Search Results (61)

The kinetics of insulin aggregation and fibril formation were studied in vitro using Scanning Electron Microscopy (SEM) and Fourier Transform Infrared (FTIR) spectroscopy. Our investigation centered on the protein’s morphological and structural changes to better understand the transient molecular configurations that occur during the lag phase. SEM images showed that, already at early incubation stages, a network of disordered pseudo-filaments, ranging in length between 200 and 500 nanometers, develops on the surface of large aggregates. At later stages, fibrils catalyzed by protein aggregates were observed. Principal Component Analysis (PCA) of the FTIR data identified signatures of intramolecular β-sheet secondary structures forming during the lag phase and at the onset of the exponential growth phase. These absorption bands are linked to secondary nucleation mechanisms due to their transient nature. This interpretation is further supported by a chemical equilibrium model, which yielded a reliable secondary nucleation rate constant, K₂, on the order of 10⁴ M⁻² s⁻¹. Full article

The misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection sites poses a challenge for diabetic patients who rely on insulin therapy. Furthermore, decreased responsiveness to insulin in type 2 diabetic (T2D) patients may lead to its overproduction and accumulation as aggregates. Earlier reports have reported that various factors such as pH, temperature, agitation, and the presence of lipids or other proteins influence insulin aggregation. Our present study aims to elucidate the effects of non–micellar anionic DMPG (1,2–dimyristoyl–sn–glycero–3–phosphoglycerol) lipids on insulin aggregation. Distinct pathways of insulin aggregation and intermediate formation were observed in the presence of DMPG using a ThT fluorescence assay. The formation of soluble intermediates alongside large insulin fibrils was observed in insulin incubated with DMPG via TEM, DLS, and NMR as opposed to insulin aggregates generated without lipids. ¹³C magic angle spinning solid–state NMR and FTIR experiments indicated that lipids do not alter the conformation of insulin fibrils but do alter the time scale of motion of aromatic and aliphatic side chains. Furthermore, the soluble intermediates were found to be more cytotoxic than fibrils generated with or without lipids. Overall, our study elucidates the importance of anionic lipids in dictating the pathways and intermediates associated with insulin aggregation. These findings could be useful in determining various approaches to avoid toxicity and enhance the effectiveness of insulin in therapeutic applications. Full article

A hallmark of type 2 diabetes mellitus (T2DM) is the presence of abundant amyloid deposits composed of amyloid polypeptide (amylin) within the pancreatic islets of Langerhans. Given its high prevalence among diabetic individuals, human amylin fibrillization has long been considered a key pathogenic factor in T2DM. Co-secreted with insulin, amylin can misfold and aggregate, inducing β-cell toxicity, impairing insulin secretion, and accelerating disease progression. Emerging evidence also indicates that amylin accumulates in the brains of patients with Alzheimer’s disease, where it may interact with amyloid-β (Aβ) to promote neurodegeneration. Although the underlying mechanisms remain under investigation, amylin aggregates have been shown to disrupt mitochondrial function, trigger endoplasmic reticulum stress, and activate the NLRP3 inflammasome. Additionally, T2DM-associated cerebrovascular alterations may compound cognitive decline. This review, based on a comprehensive literature search across major biomedical databases up to January 2025, synthesizes current evidence on amylin as a molecular link between metabolic and neurodegenerative disorders. We highlight pancreatic β-cell amylin aggregation as a potential early marker of dementia risk in T2DM and examine its relationship with proteostasis-associated proteins. Finally, we discuss emerging diagnostic and therapeutic strategies targeting amylin pathology, offering new perspectives on preventing or delaying neurodegeneration in individuals with T2DM. Full article

Type 2 diabetes is a significant risk factor for cardiovascular disease, particularly coronary heart disease, heart failure, and diabetic cardiomyopathy. Diabetic cardiomyopathy, characterized by heart dysfunction in the absence of coronary artery disease or hypertension, is triggered by various mechanisms, including hyperinsulinemia, insulin resistance, and inflammation. At the cellular level, increased insulin resistance leads to an imbalance in lipid and glucose metabolism, causing oxidative stress, mitochondrial dysfunction, and excess production of reactive oxygen species (ROS). This disrupts normal heart function, leading to fibrosis, hypertrophy, and cardiac remodeling. In diabetic patients, the excessive accumulation of fatty acids, advanced glycation end products (AGEs), and other metabolic disturbances further contribute to endothelial dysfunction and inflammatory responses. This inflammatory environment promotes structural damage, apoptosis, and calcium-handling abnormalities, resulting in heart failure. Additionally, diabetes increases the risk of arrhythmias, such as atrial fibrillation, which worsens cardiac outcomes. New insights into these molecular mechanisms have led to improvements in diabetes management, focusing on mitigating complications and understanding the cellular processes involved. Recent therapeutic advances, such as SGLT-2 inhibitors, have shown promise in addressing the energy imbalance and cardiac dysfunction seen in diabetic cardiomyopathy, offering new hope for better cardiovascular outcomes. Full article

Background: The spontaneous rupture of the internal iliac artery (IIA) is an exceedingly rare vascular event, typically associated with congenital anomalies or degenerative conditions. This report details an unprecedented case of isolated IIA rupture in an elderly patient with evidence of plaque rupture but devoid of congenital vascular pathology. Case Presentation: An 81-year-old Caucasian male presented to the Emergency Department following a syncopal episode and acute right iliac fossa pain. His significant medical history was atrial fibrillation managed with anticoagulation (Apixaban), non-insulin-dependent diabetes mellitus, and recent hospitalization for multidrug-resistant Klebsiella pneumoniae pneumonia. Initial imaging with contrast-enhanced computed tomography revealed an aneurysmatic dilatation of the right IIA, indicative of rupture. An endovascular repair was performed, employing a combination of stent grafts to achieve proximal and distal sealing and to restore vascular continuity. Outcome: The patient exhibited hemodynamic stability throughout the perioperative period and was transferred to the general ward postoperatively. However, he suffered a recurrent rupture on the 30th postoperative day, prompting a second endovascular intervention to extend the graft landing zone into the common iliac artery. Intraoperative findings confirmed localized plaque rupture as the underlying trigger for the initial vessel rupture. He ultimately achieved clinical stability and was discharged on the 35th postoperative day. Discussion: This case illustrates the critical importance of recognizing spontaneous IIA rupture as a potential complication in elderly patients, particularly in the context of recent severe infections. While the relationship between the rupture and the Klebsiella pneumoniae infection remains speculative, this report underscores the necessity of further research into the role of infectious processes in vascular integrity and susceptibility to rupture. Conclusions: The successful management of this rare and complex vascular emergency using endovascular techniques underscores the evolving landscape of minimally invasive interventions. This case contributes to the limited existing literature on spontaneous IIA rupture and highlights the need for increased clinical vigilance regarding atypical presentations in similar patient populations. Full article

The misfolding and amyloid aggregation of proteins have been attracting scientific interest for a few decades, due to their link with several diseases, particularly neurodegenerative diseases. Proteins can assemble and result in insoluble aggregates that, together with intermediate oligomeric species, modify the extracellular environment. Many efforts have been and are devoted to the search for cosolvents and cosolutes able to interfere with amyloid aggregation. In this work, we intensively study the effect of saponins, bioactive compounds, on human insulin aggregation. To monitor the kinetic of amyloid aggregation following secondary structure changes, we perform fluorescence and UV-Visible absorption spectroscopies, using Thioflavin T and Congo Red as amyloid specific probes, and Circular Dichroism. To study the overall structural features and size of aggregates, we perform Synchrotron Small-Angle X-ray Scattering and Dynamic Light Scattering experiments. The morphology of the aggregates was assessed by Atomic Force Microscopy. To deepen the understanding of the saponins interaction with insulin, a Molecular Dynamics investigation is performed, too. The reported data demonstrate that saponins interfere with the amyloid aggregation by inducing a strong inhibition on the formation of insulin fibrils, likely through specific interactions with insulin monomers. A dose-dependent effect is evident, and amyloid inhibition is already clear when saponins are just 0.01% w/w in solution. We suggest that saponins, which are natural metabolites present in a wide range of foods ranging from grains, pulses, and green leaves to sea stars and cucumbers, can be promising metabolites to inhibit human insulin aggregation. This basic research work can pave the way to further investigations concerning insulin amyloidosis, suggesting the use of saponins as amyloid inhibitors and/or stabilizing agents in solution. Full article

Lipopolysaccharides (LPS) are bacterial mediators of neuroinflammation that have been detected in close association with pathological protein aggregations of Alzheimer’s disease. LPS induce the release of cytokines by microglia and mediate the upregulation of inducible nitric oxide synthase (iNOS)—a mechanism also associated with amyloidosis. Curcumin is a recognized natural medicine but has extremely low bioavailability. V-Cur, a novel hemocompatible Vanadium(IV)-curcumin complex with higher solubility and bioactivity than curcumin, is studied here. Co-cultures consisting of rat primary neurons and microglia were treated with LPS and/or curcumin or V-Cur. V-Cur disrupted LPS-induced overexpression of amyloid precursor protein (APP) and the in vitro aggregation of human insulin (HI), more effectively than curcumin. Cell stimulation with LPS also increased full-length, inactive, and total iNOS levels, and the inflammation markers IL-1β and TNF-α. Both curcumin and V-Cur alleviated these effects, with V-Cur reducing iNOS levels more than curcumin. Complementary insights into possible bioactivity mechanisms of both curcumin and V-Cur were provided by In silico molecular docking calculations on Aβ_1-42, APP, Aβ fibrils, HI, and iNOS. This study renders curcumin-based compounds a promising anti-inflammatory intervention that may be proven a strong tool in the effort to mitigate neurodegenerative disease pathology and neuroinflammatory conditions. Full article

Introduction: The most frequent local complication of insulin injection is the occurrence of subcutaneous nodules due to incorrect injection technique. Injection into nodules negatively impacts metabolic compensation and the requirement for greater insulin doses due to its partial and erratic absorption. Despite these concepts being accepted by the scientific community, it is not yet clear whether injection into nodules is causally related to worsening chronic diabetes (DM) complications and the morphological nature of such nodules. Aim: This multicenter study aimed to evaluate the associations between structural characteristics of skin nodules and chronic DM complications. A secondary endpoint was to evaluate the histological structure of those nodules, looking for differences between lipohypertrophies (LH) and amyloid nodules (LIDA). Methods: For this purpose, 816 DM patients with LH and 1033 without LH underwent a clinical and ultrasound study comparing metabolic data, injection habits, and frequency of complications. Excisional biopsies of the skin nodules were performed in a small series of eight subjects. Results: Data observed confirm a strong relationship between LH and diabetes chronic complications other than poor glycemic control. Histology of biopsies from the skin nodules showed mild foreign-body-like inflammation, prevailing mega-adipocytes (65%), apoptosis, and fibrosis but could not detect any amyloid fibrils. In four cases, intra-nodular fluid was present with an insulin concentration several times higher than in blood. Conclusions: We confirmed LHs to be significantly associated with insulin administration errors, duration of insulin therapy, greater daily doses and duration of insulin administration, and the presence of micro- and macro-vascular DM complications. LH nodules displayed no typical morphological features and were indistinguishable from LIDA nodules with which they shared several histologic similarities, albeit within the frame of a general picture of LIDA inhomogeneity. Further targeted studies are warranted to clarify the remaining doubts. Full article

Heart failure with preserved ejection fraction (HFpEF) is increasing at an alarming rate worldwide, with limited effective therapeutic interventions in patients. Sudden cardiac death (SCD) and ventricular arrhythmias present substantial risks for the prognosis of these patients. Obesity is a risk factor for HFpEF and life-threatening arrhythmias. Obesity and its associated metabolic dysregulation, leading to metabolic syndrome, are an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese, leading to an enhanced risk of incidence and mortality due to cardiovascular disease (CVD). Obesity predisposes patients to atrial fibrillation and ventricular and supraventricular arrhythmias—conditions that are caused by dysfunction in the electrical activity of the heart. To date, current therapeutic options for the cardiomyopathy of obesity are limited, suggesting that there is considerable room for the development of therapeutic interventions with novel mechanisms of action that will help normalize sinus rhythms in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca-handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels and Ca-handling proteins remain incompletely understood. Obesity is marked by the accumulation of adipose tissue, which is associated with a variety of adverse adaptations, including dyslipidemia (or abnormal systemic levels of free fatty acids), increased secretion of proinflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, which cause electrical remodeling and, thus, predispose patients to arrhythmias. Furthermore, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which is marked by distinct signaling mechanisms. Thus, there may also be functional differences in the effects of the regional distribution of fat deposits on ion channel/Ca-handling protein expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge of the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. Nevertheless, substantial knowledge gaps remain regarding HFpEF treatment, requiring further investigations to identify potential therapeutic targets. The objective of this study is to review cardiac ion channel/Ca-handling protein remodeling in the predisposition to metabolic HFpEF and arrhythmias. This review further highlights interleukin-6 (IL-6) as a potential target, cardiac bridging integrator 1 (cBIN1) as a promising gene therapy agent, and leukotriene B4 (LTB4) as an underappreciated pathway in future HFpEF management. Full article

Background: Depression is a known factor in poor cardiovascular outcomes but is often underassessed in cardiac units. This study evaluates the impact of depression on cardiovascular outcomes in patients undergoing cardiac interventions. Methods: The study included 133 patients who underwent uncomplicated procedures for degenerative aortic valve stenosis (n = 40), acute coronary syndrome (n = 29), or chronic coronary artery disease (n = 64). Depression was assessed using the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAM-D). The primary endpoint was a major adverse cardiac and cerebrovascular event (MACCE). Patients were followed up for 12 months. Cox proportional hazards analysis was used to identify MACCE risk factors. Results: Depression was more frequently screened by HAM-D than BDI (42.9% vs. 30.8%, p < 0.001). During follow-up, 26 (19.5%) MACCEs occurred. In univariate analysis, risk factors included BDI score ≥ 11, HAM-D score ≥ 8, diabetes on insulin, anticoagulant use, atrial fibrillation, and serum creatinine level ≥ 130 µmol/L. Depression in the BDI increased the risk of the MACCE 3.6-fold (95%CI: 1.64–8.0, p = 0.001), whereas in the HAM-D, it increased the risk 4.9-fold (95%CI: 1.97–12.24, p < 0.001). Multivariate analysis showed HAM-D score ≥ 8 as the strongest predictor of MACCE (HR: 3.08, 95%CI: 1.18–8.08). Conclusions: Depression is a common finding in cardiovascular patients, and it is a strong risk factor for one-year cardiovascular mortality and adverse event risk. Therefore, we believe that common guidelines should be elaborated between relevant psychiatry and cardiology scientific societies. Full article

Protein amyloid aggregation is linked with widespread and fatal neurodegenerative disorders as well as several amyloidoses. Insulin, a small polypeptide hormone, is associated with injection-site amyloidosis and is a popular model protein for in vitro studies of amyloid aggregation processes as well as in the search for potential anti-amyloid compounds. Despite hundreds of studies conducted with this specific protein, the procedures used have employed a vast array of different means of achieving fibril formation. These conditions include the use of different solution components, pH values, ionic strengths, and other additives. In turn, this variety of conditions results in the generation of fibrils with different structures, morphologies and stabilities, which severely limits the possibility of cross-study comparisons as well as result interpretations. In this work, we examine the condition–structure relationship of insulin amyloid aggregation under a range of commonly used pH and ionic strength conditions as well as solution components. We demonstrate the correlation between the reaction solution properties and the resulting aggregation kinetic parameters, aggregate secondary structures, morphologies, stabilities and dye-binding modes. Full article

Speckle tracking echocardiography is an innovative imaging technique that evaluates myocardial motion, including the function of the left atrium (LA). The assessment of the left atrium’s function across its dimensions can have diagnostic and prognostic roles in various cardiovascular conditions. Left atrial strain has been recognized as a valuable predictor of mortality and cardiovascular incidents in the general population across various conditions. For individuals with type 2 diabetes mellitus (T2DM), left atrial dysfunction, as gauged by speckle tracking echocardiography, appears particularly prognostic. Parameters such as peak atrial longitudinal strain (PALS) and left atrial stiffness have been linked with heightened risks of severe cardiovascular events, including atrial fibrillation (AF), heart failure (HF) hospitalizations, or mortality. Consequently, recognizing left atrial dysfunction early is crucial for accurate diagnosis, guiding treatment choices, comprehensive patient management, and prognosis evaluation. Using two-dimensional (2D) speckle tracking echocardiography, results from recent studies report that treatment with empagliflozin significantly enhanced LA function in patients with type 2 diabetes mellitus, improving left atrial strain (LAS) contraction and reservoir values. Furthermore, treatments with glucagon-like peptide-1 (GLP)-1 receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors were shown to improve LA reservoir strain more effectively than insulin alone, suggesting their potential in reducing cardiovascular complications in T2DM patients. This narrative review further addresses ongoing challenges and potential enhancements needed to boost the clinical value of left atrium strain, emphasizing its significance in managing and improving outcomes for diabetic patients. Full article

Background: Minimally invasive mitral valve surgery (MIMVS) is a treatment for severe mitral valve pathologies. In redo cases, especially after coronary artery bypass grafting (CABG) surgery with patent mammary bypass grafts, establishing aortic clamping followed by antegrade cardioplegia application might be challenging. Here, we present the outcome of hypothermic ventricular fibrillation as an alternative to conventional cardioprotection. Methods: Patients who underwent MIMVS either received hypothermic ventricular fibrillation (study group, n = 48) or antegrade cardioprotection (control group, n = 840) and were observed for 30 postoperative days. Data were retrospectively analyzed and collected from January 2011 until December 2022. Results: Patients in the study group had a higher preoperative prevalence of renal insufficiency (p = 0.001), extracardiac arteriopathy (p = 0.001), insulin-dependent diabetes mellitus (p = 0.001) and chronic lung disease (p = 0.036). Furthermore, they had a longer surgery time and a lower repair rate (p < 0.001). No difference, however, was seen in postoperative incidences of stroke (p = 0.26), myocardial infarction (p = 1) and mitral valve re-operation (p = 1) as well as 30-day mortality (p = 0.1) and postoperative mitral valve insufficiency or stenosis. Conclusions: The patients who underwent redo MIMVS with hypothermic ventricular fibrillation did not have worse outcomes or more serious adverse events compared to the patients who received routine conventional cardioprotection. Therefore, the use of hypothermic ventricular fibrillation appears to be a promising cardioprotective technique in this challenging patient population requiring redo MIMVS. Full article

Obesity has increasingly become a worldwide epidemic, as demonstrated by epidemiological and clinical studies. Obesity may lead to the development of a broad spectrum of cardiovascular diseases (CVDs), such as coronary heart disease, hypertension, heart failure, cerebrovascular disease, atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. In addition to hypertension, there are other cardiometabolic risk factors (CRFs) such as visceral adiposity, dyslipidemia, insulin resistance, diabetes, elevated levels of fibrinogen and C-reactive protein, and others, all of which increase the risk of CVD events. The mechanisms involved between obesity and CVD mainly include insulin resistance, oxidative stress, inflammation, and adipokine dysregulation, which cause maladaptive structural and functional alterations of the heart, particularly left-ventricular remodeling and diastolic dysfunction. Natural products of plants provide a diversity of nutrients and different bioactive compounds, including phenolics, flavonoids, terpenoids, carotenoids, anthocyanins, vitamins, minerals, fibers, and others, which possess a wide range of biological activities including antihypertensive, antilipidemic, antidiabetic, and other activities, thus conferring cardiometabolic benefits. In this review, we discuss the main therapeutic interventions using extracts from herbs and plants in preclinical and clinical trials with protective properties targeting CRFs. Molecular mechanisms and therapeutic targets of herb and plant extracts for the prevention and treatment of CRFs are also reviewed. Full article

Cerebrovascular accident is the most ominous complication observed after cardiac surgery, carrying an increased risk of morbidity and mortality. Analysis of the problem shows its multidimensional nature. In this study, we aimed to identify major determinants among classic variables, either demographic, clinical or type of surgical procedure, based on the analysis of a large dataset of 580,117 patients from the UK National Adult Cardiac Surgical Audit (NACSA). For this purpose, univariate and multivariate logistic regression models were utilized to determine associations between predictors and dependent variable (Stroke after cardiac surgery). Odds ratios (ORs) and 95% confidence intervals (CIs) were constructed for each independent variable. Statistical analysis allows us to confirm with greater certainty the predictive value of some variables such as age, gender, diabetes mellitus (diabetes treated with insulin OR = 1.37, 95%CI = 1.23–1.53), and systemic arterial hypertension (OR = 1.11, 95%CI = 1.05–1.16);, to emphasize the role of preoperative atrial fibrillation (OR = 1.10, 95%CI = 1.03–1.16) extracardiac arteriopathy (OR = 1.70, 95%CI = 1.58–1.82), and previous cerebral vascular accident (OR 1.71, 95%CI = 1.6–1.9), and to reappraise others like smoking status (crude OR = 1.00, 95%CI = 0.93–1.07 for current smokers) or BMI (OR = 0.98, 95%CI = 0.97–0.98). This could allow for better preoperative risk stratification. In addition, identifying those surgical procedures (for example thoracic aortic surgery associated with a crude OR of 3.72 and 95%CI = 3.53–3.93) burdened by a high risk of neurological complications may help broaden the field of preventive and protective techniques. Full article