Search Results (189)

Background: Esophagectomy remains the definitive curative treatment for esophageal cancer but is historically burdened by significant procedure-related morbidity. Anastomotic leakage (AL) is still the “Achilles’ heel” of esophageal surgery, serving as a primary benchmark for surgical quality due to its profound impact on patient recovery, healthcare costs, and long-term oncological outcomes. While surgical expertise and perioperative care have matured, reported AL rates remain persistently high. This necessitates a shift in focus from purely technical modifications toward integrated, data-driven preventive strategies. Purpose: Five years after our initial review, this update synthesizes the rapid evolution in AL prevention. We evaluate the transition from empirical surgical pragmatism to evidence-based protocols, integrating recent breakthroughs in real-time perfusion monitoring, prophylactic endoluminal technologies, and multidisciplinary patient optimization. This work provides a contemporary “roadmap” for navigating the complexities of esophageal reconstruction. Conclusions: The prevention of AL has evolved into a multimodal “bundle” that begins well before the index operation. This review highlights the critical shift toward quantitative perfusion assessment via indocyanine green fluorescence angiography, which is increasingly replacing subjective visual inspection as the standard for anastomotic site selection. We discuss the emerging role of gastric ischemic preconditioning as a biological strategy to enhance conduit vascularity, alongside the paradigm of proactive management using preemptive endoluminal vacuum therapy to mitigate septic sequelae in high-risk cases. Furthermore, we examine technical refinements in conduit construction and conditioning—focusing on the ‘tension-perfusion’ relationship—and the essential role of structured prehabilitation within enhanced recovery after surgery frameworks. While the quality of evidence remains heterogeneous, the move toward standardized reporting and objective monitoring marks a new era of precision in esophageal surgery. Full article

In an era marked by rising stress-related disorders and cardiovascular morbidity, understanding how the brain and heart adapt to environmental, physiological, and social stressors has become an urgent biomedical priority. This review advances an integrative framework centered on sociostasis, defined as the dynamic regulation of physiological state through social interaction, and its intersection with hormesis, a biphasic adaptive response to controlled stress that enhances resilience. We focus on four evolutionarily conserved neuropeptides, vasopressin, oxytocin, corticotropin-releasing hormone, and the urocortins, which serve as molecular bridges linking social behavior, neuroendocrine signaling, autonomic regulation, and cardiovascular function. Operating within an organized autonomic architecture, these systems calibrate responses to acute and chronic stress. Their context-dependent synergy enables adaptive flexibility under manageable challenge but may promote maladaptive cardiovascular remodeling when chronically dysregulated. Genetic vulnerability, developmental adversity, and persistent psychosocial stress can shift neuroendocrine–autonomic set points, increasing susceptibility to hypertension, endothelial dysfunction, and stress-induced cardiomyopathy. Conditioning and preconditioning paradigms illustrate how repeated exposure to subthreshold stressors primes cardiovascular tissues for future insults, enhancing ischemic tolerance and adaptive gene expression. We propose that cardiovascular hormesis depends not only on stimulus intensity but also on the integrity of neuroautonomic regulatory mechanisms that support recovery and flexibility. Vagal efficiency, a dynamic index of cardioinhibitory regulation, is discussed as a potential translational metric of adaptive capacity. By integrating molecular, physiological, and psychosocial perspectives, this framework conceptualizes cardiovascular resilience as an emergent property of coordinated hormetic signaling, neuropeptidergic modulation, autonomic regulation, and social buffering. Translational implications include peptide-based therapies, autonomic biofeedback, and behavioral interventions designed to enhance stress adaptability. Full article

Background: Interest in inhalational anesthesia in cardiac surgery has resurged as volatile anesthetics exert biological effects extending beyond hypnosis. Sevoflurane and desflurane activate mitochondrial cytoprotective signaling pathways, modulate inflammatory and endothelial responses and may attenuate ischemia–reperfusion injury during cardiopulmonary bypass, potentially influencing postoperative organ function and recovery. Methods: This narrative review critically examines experimental and clinical evidence on the use of volatile anesthetics in cardiac anesthesia. The current literature was analyzed to elucidate mechanistic foundations of myocardial and extracardiac organ protection, hemodynamic and metabolic effects, and the influence of patient-specific vulnerability profiles on perioperative outcomes. Results: Preclinical studies consistently demonstrate that volatile anesthetics trigger mitochondrial protective pathways, including K-ATP channel activation, controlled reactive oxygen species signaling and inhibition of the mitochondrial permeability transition pore. Clinical studies suggest potential benefits in myocardial protection and modulation of systemic inflammatory and microcirculatory responses. However, translation into consistent clinical outcome improvement remains heterogeneous, influenced by variability in surgical procedures, anesthetic protocols and patient risk stratification. Conclusions: Volatile anesthetics exhibit mechanistic properties supporting a potential role in organ protection during cardiac surgery. Nevertheless, clinical evidence remains inconclusive, underscoring the need for refined patient stratification and precision-based perioperative strategies. Identifying knowledge gaps and research priorities may facilitate rational, individualized integration of inhalational anesthesia into contemporary cardiac surgical practice. Full article

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin–NFAT or oxygen-binding globins—offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell–derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation. Full article

Small extracellular vesicles (sEVs) are increasingly recognized as crucial mediators of cell-cell communication. This study aims to determine the influence of sEV mediation on cardiomyocytes (CMs) under hypoxic conditions and identify the molecular modifications induced by hypoxia-derived sEVs (H-sEVs). Using a preconditional approach, we administered hypoxic AC16 CM-derived sEVs to recipient AC16 CMs before hypoxic stimulation. Molecular and biochemical analyses were performed to evaluate the biological effects of H-sEVs, e.g., cell viability assay, caspase assays, Western blotting, and quantitative sandwich ELISA. Our results showed a significant decrease in CM viability following hypoxic stimulation, as well as elevated caspase-3 and caspase-8 activity, and increased Bcl-2-associated X protein (BAX) translocation to the mitochondria followed by an increased release of Cytochrome C from mitochondria to cytosol. Preconditioning with H-sEVs further exacerbated caspase-3 and caspase-8 activation, which was explained by aggravated translocation of BAX to the mitochondria with consequences of cytochrome C release and increased apoptotic signaling. Our research indicates that sEVs secreted by hypoxic AC16 CMs negatively impact the biological properties of recipient CMs exposed to hypoxic stress. Thus, these findings widen our current understanding of sEV-mediated cellular communication during hypoxic events and provide insights into potential therapeutic targets for cardiac ischemic injury. Full article

Cardioprotection refers to the natural capacity of heart tissue to resist damage under conditions such as ischemia–reperfusion and various metabolic stresses. First identified in the phenomenon of ischemic preconditioning, the concept has since broadened to encompass other triggers of protective signaling, including hypoxia, temperature shifts, and a wide range of pharmacological compounds. This expansion indicates the presence of common molecular pathways and defense mechanisms. Known intracellular contributors to cardioprotection involve numerous factors, such as protein kinases, the reperfusion injury salvage kinase (RISK) cascade, the Survivor Activating Factor Enhancement (SAFE) pathway, hypoxia-inducible factor-1α (HIF1α), microRNAs, and Connexin 43, among others. These components are crucial in initiating downstream signaling, promoting the expression of protective genes, optimizing mitochondrial function, and regulating cytosolic and protein processes to maintain cardiac resilience. Key end-effectors include SUR2A, a regulatory subunit of sarcolemmal ATP-sensitive potassium (KATP) channels, autophagy, and mitochondria. Central mechanisms, such as modulation of the mitochondrial permeability transition pore and activation of KATP channels, play essential roles in the cardioprotective response. Although significant progress has been made in mapping these networks, many facets remain poorly understood. One of the most pressing challenges is to translate this knowledge into practical therapies and eventually create clinically applicable strategies to protect the heart. Full article

Cardiac troponins (cTn) T and I are biochemical markers of myocardial injury. In this review article, we aim to summarize the mechanisms and significance of cardiac troponin (cTn) elevation unrelated to acute myocardial infarction (AMI) in the most frequently occurring non-cardiac conditions, where the accurate interpretation of elevated cTn levels is often challenging. Different mechanisms in non-cardiac conditions can cause non-ischemic myocardial injury. Understanding the pathophysiology of cTn release is an essential precondition for minimizing unnecessary, costly, and potentially risky (cardiac) interventions and for providing timely and appropriate medical care. Elevated cTn in critically ill patients and in patients with chronic disease/conditions is an independent predictor (risk factor) of cardiovascular and overall mortality. Treatment of underlying conditions is of primary importance, and close monitoring for the occurrence of cardiovascular complications during hospitalizations should be considered in these patients. Also, when the patient recovers from the underlying disease, clinical judgement should be employed to decide whether and to what extent further cardiological evaluation is indicated. Full article

Alzheimer’s disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5–2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke. Full article

Hypoxic-ischemic (HI) brain injury is associated with high mortality and severe long-term neurodevelopmental impairments in term newborns. Intranasal mesenchymal stem cell (MSC) therapy is a promising strategy to boost neurorepair after injury, and optimization strategies to further enhance its therapeutic potential are under development. In this study, we explored whether 24 h preconditioning of MSCs with 1000 ng/mL of osteopontin (OPN) could enhance MSC properties in vitro and in vivo. OPN-preconditioned MSCs (OPN-MSCs) showed increased activation of the ERK transcription pathway at 1 h during preconditioning and enhanced migration compared to naïve-MSCs. OPN preconditioning also altered gene expression of neurotrophic and immunomodulatory factors in MSCs. In vitro assessment of MSC potency showed that while OPN-MSCs were as effective as naïve-MSCs in reducing microglia activation, OPN preconditioning enhanced the potency of MSCs to boost neural stem cell differentiation into more complex neurons. However, in vivo, OPN-MSCs were not superior to naïve-MSCs in reducing lesion size in mice when applied at 3 days post-HI. Altogether, OPN preconditioning enhanced the migratory and neurotrophic properties of MSCs in vitro but not in vivo, highlighting its potential to optimize MSC function while underscoring the need for further research to refine in vivo translation and to evaluate functional outcomes for therapeutic efficacy. Full article

Background: Remote ischemic conditioning (RIC) has shown promise as a neuroprotective strategy, but its application in children with cerebral palsy (CP) remains unexplored. We conducted a randomized controlled trial to evaluate the feasibility, safety, and tolerability of repeated, 6–7 sessions of RIC in children with unilateral CP. Methods: Fifty-one children aged 6–16 years with unilateral CP were randomized (1:1) to receive RIC or sham conditioning on the more affected arm. Primary feasibility outcomes included recruitment metrics, intervention adherence, retention, and protocol fidelity. Safety endpoints included continuous monitoring of oxygen saturation, blood pressure, heart rate, and adverse event incidence. Tolerability was assessed via child-reported pain ratings, conditioning pressure tolerance, skin integrity evaluations, and session adherence. Results: Of 148 children screened, 51 were randomized to RIC (n = 25), sham (n = 26) groups; 48 (94.1%) completed the intervention as allocated. Recruitment yielded 2.04 participants/month. Intervention adherence was 100% in both groups. RIC was well tolerated, with mean pain scores 2.8 ± 3.1 during inflation in RIC and 0.3 ± 0.8 in Sham group. No serious adverse events occurred. Physiological parameters remained stable across 314 conditioning sessions; no clinically significant hypoxemia, blood pressure derangements, or arrhythmias were detected. Minor adverse events (transient erythema, mild discomfort) were rare (2.22%) and self-limiting. Skin integrity was preserved, and no participants required session termination. Conclusions: Repeated RIC is feasible, safe, and tolerable in children with unilateral CP. These findings support the design of future trials using RIC as a priming agent to enhance pediatric neurorehabilitation outcomes. Full article

Background: There is no information on how the dose of exercise training prior to myocardial infarction (MI) affects cardioprotection. Objective: This study aimed to evaluate the cardioprotective role of different volumes of exercise training prior to MI. Methods: Wistar female rats were allocated to one of the following groups: SHAM (not trained and undergoing simulated MI surgery), NT+MI (untrained and undergoing MI surgery), T60+MI (trained 60 min per session and undergoing MI surgery), T90+MI (trained 90 min per session and undergoing MI surgery), and T180+MI (trained 180 min per session and undergoing MI surgery). The training protocol was performed in a swimming pool for eight weeks. On the seventh day after MI, the animals underwent left ventricular (LV) structural and functional evaluation and were euthanized for molecular analyses. Results: Exercise training groups had greater VO₂peak and LV mass than did the SHAM group. The MI size did not differ statistically among the experimental groups. Compared with the SHAM group, all the MI groups presented a lower LV shortening fraction. LV systolic pressure was significantly lower in the T60+MI group than in the SHAM and T180+MI groups. The +dP/dt of the LV was significantly lower in the NT+MI, T60+MI, and T90+MI groups than in the SHAM group. We did not find significant changes in the inflammatory mediators and oxidative stress markers as well as proteins involved in calcium handling. Conclusions: Exercise training prior to MI enhanced cardiorespiratory fitness and induced LV hypertrophy, however, regardless of volume, was unable to counteract the detrimental effects of MI. Full article

Background: This study examined the effects of repeated ischemic preconditioning (IPC) combined with normobaric hypoxia on anaerobic performance and physiological stress markers. Methods: Fourteen physically active males (22.3 ± 3.1 years) completed three randomized, single-blind crossover sessions under the following conditions: (1) normoxia (NOR), (2) normobaric hypoxia (HYP; FiO₂ = 14.7%), and (3) hypoxia with IPC (IPC-HYP). Each session included three 30 s cycling Wingate tests separated by four minutes of passive recovery. Blood samples were collected pre-exercise, immediately post-exercise, and 15 min post-exercise to assess lactate, pH, bicarbonate (HCO₃⁻), and creatine kinase (CK) activity. Results: Peak power output was highest under NOR during Wingate II and III. IPC-HYP attenuated the decline in peak power compared to that under HYP (e.g., Wingate II: 15.56 vs. 12.52 W/kg). IPC-HYP induced greater lactate accumulation (peak: 15.45 mmol/L, p < 0.01), more pronounced acidosis (pH: 7.18 post-exercise), and lower bicarbonate (9.9 mmol/L, p < 0.01). CK activity, measured immediately and then 1 h and 24 h post-exercise, was highest under IPC-HYP at 24 h (568.5 U/L). Conclusions: IPC-HYP mitigates the decline in peak anaerobic power observed under hypoxia, despite eliciting greater metabolic and muscular stress. These findings suggest that IPC may enhance physiological adaptation to hypoxic training, potentially improving anaerobic performance. Full article

The purpose of this article is to examine a previously unrecognized role for the vasopressin–oxytocin (VP-OT) system in mammalian “stress-response hormesis.” The current review adds hormesis to the long list of beneficial effects of OT. Hormesis, a biphasic adaptive response to low-level stressors, is introduced here to contextualize the dynamic roles of oxytocin and vasopressin. As with hormesis, the properties of the VP-OT system are context-, time-, and dose-sensitive. Here we suggest that one key to understanding hormesis is the fact that VP and OT and their receptors function as an integrated system. The VP-OT system is capable of changing and adapting to challenges over time, including challenges necessary for survival, reproduction and sociality. Prior research suggests that many beneficial effects of OT are most apparent only following stressful experiences, possibly reflecting interactions with VP, its receptors and other components of the hypothalamic–pituitary–adrenal axis. The release of OT is documented following various kinds of hormetic experiences such as birth, vigorous exercise, ischemic events and the ingestion of emetics, including psychedelics. The phasic or cyclic modulation of VP and related “stress” hormones, accompanied or followed by the release of OT, creates conditions that conform to the core principles of hormesis. This concept is reviewed here in the context of other hormones including corticotropin releasing hormone (CRH) and urocortin, as well as cytokines. In general, VP and classic “stress hormones” support an active response, helping to quickly mobilize body systems. OT interacts with all of these, and may subsequently re-establish homeostasis and precondition the organism to deal with future stressors. However, the individual history of an organism, including epigenetic modifications of classical stress hormones such as VP, can moderate the effects of OT. Oxytocin’s effects also help to explain the important role of sociality in mammalian resilience and longevity. A hormetic perspective, focusing on a dynamic VP-OT system, offers new insights into emotional and physical disorders, especially those associated with the management of chronic stress, and helps us to understand the healing power of social behavior and perceived safety. Full article

Background/Objectives: Heart failure with preserved ejection fraction (HFpEF) has increased in prevalence as the population ages and associated comorbidities increase. Remote ischemic preconditioning (RIPC) has been shown to provide protection against ischemic injury to the heart and other organs. Therefore, the aim of this project will be to analyse the effectiveness of RIPC in terms of arterial stiffness, endothelial function, diastolic function, and exercise capacity in patients with HFpEF. Methods: The PIRIC-FEp study will be a parallel, randomised controlled trial with two groups conducted at the Faculty of Nursing in Cuenca, University of Castilla-La Mancha. Individuals who are diagnosed with HFpEF and are older than 40 years, with a left ventricular ejection fraction ≥50% and a sedentary lifestyle, will be included. The exclusion criteria will include, among others, patients with noncardiac causes of heart failure symptoms, significant pulmonary disease, diabetes, peripheral vascular disease, or myocardial infarction within the previous three months. A sample size of 48 patients was estimated, with 24 for each group. Participants will be randomly allocated (1:1) to either the RIPC intervention group or the control group to evaluate the effects on arterial stiffness, endothelial function, diastolic function, and exercise capacity. Assessments will be conducted at baseline and after a three-month follow-up period. Results: The findings will be published in a peer-reviewed journal article. Conclusions: This study is important for daily clinical practice because it provides a new approach for the treatment of HFpEF patients via RIPC. Full article

This study aimed to investigate the differences in proprioceptive changes at different time points (Pre vs. Post vs. 90 min vs. 24 h) before and after ischemic preconditioning. It followed a within-subject, self-controlled design, and a total of 21 trained male participants were assessed using two-point discrimination threshold tests on thigh and knee joint position sense testing. The results demonstrated that ischemic preconditioning effectively improved proprioceptive accuracy (two-point discrimination, right lower limb, p < 0.001; two-point discrimination, left lower limb, p < 0.001; knee position sense, right lower limb, p = 0.001; knee position sense, left lower limb, p = 0.014) and stability (two-point discrimination, right lower limb, p < 0.001; two-point discrimination, left lower limb, p = 0.002; knee position sense, right lower limb, p < 0.001; knee position sense, left lower limb, p = 0.003), with the optimal time point for enhancement identified at 90 min. This research suggests administering IPC 90 min before warm-up or competition to enhance athletic performance. Full article