Search Results (917)

The association between COVID-19 vaccination and thromboembolic events has garnered significant research attention, particularly with the advent of vaccines based on adenoviral vectors, including AstraZeneca’s and Johnson & Johnson’s vaccines. This review underscores the uncommon occurrence of venous thromboembolism (VTE), arterial thromboembolism (ATE), and vaccine-induced thrombotic thrombocytopenia (VITT) following COVID-19 vaccination. Although these complications are extremely rare compared to the heightened risk of thrombosis from COVID-19 infection, elements like age, biological sex, type of vaccine and underlying health conditions may contribute to their development. In addition, rare renal complications such as acute kidney injury and thrombotic microangiopathy have been documented, broadening the spectrum of potential vaccine-associated thrombotic manifestations. Current guidelines emphasize early detection, individualized risk assessment, and use of anticoagulation therapy to mitigate risks. Despite these events, the overwhelming majority of evidence supports the continued use of COVID-19 vaccines, given their proven efficacy in reducing severe illness and mortality. In addition, recent comparative data confirm that mRNA-based vaccines are associated with a significantly lower risk of serious thrombotic events compared to adenoviral vector platforms. Ongoing research is essential to further refine preventive and therapeutic strategies, particularly for at-risk populations. Full article

Clozapine, a second-generation antipsychotic known for its effectiveness in treating resistant schizophrenia, is often linked with serious hematological side effects, particularly neutropenia and agranulocytosis. This review investigates the underlying pathophysiological mechanisms of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA), outlines associated risk factors, and evaluates current clinical management strategies. Clozapine’s pharmacological profile, marked by its antagonism of dopamine D4 and serotonin receptors, contributes to both its therapeutic advantages and hematological toxicity. Epidemiological data show a prevalence of CIN and CIA at approximately 3.8% and 0.9%, respectively, with onset typically occurring within the first six months of treatment. Key risk factors include older age, Asian and African American ethnicity, female sex, and certain genetic predispositions. The development of CIN and CIA may involve bone marrow suppression and autoimmune mechanisms, although the exact processes remain partially understood. Clinical presentation often includes nonspecific symptoms such as fever and signs of infection, necessitating regular hematological monitoring in accordance with established guidelines. Management strategies include dosage adjustments, cessation of clozapine, and the administration of granulocyte colony-stimulating factors (G-CSF). Advances in pharmacogenomics show promise for predicting susceptibility to CIN and CIA, potentially improving patient safety. This review emphasizes the importance of vigilant monitoring and personalized treatment approaches to reduce the risks associated with clozapine therapy. Full article

Background: Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells. Methods: AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC₅₀ of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments. Results: SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC₅₀ of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p < 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p < 0.0001), while Dex moderated this effect in the combination group APB+Dex (p < 0.0001). Notably, the APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (−1.34), exemplified by increased expression of SERPINE1 (1.99) within the “Response to elevated platelet cytosolic Ca²⁺” pathway. Conclusions: These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer. Full article

As the global population continues to age, the incidence of neurodegenerative diseases and neural injuries is increasing, presenting major challenges for healthcare systems. Due to the brain’s limited regenerative capacity, there is an urgent need for strategies that promote neuronal repair and functional integration. Brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and neuronal development. In this study, we investigated whether constitutive BDNF expression in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) enhances their neurogenic and integrative potential in vitro. We found that NPCs engineered to overexpress BDNF produced neuronal cultures with increased numbers of mature and spontaneously active neurons, without altering the overall structure or organization of functional networks. Furthermore, BDNF-expressing neurons exhibited significantly greater axonal outgrowth, including directed axon extension in a compartmentalized microfluidic system, suggesting a chemoattractive effect of localized BDNF secretion. These effects were comparable to those observed with the early supplementation of recombinant BDNF. Our results demonstrate that sustained BDNF expression enhances neuronal maturation and axonal projection without disrupting network integrity. These findings support the use of BDNF not only as a therapeutic agent to improve cell therapy outcomes but also as a tool to accelerate the development of functional neural networks in vitro. Full article

Background/Objectives: The Pleth Variability Index (PVI) is a non-invasive parameter used to guide fluid management by reflecting respiratory-induced variations in the plethysmographic waveform. While PVI’s reliability in various positions has been studied, data on its behavior in geriatric patients undergoing transurethral resection of the prostate (TUR-P) in the lithotomy position remain limited. This study aimed to evaluate the effect of the lithotomy position on PVI in geriatric versus non-geriatric patients under spinal anesthesia. Methods: This prospective observational study included 90 patients undergoing elective TUR-P in the lithotomy position under spinal anesthesia. Patients were divided into geriatric (≥65 years, n = 48) and non-geriatric (<65 years, n = 42) groups. PVI and Perfusion Index (PI) were recorded at baseline, in the supine position, and in the lithotomy position. Fluid and vasopressor requirements, along with hemodynamic parameters, were also analyzed. Results: PVI values at the 5th minute in the lithotomy position were significantly higher in the geriatric group compared to the non-geriatric group (p = 0.019). No significant differences were observed in PI values or intraoperative hypotension rates between the groups. Neurological comorbidities were more prevalent in the geriatric group (p = 0.025). Conclusions: PVI appears to be a more sensitive indicator of fluid responsiveness in elderly patients under spinal anesthesia in the lithotomy position. Its age-dependent variability suggests clinical utility in guiding fluid management in geriatric populations, while the stable hypotension rates support the effectiveness of PVI-guided goal-directed therapy. Full article

Alcohol dependency is a complex and chronic condition that negatively impacts multiple organ systems, including the skin. A key pathological factor in this process is oxidative stress, leading to progressive cellular damage, chronic inflammation, and accelerated cutaneous aging. Alcohol metabolism generates reactive oxygen species (ROS), which overwhelm endogenous antioxidant defenses and contribute to a range of skin alterations, including nonspecific changes such as xerosis, erythema, and wrinkle formation, as well as inflammatory and neoplastic skin disorders. Additionally, alcohol-induced alterations of the skin microbiome may further exacerbate skin barrier dysfunction and inflammatory responses. This review explores the biochemical mechanisms and skin microbiome alterations linking alcohol-induced oxidative stress to skin damage and disease. Furthermore, it evaluates the therapeutic potential of antioxidant-based interventions, both natural and synthetic. Antioxidants may offer protective and regenerative effects by scavenging free radicals, modulating inflammatory responses, and enhancing skin barrier function. The paper aims to provide a comprehensive overview of the molecular and microbial interplay between alcohol, oxidative stress, and skin health, while identifying future directions for targeted antioxidant therapy in individuals with alcohol dependency. Full article

Tendinopathies are a significant challenge in musculoskeletal medicine, with current treatments showing variable efficacy. Electromagnetic transduction therapy (EMTT) has emerged as a promising therapeutic approach, but its biological effects on tendon cells remain largely unexplored. Here, we investigated the effects of EMTT on primary cultured human tenocytes’ behavior and functions in vitro, focusing on cellular responses, senescence-related pathways, and molecular mechanisms. Primary cultures of human tenocytes were established from semitendinosus tendon biopsies of patients undergoing anterior cruciate ligament (ACL) reconstruction (n = 6, males aged 17–37 years). Cells were exposed to EMTT at different intensities (40 and 80 mT) and impulse numbers (1000–10,500). Cell viability (MTT assay), proliferation (Ki67), senescence markers (CDKN2a/INK4a), migration (scratch test), cytoskeleton organization (immunofluorescence), and gene expression (RT-PCR) were analyzed. A 40 mT exposure elicited minimal effects, whereas 80 mT treatments induced significant cellular responses. Repeated 80 mT exposure demonstrated a dual effect: despite a moderate decrease in overall cell vitality, increased Ki67 expression (+7%, p ≤ 0.05) and significant downregulation of senescence marker CDKN2a/INK4a were observed, suggesting potential senolytic-like activity. EMTT significantly enhanced cell migration (p < 0.001) and triggered cytoskeletal remodeling, with amplified stress fiber formation and paxillin redistribution. Molecular analysis revealed upregulation of tenogenic markers (Scleraxis, Tenomodulin) and enhanced Collagen I and III expressions, particularly with treatments at 80 mT, indicating improved matrix remodeling capacity. EMTT significantly promotes tenocyte proliferation, migration, and matrix production, while simultaneously exhibiting senolytic-like effects through downregulation of senescence-associated markers. These results support EMTT as a promising therapeutic approach for the management of tendinopathies through multiple regenerative mechanisms, though further studies are needed to validate these effects in vivo. Full article

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H₂O₂-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD⁺/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H₂O₂-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases. Full article

Background: Inhaled corticosteroids (ICSs) are a cornerstone in asthma management, particularly during exacerbations, when high doses are often prescribed. However, patient concerns about potential side effects such as increased appetite, weight gain, and metabolic disturbances may reduce adherence, compromising treatment outcomes. While oral corticosteroids (OCSs) are well known to induce such effects, the metabolic impact of short-term high-dose ICSs remains poorly studied. Objective: This prospective pilot study aimed to assess whether a 14-day course of high-dose ICSs in adults with stable asthma induces changes in appetite, dietary intake, leptin levels, or body weight. Methods: Thirty-five adults (19 males, 16 females; mean age 48.7 ± 15.1 years) with stable mild asthma received ≥400 µg/day extrafine beclomethasone dipropionate/formoterol via pressurized metered-dose inhaler for 14 days. Participants underwent assessments at baseline and after 14 days, including body weight, BMI, fasting serum leptin levels, dietary intake (evaluated using 24 h dietary recalls), and appetite (measured via a visual analogue scale). Results: No significant changes were observed in body weight (mean change: −0.38 kg; 95% CI: −0.81 to 0.05; p = 0.083) or BMI (p = 0.912) following high-dose ICS use. Similarly, serum leptin levels (mean change: 0.13 ng/mL; 95% CI: −3.47 to 3.72; p = 0.945), subjective appetite scores (mean change: −4.93 mm; 95% CI: −13.64 to 3.79; p = 0.267), and dietary energy intake (mean change: +255 kJ/day; 95% CI: −380 to 891; p = 0.431) did not differ significantly post-intervention. Conclusions: Short-term high-dose ICS therapy in adults with mild asthma may not significantly affect appetite, dietary intake, leptin levels, or body weight. These findings support the metabolic safety of short-term high-dose ICSs and may help alleviate patient concerns, improving adherence during exacerbation management. Full article

Osteoporosis and sarcopenia are two aspects of the geriatric syndrome that frequently occur together and affect one another in a condition referred to as osteosarcopenia. Preventive and treatment options for osteosarcopenia exist but are mainly focused on the treatment of osteoporosis, as there is still no FDA-approved treatment for sarcopenia. Drugs for osteoporosis include antiresorptive and anabolic drugs and hormonal replacement therapies and are prescribed based on age, BMD and other patient characteristics, which, however, do not include the possible co-existence of sarcopenia. As several studies and clinical trials have shown that the pharmacological treatment of osteoporosis can also affect muscle tissue, in either a positive or negative manner, sarcopenia should be another factor affecting the choice of treatment, especially when facing equal treatment options for osteoporosis. The aim of this review was to summarize our current knowledge on the effects of FDA-approved drugs for the treatment of osteoporosis on muscle quality, mass and function. A better understanding of the effects that certain drugs have on muscle tissue might in the future help us to simultaneously at least partially also address the wasting of muscle tissue and avoid further pharmacologically induced decline. Full article

Skeletal muscle atrophy is a debilitating condition characterized by the loss of muscle mass and function. It is commonly associated with aging, chronic diseases, disuse, and prolonged glucocorticoid therapy. Oxidative stress and catabolic signaling pathways play significant roles in the progression of muscle degradation. Despite its clinical relevance, few effective therapeutic options are currently available. In this study, we investigated the protective effects of an ethanolic extract of Glycine Semen Preparata (GSP), i.e., fermented black soybeans, using in vitro and in vivo models of dexamethasone (Dexa)-induced muscle atrophy. In C2C12 myoblasts and myotubes, GSP significantly attenuated both oxidative stress-induced and Dexa-induced damages by reducing reactive oxygen species levels and by suppressing the expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. Moreover, GSP upregulated key genes involved in muscle regeneration (Myod1 and Myog) and mitochondrial biogenesis (PGC1α), indicating its dual role in muscle protection and regeneration. Oral administration of GSP to mice with Dexa-induced muscle atrophy resulted in improved muscle fiber integrity, increased proportion of large cross-sectional area fibers, and partial recovery of motor function. Isoflavone aglycones, such as daidzein and genistein, were identified as active compounds that contribute to the beneficial effects of GSP through antioxidant activity and gene promoter enhancement. Thus, GSP is a promising nutraceutical that prevents or mitigates muscle atrophy by targeting oxidative stress and promoting myogenesis and mitochondrial function. Further studies are warranted to standardize the bioactive components and explore their clinical applications. Full article

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Background: Surface electromyography (sEMG) enables the non-invasive assessment of muscle activity and is widely used in orthodontics for evaluating masticatory muscles. However, little is known about the dynamic changes in facial expression muscles during orthodontic treatment. This study aimed to investigate alterations in facial muscle tone during the leveling and alignment phase in adult female patients undergoing fixed appliance therapy. Methods: The study included 30 female patients aged 20–31 years who underwent sEMG assessment at four time points: before treatment initiation (T0), at the start of appliance placement (T1), three months into treatment (T2), and six months into treatment (T3). Muscle activity was recorded during four standardized facial expressions: eye closure, nasal strain, broad smile, and lip protrusion. Electrodes were placed on the orbicularis oris, orbicularis oculi, zygomaticus major, and levator labii superioris alaeque nasi muscles. A total of 1440 measurements were analyzed using Friedman and Conover-Inman tests (α = 0.05). Results: Significant changes in muscle tone were observed during treatment. During lip protrusion, the orbicularis oris and zygomaticus major showed significant increases in peak and minimum activity (p < 0.01). Eye closure was associated with altered orbicularis oris activation bilaterally at T3 (p < 0.01). Nasal strain induced significant changes in zygomaticus and levator labii muscle tone, particularly on the right side (p < 0.05). No significant changes were noted during broad smiling. Conclusions: Orthodontic leveling and alignment influence the activity of selected facial expression muscles, demonstrating a dynamic neuromuscular adaptation during treatment. These findings highlight the importance of considering soft tissue responses in orthodontic biomechanics and suggest potential implications for facial esthetics and muscle function monitoring. Full article

DNA is inherently unstable and is susceptible to damage from both endogenous sources (such as reactive oxygen species) and exogenous factors (including UV, ionizing radiation, and chemicals). The accumulation of DNA damage manifests as genetic mutations, chromosomal instability, and the stalling of DNA replication and transcription processes. Accumulated DNA damage influences apoptosis and cell cycle checkpoints, serving as one of the key triggers for the manifestation of the senescent phenotype. Both aging and cancer are associated with the accumulation of mutations in somatic cells. Disruption of cell cycle control and uncontrolled proliferation are fundamental characteristics of any cancer cell, with the majority of anticancer drugs acting as inhibitors of cyclin-dependent kinases, thereby inducing a transition of cells into a senescent state. Consequently, disturbances in the dynamics and regulation of inflammatory responses, oxidative stress, cell proliferation, DNA damage repair, and epigenetic anomalies, along with the influence of retroviruses and transposons, lead to the accumulation of senescent cells within the human body, characterized by blocked replication and cell cycle, as well as a distinct secretory phenotype. The age-related or disease-associated accumulation of these senescent cells significantly alters the physiology of tissues and the organism as a whole. Many secondary metabolites of higher plants exhibit senolytic and senomorphic activities, although most of them are not fully characterized. In this review, we will explore the principal signaling pathways in mammalian cells that govern the cell cycle and cellular senescence, with a particular emphasis on how their dynamics, expression, and regulation have been modified through the application of senotherapeutic compounds. The second section of the review will identify key target genes for the metabolic engineering, primarily aimed at enhancing the accumulation of plant secondary metabolites with potential therapeutic benefits. Lastly, we will discuss the rationale for utilizing liver cells as a model system to investigate the effects of senolytic compounds on human physiology and health, as well as how senotherapeutic substances can be leveraged to improve gene therapy approaches based on CRISPR/Cas9 and prime-editing technologies. Full article

With the intensification of global aging, the incidence of age-related diseases (including cardiovascular, neurodegenerative, and musculoskeletal disorders) has been on the rise, and cellular senescence is identified as the core driving mechanism. Cellular senescence is characterized by irreversible cell cycle arrest, which is caused by telomere shortening, imbalance in DNA damage repair, and mitochondrial dysfunction, accompanied by the activation of the senescence-associated secretory phenotype (SASP). In this situation, proinflammatory factors and matrix-degrading enzymes can be released, thereby disrupting tissue homeostasis. This disruption of tissue homeostasis induced by cellular senescence manifests as characteristic pathogenic mechanisms in distinct disease contexts. In cardiovascular diseases, senescence of cardiomyocytes and endothelial cells can exacerbate cardiac remodeling. In neurodegenerative diseases, senescence of glial cells can lead to neuroinflammation, while in musculoskeletal diseases, it can result in the degradation of cartilage matrix and imbalance of bone homeostasis. This senescence-mediated dysregulation across diverse organ systems has spurred the development of intervention strategies. Interventional strategies include regular exercise, caloric restriction, senolytic drugs (such as the combination of dasatinib and quercetin), and senomorph therapies. However, the tissue-specific regulatory mechanisms of cellular senescence, in vivo monitoring, and safety-related clinical translational research still require in-depth investigation. This review summarizes the progress in pathological mechanisms and interventions, providing theoretical support for precision medicine targeting senescence, which is of great significance for addressing health challenges associated with aging. Full article