RAs such as liraglutide and exendin-4 may attenuate periodontal inflammation, reduce alveolar bone loss, and enhance osteogenic differentiation of periodontal ligament and dental pulp stem cells through modulation of pathways including MAPK/ERK, Wnt/β-catenin, NF-κB, and PKCβ2. Clinical observations additionally indicate a bidirectional relationship between periodontitis and incretin signalling, with periodontal therapy associated with increased systemic GLP-1 levels. However, the current evidence remains heterogeneous and is largely limited to preclinical and observational studies. Randomised clinical trials are required to determine the clinical efficacy and therapeutic relevance of GLP-1-based therapies in periodontitis management.
Tirzepatide Attenuates Wire Injury-Induced Arterial Remodeling in Non-Diabetic and Diabetic Mice: Comparison with Semaglutide.
Biomedicines
Yusaku Mori, Naoya Osaka, Michishige Terasaki +6 more
Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RAs) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia, including at a low dose that did not affect metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide, but not semaglutide, exerted vasoprotective effects under non-diabetic conditions in a NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions.
Oral Health Implications of GLP-1 Receptor Agonists and Other Incretin-Based Therapies.
J Clin Med
Julia Bijoch
Incretin-based therapies have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Established agents-the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) semaglutide and liraglutide, and the dual GIP/GLP-1 receptor agonist tirzepatide-are now widely used, while a diverse pipeline of multi-receptor agents is advancing through late-phase development. GLP-1 receptors are expressed in several oral and other craniofacial tissues, raising the question of how these drugs affect oral health. This narrative review (PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov; January 2010-June 2026) integrates mechanistic studies, randomised controlled trials, pharmacovigilance data, society guidance, and the patient-facing phenomena increasingly raised in the dental chair. Preclinical and limited clinical evidence suggests that GLP-1 RAs may attenuate periodontal inflammation, while their effects on alveolar bone remain uncertain, reflecting both direct receptor and indirect metabolic influences. Concurrently, gastrointestinal adverse effects (nausea, vomiting, belching), reduced fluid intake, and possible salivary changes underlie a cluster of patient-reported complaints colloquially termed "Ozempic mouth", "Ozempic teeth", and "Ozempic breath", alongside the facial soft-tissue changes seen in "Ozempic face". Human oral-health-endpoint data remain scarce; much evidence is preclinical, indirect, or derived from case-level or pharmacovigilance reports. The oral cavity is nonetheless a plausible direct target of incretin pharmacotherapy and a practical monitoring site for tolerability. Dental practitioners should proactively manage the oral consequences of these agents, and validated oral health endpoints should be incorporated into future incretin trials.
Development and Validation of a Liquid Chromatography/Tandem Mass Spectrometry Method for the Quantification of the GLP-1 Analog Semaglutide in Rat Plasma, and Its Application in a Pharmacokinetic Study.
Pharmaceutics
Jong-Min Kim, Kyoung-Ah Kim, Na-Young Yu +5 more
Background/Objectives: Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog for type 2 diabetes and obesity, requires sensitive and high-throughput bioanalytical methods to support pharmacokinetic studies. However, previously reported liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays have been limited by lengthy run times (~18 min) and suboptimal sensitivity. This study aimed to develop and validate a rapid, sensitive LC-MS/MS method for quantifying semaglutide in plasma. Methods: Plasma samples (50 μL) were prepared by acetone-mediated protein precipitation followed by solid-phase extraction. Chromatographic separation was performed on a Cadenza CD-C18 MF column within 9 min, using positive electrospray ionization in multiple reaction monitoring mode with the transitions m/z 1029.4 → 110.1 for semaglutide and m/z 938.9 → 109.9 for liraglutide (internal standard). Validation followed the U.S. Food and Drug Administration (FDA) bioanalytical guidelines. Results: The assay showed a lower limit of quantification of 1 ng/mL with linearity across 1-500 ng/mL (R2 = 0.9999), with sharp peak shape and no carryover. Intra- and inter-day accuracies were 95.69-103.76% and 94.93-100.08%, with precision ≤4.50% and ≤5.88%. Recovery (93.05-107.95%) and matrix effects (96.34-104.12%) were consistent across quality control levels, and the analyte was stable under all tested conditions. The method was successfully applied to a pharmacokinetic study in Sprague-Dawley rats following subcutaneous administration of 50 μg semaglutide. Conclusions: The validated method offers shorter analysis time, improved sensitivity, and reduced sample volume compared with previously reported assays, supporting its application in preclinical pharmacokinetic studies of semaglutide and related GLP-1 analogs.
AMPK/USP10 loop activation of ACE2: implications for pulmonary hypertension.
Eur Heart J
Zixuan Chen, Dedong Ge, Xinxin Li +15 more
The intricate balance between angiotensin-converting enzyme 1 (ACE1) and 2 (ACE2) in the pulmonary vasculature is pivotal for the pathogenesis of pulmonary arterial hypertension (PAH). Catalysing the K48-linked deubiquitination, ubiquitin carboxyl-terminal hydrolase 10 (USP10) is involved in tumour suppression, autophagy, and cell proliferation. This study aims to determine whether a positive feedback loop of USP10 and AMP-activated protein kinase (AMPK) in pulmonary endothelium is protective against PAH.
Phenotypic and genomic frameworks for precision pharmacotherapy in obesity: a narrative review.
Front Med (Lausanne)
Dario S Lopez Delgado, Miriam Gabriela Reyes-Zermeño, Elian David Sanjuanelo Lemus +10 more
Obesity is a chronic, heterogeneous disease with marked interindividual variability in response to anti-obesity medications. Although GLP-1 receptor agonists (GLP-1RAs) and dual incretin agonists produce substantial average weight loss in clinical trials, real-world effectiveness is limited by interindividual variability, gastrointestinal intolerance, incomplete dose escalation, cost and access barriers, poor long-term persistence, and weight plateau or regain in a subset of treated patients. Weight regain is particularly consistent after treatment discontinuation, reinforcing the chronic-care nature of obesity pharmacotherapy.
Incretin-Based Therapies in Sports: Pharmacological Mechanisms, Performance-Enhancing Potential, and Anti-Doping Implications-A Narrative Review.
Int J Mol Sci
Sandro La Vignera, Rosita A Condorelli
Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests these agents may influence athletic performance through effects on body composition, energy metabolism, and cardiovascular function. This narrative review critically evaluates whether incretin therapies could constitute doping under World Anti-Doping Agency (WADA) criteria. We narratively reviewed the literature on incretin pharmacology, metabolic effects relevant to athletic performance, and anti-doping regulations, searching PubMed, Scopus, and Web of Science using terms including "GLP-1 receptor agonists", "DPP-4 inhibitors", "doping", "athletic performance", "WADA", and "sports pharmacology", without date restrictions. GLP-1 RAs (semaglutide, liraglutide, tirzepatide, exenatide) induce substantial weight loss (predominantly fat mass) but also reduce lean mass by 20-30% of total weight loss. Preclinical studies demonstrate enhanced exercise endurance, mitochondrial biogenesis, and glucose uptake via GLP-1R/AMPK signaling. However, clinical trials show no consistent improvement in physical performance in humans. Currently, incretin therapies are not listed on the WADA Prohibited List. While incretin therapies offer theoretical performance-enhancing potential through weight management and metabolic optimization, current evidence does not support classification as doping agents. Continued surveillance is warranted as misuse patterns emerge.
Exenatide Attenuates Doxorubicin-Induced Acute Hepatic Injury Through Modulation of SIRT1-HMGB1 Signaling and Oxidative Stress.
Pharmaceuticals (Basel)
Haluk Kerim Karakullukcu, Serdar Savaş Gül, Hatice Aygun +5 more
Background: Doxorubicin is an effective antineoplastic agent, but its use is constrained by off-target toxicities, including acute liver injury driven by mitochondrial dysfunction, oxidative stress, sterile inflammation, and redox-sensitive signaling pathways. Exenatide, a glucagon-like peptide-1 receptor agonist, exerts antioxidant and anti-inflammatory effects in several experimental liver injury models, but its role in doxorubicin-induced hepatic injury has not been investigated to our knowledge. This study evaluated whether exenatide attenuates acute doxorubicin-induced hepatic injury and examined whether the observed biochemical changes are consistent with modulation of oxidative stress and SIRT1-HMGB1/NF-κB-related signaling. Methods: Male Wistar albino rats were allocated to four groups (n = 7/group): control, exenatide, doxorubicin, and exenatide + doxorubicin. Exenatide (10 µg/kg/day, intraperitoneally) was administered for seven days. Doxorubicin was given intraperitoneally on days 5-7 at a cumulative dose of 18 mg/kg. The pretreatment design was used to test preventive attenuation rather than reversal of established injury. Hepatic injury-associated enzyme activities, serum HMGB1, hepatic SIRT1, NF-κB, TNF-α, IL-6, IL-10, malondialdehyde, glutathione, total antioxidant status, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake were assessed. Results: Doxorubicin substantially increased intrahepatic ALT and AST activities, serum HMGB1, hepatic NF-κB, TNF-α, IL-6, malondialdehyde, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake, while reducing SIRT1, IL-10, glutathione, and total antioxidant status. Relative to the doxorubicin group, exenatide lowered HMGB1 by 48.3%, hepatic 99mTc-pyrophosphate uptake by 48.7%, malondialdehyde by 45.0%, total oxidant status by 37.3%, nitric oxide by 40.7%, NF-κB by 40.4%, TNF-α by 48.6%, and IL-6 by 41.1%, while increasing SIRT1 by 91.7%, IL-10 by 115%, glutathione by 115%, and total antioxidant status by 87.8%. None of the altered parameters returned completely to control levels, indicating attenuation rather than full normalization of acute injury-related changes. Conclusions: Exenatide attenuated doxorubicin-induced acute hepatic injury in this rat model and was associated with reduced oxidative stress, reduced inflammatory activation, higher hepatic SIRT1 levels, lower serum HMGB1 levels, and reduced hepatic 99mTc-pyrophosphate uptake. The findings are consistent with involvement of SIRT1-HMGB1/NF-κB-related signaling, but they do not establish causality. Hepatic 99mTc-pyrophosphate uptake should be interpreted as an exploratory imaging correlate of tissue injury rather than an established liver biomarker. Additional studies incorporating histopathology, immunohistochemistry, functional liver indices, mechanistic validation of SIRT1, and tumor-bearing models are required before translational conclusions can be drawn.
Real-World Comparative Weight Loss of GLP-1 Receptor Agonists in the All of Us Research Program: A Retrospective Cohort Study.
Drug Des Devel Ther
Inyoung Hwang, Sang Won Lee, Yun Kim
To assess the real-world associations of five glucagon-like peptide-1 receptor agonists (GLP-1RAs) with weight loss in a diverse US population of adults with obesity, with and without type 2 diabetes, and whether the relative ordering of weight loss observed in trials is mirrored in routine practice.
Decoding Lupus Diagnosis, Pathogenesis and Therapy: From Systemic Autoimmunity to Renal Damage.
Diagnostics (Basel)
Giuseppe Stefano Netti, Dario Troise, Barbara Infante +10 more
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the loss of self-tolerance to nuclear and cytoplasmic antigens, triggering immune activation and tissue inflammation. Lupus nephritis (LN) is a major determinant of disease-related morbidity, disability, chronic kidney disease progression, kidney failure, and mortality in SLE, affecting approximately 30% of patients at diagnosis and up to 50-60% within the first decade. This review examines the disease's pathogenic mechanisms, emphasizing the innate immune system's role in the loss of self-tolerance and subsequent activation of the adaptive immune response. Mechanisms include dysregulated cell death pathways, impaired clearance of nucleic acid-containing debris and immune complexes, and involvement of antigen-presenting cells and other innate immune cells. These processes lead to the clonal expansion of autoreactive lymphocytes, generating effector T cells, memory B cells, and plasma cells that produce autoantibodies, resulting in renal injury. The review further explores the immunological processes driving kidney damage, beginning with autoantibody binding and immune complex deposition, followed by complement-mediated microvascular injury, kidney stromal cell activation, and leukocyte recruitment. Lastly, it discusses LN treatment strategies, from traditional to novel targeted therapies, with a focus on their systemic immunologic impacts and the protection of podocytes.
FOXO4 as a Redox-Sensitive Regulator of Antioxidant Defense and Cellular Senescence: Cysteine-Based Signaling, p53 Interaction, and Therapeutic Targeting.
Antioxidants (Basel)
Diana-Maria Mateescu, Dragos-Mihai Gavrilescu, Adelina-Raluca Marinescu +5 more
(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4-p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4-p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance.
Nanotechnological Strategies to Promote Skeletal Muscle Regeneration in Aging.
Int J Mol Sci
Flavia Carton, Manuela Malatesta
During aging, skeletal muscle undergoes a decline in mass and strength. This condition, known as sarcopenia, involves many physiological and metabolic impairments, thus representing a healthcare, social, and economic burden. Various pharmacological and non-pharmacological approaches have been explored to counteract sarcopenia; however, no definite treatment has so far been found. The present narrative review summarizes nanotechnology-based strategies designed to promote muscle preservation and functional recovery in aging. Synthetic organic or inorganic nanoconstructs and natural extracellular vesicles have been used as nanocarriers for drug delivery, have been active as intrinsic therapeutic agents, have been employed to build biomimetic nanoscaffolds to sustain muscle regeneration, or have been combined to form hybrid nanosystems with multiple therapeutic functions. These nanotools demonstrated promising results in vitro and in animal models, being able to counteract major factors responsible for sarcopenia, such as oxidative stress, inflammation, mitochondrial dysfunction, increased proteolysis, and impaired stem cell function. However, nanotools have mostly been tested on biological models far from the physiologically aged human muscle. Moreover, limitations still remain to be solved to make these nanotools suitable for regenerative medicine; in particular, the systemic administration requires nanoconstruct functionalization for skeletal muscle targeting, and proper clearance should be ensured to avoid toxicity and immunogenicity related to long-term use.
Senotherapeutics for Knee Osteoarthritis.
Med Res Rev
Ezgi Duman, Girish Pattappa, Patrick Pann +4 more
Osteoarthritis (OA) is a chronic disease that imposes a significant economic burden and deteriorates quality of life. Nevertheless, current therapeutic options for OA are limited to symptomatic remedies. As such, there is a high interest in novel methods for treating or preventing OA. One of the most promising medication modalities is through the clearance of cells that are cell cycle arrested but resistant to apoptosis, termed senescent cells. Additionally, these cells are also resistant to alternative programmed cell death modes, such as ferroptosis and pyroptosis. Senescent cells tend to accumulate with age due to increasing cellular and genetic damage. These cells can release inflammatory factors and signaling molecules termed senescence-associated secretory phenotype (SASP). In addition to triggering an inflammatory milieu in joints, SASP can also induce senescence in other cells through autocrine signaling. It has been shown via in vitro and in vivo tests that clearance of senescent cells through a class of drugs known as senolytics, or neutralization of SASP with senomorphics, can improve OA pathogenesis. Following these results, several clinical trials have been conducted to evaluate the efficacy of senotherapeutics against knee OA. Yet there remains a need for a comprehensive assessment of safety and optimization of senotherapeutic treatment regimens for knee OA. To this end, a better understanding of molecular mechanisms behind chondrocyte senescence and knee OA pathogenesis is necessary. Identification of novel compounds that can specifically target chondrocyte senescence pathways can assist in developing more effective therapies against OA.
Escape and evasion: when immunosurveillance of senescent cells goes wrong.
Front Genet
Elina Shakur, Abraham Jacobs, Rituparna Ghosh +1 more
Aging involves molecular changes that can give rise to different cell fates, one of those being cellular senescence. Senescent cells stably arrest in the cell cycle and play important roles in physiological processes and can act in a tumor-suppressive manner. However, senescent cells accumulate throughout the body with both chronological and biological aging, promoting chronic inflammation and tissue dysfunction. One of the features of senescent cells is their ability to adopt a secretory phenotype, which can act as a chemotactic gradient to attract immune cells. These infiltrating immune cells are capable of recognizing senescent cells and targeting them for destruction, thus maintaining a balance between senescent cell generation and elimination. Unfortunately, with age, the immune system undergoes changes that alter functional capacity, referred to as immunosenescence. Immunosenescence impacts both innate and adaptive immune cells, impairing their protective functions, like immunosurveillance, or causing them to adopt a hyperinflammatory phenotype, which may further enhance senescent cell burden. These age-related changes in immune function can compromise immunosurveillance, further exacerbating senescent cell burden and its effects. Additionally, senescent cells themselves can modulate markers on their cell surface that make detection by immune cells more difficult and allow them to escape immune clearance. The role of the immune system in limiting senescent cell burden to maintain homeostasis and how immunosurveillance is compromised with age is explored. Furthermore, mechanisms by which senescent cells evade immunosurveillance and potential strategies to restore age-related deficits in immune cell-mediated clearance of senescent cells are also discussed.
Retrospective Evaluation of Recombinant Human Brain Natriuretic Peptide Therapy for Decompensated Right Heart Failure Across Pulmonary Hypertension Groups.
Medicina (Kaunas)
Lixing Hu, Qing Zhao, Zhihui Zhao +3 more
Background and Objectives: Right heart failure is a life-threatening complication of pulmonary hypertension (PH), with limited treatment options. Although recombinant human brain natriuretic peptide (rhBNP) is widely used in left heart failure, its effectiveness in right heart failure associated with varying groups of PH (Groups 1, 2, and 4) is unknown. Materials and Methods: 763 patients with varying groups of PH (PH Groups 1, 2, and 4) were enrolled and received both conventional therapy and rhBNP treatment. Therapeutic efficacy and adverse event incidence were evaluated among the PH groups. Results: Significant reductions in variables reflecting cardiac congestion, including NT-proBNP, total bilirubin, and body weight, were observed in all PH subgroups (all p < 0.001). The median percentage changes were -47% (IQR -76 to -24), -21% (IQR -33 to -1), and -3% (IQR -7 to -1), respectively. Alanine transaminase levels presented a decreasing trend (p < 0.001), whereas creatinine levels remained unchanged (p > 0.05), with consistent trends across PH subgroups. The hemodynamic response was heterogeneous, with marked decreases in the mean arterial pressure in Groups 1 and 4 (p < 0.001) but not in Group 2. Improvement in dyspnea and edema of the lower limbs was observed in 49.9% and 66.6% of cases, respectively. The overall incidence of adverse events was 0.66%, with 0.26% (2/763) being serious, all of which were in Group 1 PH. Conclusions: Findings from this exploratory analysis indicated that rhBNP treatment was associated with favorable changes in congestive status and clinical symptoms across different PH subgroups, as well as stable end-organ function. Of note, all patients received comprehensive conventional background therapy; thus, these improvements cannot be exclusively attributed to rhBNP alone. Given the observed hemodynamic fluctuations, close blood pressure monitoring should be considered throughout the treatment course, particularly for patients in Groups 1 and 4, and most notably for high-risk PAH patients (Group 1 PH).
Holistic Management of Obesity in Patients with Incidental Cancer After Unprovoked Deep Vein Thrombosis: A Cardiometabolic and Antithrombotic Framework.
Cancers (Basel)
Calogero Geraci, Rossella Cannarella, Valentina Morello +7 more
Background: Obesity has evolved from a morphometric descriptor to a chronic, relapsing, multisystem disease in which low-grade adipose-tissue inflammation, insulin resistance, endothelial dysfunction, and a prothrombotic, pro-tumorigenic milieu coexist. Venous thromboembolism (VTE) and malignancy share this substrate through a well-established bidirectional link: within twelve months of an unprovoked deep vein thrombosis (DVT), 6-15% of patients are diagnosed with occult cancer, a substantial proportion of which are already locally advanced or metastatic at detection. In this context, obesity acts as a dual amplifier of both thrombotic and oncologic risk, making the post-DVT patient with an incidentally diagnosed cancer a paradigmatic candidate for integrated management. Objective: To propose an evidence-based, unifying cardiometabolic and antithrombotic clinical framework that reconciles (i) risk-stratified screening for occult malignancy after unprovoked DVT, (ii) contemporary pharmacotherapy of obesity, and (iii) cancer-associated thrombosis (CAT) management, in the light of evidence published through 2025. Methods: Narrative synthesis based on a structured literature search (PubMed/MEDLINE, Embase, Scopus; 2000-March 2025) of current guidelines (ISTH, ASH, ESC Cardio-Oncology, EASO) and pivotal randomized evidence on GLP-1 and dual GLP-1/GIP receptor agonists (semaglutide, tirzepatide), SGLT2 inhibitors (empagliflozin, dapagliflozin), and direct oral anticoagulants (DOACs), with critical interpretation of recent meta-analytic data on oncologic signals, cardiovascular outcomes, and bleeding safety. Results: Three evidence-based pillars emerge: (1) limited screening complemented by age- and sex-specific testing in patients ≥ 50 years with unprovoked DVT, enhanced by FDG-PET/CT for high-risk phenotypes in which obesity itself degrades the sensitivity of clinical examination and conventional imaging; (2) GLP-1/GIP receptor agonist-based anti-obesity pharmacotherapy, associated in observational cohorts with a 17% relative reduction in overall cancer incidence (HR 0.83; 95% CI 0.76-0.91) and neutral-to-reassuring oncologic signals, but requiring cautious, case-by-case use in patients with active cancer because of the risk of accelerating sarcopenia and cachexia; and (3) apixaban as the preferred DOAC for cancer-associated thrombosis, with a superior efficacy-to-bleeding ratio in network meta-analyses and a reduced-dose extended strategy now validated by the API-CAT trial. Conclusions: Patients with obesity presenting with unprovoked DVT and an incidentally detected cancer embody a cardiometabolic-antithrombotic continuum. A framework integrating structured occult-cancer screening, judicious obesity pharmacotherapy, and apixaban-preferred anticoagulation-coordinated by a multidisciplinary team and illustrated here by a case-based pathway-offers the most rational, evidence-aligned approach. Prospective, dedicated trials in this specific phenotype are urgently warranted.
Hypothesis on PTSD Pathophysiology: Role of CRH, Noradrenaline, and Glucocorticoid Receptors in an Amygdala-Centered Closed-Loop System.
Int J Mol Sci
Ilaria Demori, Bruno Burlando
Post-traumatic stress disorder (PTSD) is a severe condition triggered by traumatic exposure, characterized by symptoms like trauma re-experiencing, avoidance, mood alterations, hypervigilance, and sleep disturbances. While its exact mechanisms remain uncertain, PTSD involves dysregulation across neurobiological systems underlying fear conditioning, threat appraisal, executive control, and stress response. Although research highlights the sympathetic-adreno-medullary (SAM) system and the hypothalamic-pituitary-adrenal (HPA) axis, findings on stress-related mediators remain inconsistent regarding their precise contributions over time. To address this, we propose a hypothetical model viewing PTSD as a multistable system shifting from physiological to pathological steady states. We assume that intense, repeated emotional stress triggers spike activation in the amygdala, driving an amygdala-locus coeruleus loop into a high-activation state via reciprocal excitation, mediated by corticotropin-releasing hormone (CRH) and noradrenaline. This sequentially alters amygdala-hippocampus and prefrontal cortex loops, reinforcing fear expression and impairing extinction. This model is consistent with key features of PTSD, including its higher prevalence among females, increased glucocorticoid receptor sensitivity, the frequently observed hypocortisolism, and the partial efficacy of serotonin and norepinephrine reuptake inhibitor (SNRI) and CRH receptor antagonists. While requiring experimental validation, this framework connects molecular, circuit, and behavioral data to help identify novel interventions for restoring adaptive stress-response dynamics.