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Search Results (1,018)

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Keywords = cardiovascular risk reduction

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19 pages, 3297 KiB  
Article
Utilizing Lactic Acid Bacteria to Improve Hyperlipidemia: A Comprehensive Analysis from Gut Microbiota to Metabolic Pathways
by Changlu Ma, Chen Xu, Mumin Zheng, Shuwen Zhang, Qifeng Liu, Jiaping Lyu, Xiaoyang Pang and Yinghong Wang
Foods 2024, 13(24), 4058; https://doi.org/10.3390/foods13244058 - 16 Dec 2024
Abstract
Hyperlipidemia poses significant risks for cardiovascular diseases, with emerging evidence underscoring the critical role of gut microbiota in metabolic regulation. This study explores Lactobacillus casei CAAS36, a probiotic strain with promising cholesterol-lowering capabilities, assessing its impact on hyperlipidemic hamsters. Utilizing 1H NMR-based metabolomics [...] Read more.
Hyperlipidemia poses significant risks for cardiovascular diseases, with emerging evidence underscoring the critical role of gut microbiota in metabolic regulation. This study explores Lactobacillus casei CAAS36, a probiotic strain with promising cholesterol-lowering capabilities, assessing its impact on hyperlipidemic hamsters. Utilizing 1H NMR-based metabolomics and 16S rRNA gene sequencing, we observed that L. casei CAAS36 treatment not only altered metabolic pathways but also reshaped gut microbiota composition. Notably, the treatment restored the balance between Firmicutes and Bacteroidetes and significantly increased the abundance of propionate-producing Muribaculaceae. Metabolically, L. casei CAAS36 administration led to the normalization of key lipid markers, including reductions in total cholesterol, LDL-C, and triglycerides (29.9%, 29.4% and 32.6%), while enhancing the protective HDL-C levels. These effects were accompanied by significant increases in beneficial metabolites such as propionate and succinate, which are known for their roles in preventing metabolic disorders. These findings highlight the dual regulatory effects of L. casei CAAS36 on the metabolic profile and gut microbiota, suggesting a substantial potential for this probiotic in the management of hyperlipidemia and possibly other metabolic diseases. Future applications may include its use as a natural therapeutic agent in clinical settings, aiming to reduce reliance on conventional pharmaceuticals and their associated side effects. Full article
(This article belongs to the Section Food Microbiology)
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Figure 1
<p>Box plots for effects of <span class="html-italic">L. casei</span> CAAS36 on serum TC, TG, LDL-C, and HDL-C levels in hyperlipidemia hamsters at week 8 after drug dosing. C: control group, M: model group, L: <span class="html-italic">L. casei</span> CAAS36- treated group, F: fenofibrate-treated group. The TG, TC, LDL, and HDL content in the model group was significantly increased compared with the control group, while the <span class="html-italic">L. casei</span> CAAS36-treated group was significantly decreased compared with the model group. Note: * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, * indicates that each group is compared with the model group.</p>
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<p>Metabolic changes in hyperlipidemic hamsters based on NMR metabolomics. (<b>A</b>) OPLS-DA score plots obtained from <sup>1</sup>H NMR data of serum, urine, and fecal samples. (<b>B</b>) Potential biomarkers of serum and feces, metabolic pathways, as well as fold changes (M/C, L/M) between different groups at week 8. Note: C—control group, M—model group, L—<span class="html-italic">L. casei</span> CAAS36-treated group.</p>
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<p>The ratio of fatty acid changes in different groups. C—control group, M—model group, L—<span class="html-italic">L. casei</span> CAAS36-treated group. The ratios of the model group are significantly changed compared with the control group, and the <span class="html-italic">L. casei</span> CAAS36-treated group can significantly restore these changes. Note: * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001, * indicates that each group is compared with the model group.</p>
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<p>Intestinal flora analysis. (<b>A</b>) Evaluation of microbial richness and α−diversity in different groups based on Shannon index. The distribution and density of samples are displayed in box plot. Boxes represent the degree of dispersion (spread) and skewness in the data, the inside black plots represent the interquartile range, midline, range, mid-range, and trimean. <span class="html-italic">p</span> values are from Wil−coxon rank−sum test. (<b>B</b>) The relative abundance of intestinal microflora at the phylum level. The classification level is expressed as a percentage of the total sequence. The strips of different colors represent different taxa of intestinal microorganisms. (<b>C</b>,<b>D</b>) The significant gut microbial changes between control, model, and <span class="html-italic">L. casei</span> CAAS36 groups in family level. (<b>E</b>–<b>G</b>) Relative abundance of the Bacteroidetes (<b>E</b>) and Firmicutes (<b>F</b>) phyla, and the Firmicutes/Bacteroidetes ratio (<b>G</b>) in the control, model, and <span class="html-italic">L. casei</span> CAAS36 groups. (<b>H</b>) Relative abundance of the top 40 most different genera across groups. The abundance profiles are converted to Z-scores by subtracting the average abundance and dividing the standard deviation of all samples. The abundance profile is converted to a Z-score by subtracting the average abundance of all samples and dividing by the standard deviation. When the row abundance is lower than the average, the Z-Score is negative. Note: ** <span class="html-italic">p</span> &lt; 0.01. Note: C—control group, M—model group, L—<span class="html-italic">L. casei</span> CAAS36-treated group.</p>
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<p>Correlation analysis between metabolites and intestinal flora in hyperlipidemic hamsters treated with <span class="html-italic">L. casei</span> CAAS36. (<b>A</b>) Correlation of abundance of significant changed bacterial taxa and metabolic parameters associated with obesity: red line for positive correlations and blue line for negative correlations. Only significant correlations (<span class="html-italic">p</span> &lt; 0.05), are represented. (<b>B</b>) The relative abundance of gut microbiota with significant (<span class="html-italic">p</span> &lt; 0.05) differences at different taxa. From the inside to the outside: phylum, class, order, family, genus. ○: the fold change in M/C; △: the fold change in L/M; red color: fold change &gt; 1; green color: fold change &lt; 1. Note: C—control, M—high fat diet, (L)— <span class="html-italic">L. casei</span> CAAS36-treated.</p>
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<p>Synthesis of short chain fatty acids.</p>
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11 pages, 224 KiB  
Article
AIHEMAF–P: An Innovative Healthcare Model for Atrial Fibrillation Patients
by Raffaele La Regina, Pasquale Innelli, Fulvio Glisenti, Gianbattista Bollani, Eugenio Leopardi, Gian Franco Gensini, Savina Nodari, Giuseppe La Regina, Micaela La Regina and Francesco Gabbrielli
Pharmacy 2024, 12(6), 187; https://doi.org/10.3390/pharmacy12060187 - 15 Dec 2024
Viewed by 232
Abstract
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias of clinical relevance and a major cause of cardiovascular morbidity and mortality. Following a diagnosis of AF, patients are directed towards therapy with anticoagulant drugs to reduce the thromboembolic risk and antiarrhythmics [...] Read more.
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias of clinical relevance and a major cause of cardiovascular morbidity and mortality. Following a diagnosis of AF, patients are directed towards therapy with anticoagulant drugs to reduce the thromboembolic risk and antiarrhythmics to control their cardiac rhythm, with periodic follow-up checks. Despite the great ease of handling these drugs, we soon realized the need for follow-up models that would allow the appropriateness and safety of these pharmacological treatments to be monitored over time. This pilot study was conducted at a rural pharmacy. The study comprised 47 patients (average age 71.22 years) with nonvalvular atrial fibrillation (68% being paroxysmal) on NOACs. Twenty percent of the enrolled subjects lived alone and fifty-four percent of the participants stated that they were not independent in managing their treatment. The primary aim was to describe the implementation and the outcomes of an innovative smart clinic model in which a local trained pharmacist is a case manager, and the patient carries out the required checks via telemedicine and point-of-care testing systems (POCT) under the service pharmacy regime; the results of the checks could be shared in real time with the attending general practitioner and the relevant specialist. The secondary aims of this study were to evaluate adherence to the planned controls, the prescriptive appropriateness of the dosages and drugs and adherence to the prescribed therapy, the occurrence of pharmacological problems linked to drug type interactions, the occurrence of hemorrhagic and/or thromboembolic complications, the acceptance by the general practitioners and/or the specialists of the reports made by the pharmacist on the subsequent actions undertaken, the economic and social impact of this model on the National Health Service and on the patient, and the impact on the quality perceived by the patients involved in this innovative monitoring process. Compliance with the planned checks was 93%. The dosage of the anticoagulant drug during enrollment was found to be inappropriate, without apparent clinical reasons, in 11% of the sample. Adherence to the anticoagulant therapy was found to be 98%. In total, 214 drug–drug interactions of varying clinical relevance were detected. No embolic events were detected; however, 13% of the sample reported a major hemorrhagic event, which came to light thanks to the close monitoring of hemoglobinemia. A total of 109 reports were made to the patients’ referring doctors in relation to the summarized anomalies, and 84% were accepted by the referring clinicians. Therefore, community pharmacists and pharmacy services represent ideal actors and contexts that, when integrated into the care network, can really favor individual care plan adherence and achieve daily morbidity reductions and cost savings through proper disease control and the early diagnosis of complications. Full article
14 pages, 666 KiB  
Review
Erythrocyte Membrane Fluidity and Omega-3 Fatty Acid Intake: Current Outlook and Perspectives for a Novel, Nutritionally Modifiable Cardiovascular Risk Factor
by Umberto Capece, Shawn Gugliandolo, Cassandra Morciano, Adriana Avolio, Amelia Splendore, Gianfranco Di Giuseppe, Gea Ciccarelli, Laura Soldovieri, Michela Brunetti, Teresa Mezza, Alfredo Pontecorvi, Andrea Giaccari and Francesca Cinti
Nutrients 2024, 16(24), 4318; https://doi.org/10.3390/nu16244318 - 14 Dec 2024
Viewed by 654
Abstract
Omega-3 fatty acids reduce triglycerides and have several positive effects on different organs and systems. They are also found in the plasma membrane in variable amounts in relation to genetics and diet. However, it is still unclear whether omega-3 supplementation can reduce the [...] Read more.
Omega-3 fatty acids reduce triglycerides and have several positive effects on different organs and systems. They are also found in the plasma membrane in variable amounts in relation to genetics and diet. However, it is still unclear whether omega-3 supplementation can reduce the occurrence of major cardiovascular events (MACEs). Two trials, REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), with highly purified EPA, and STRENGTH (Effect of High-Dose Omega-3 Fatty Acids vs. Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk), with a combination of EPA and DHA, have produced different outcomes, triggering a scientific debate on possible explanations for the discrepancies. Furthermore, doubts have arisen as to the anti-inflammatory and anti-aggregating activity of these compounds. Recent studies have, however, highlighted interesting effects of EPA and DHA on erythrocyte membrane fluidity (EMF). EMF is governed by a complex and dynamic biochemical framework, with fatty acids playing a central role. Furthermore, it can be easily measured in erythrocytes from a blood sample using fluorescent probes. Recent research has also shown that EMF could act as a possible cardiovascular risk factor biomarker. This review aims to synthetize the latest evidence on erythrocyte membrane fluidity, exploring its potential role as a biomarker of residual cardiovascular risk and discussing its clinical relevance. Further, we aim to dissect the possible biological mechanisms that link omega-3 modifiable membrane fluidity to cardiovascular health. Full article
(This article belongs to the Special Issue Functional Lipids and Human Health)
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Graphical abstract

Graphical abstract
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<p>This figure is a comprehensive illustration of the latest evidence on erythrocyte membrane fluidity: (<b>A</b>) This image was obtained through confocal microscopy after staining a blood sample with a specific probe (Laurdan). This probe is characterized by a shift in the emission spectrum reflecting the lipid phase state of the environment (bluish in ordered gel phases and greenish in disordered liquid–crystalline phases). After staining, five images of Laurdan emission intensity were acquired concurrently in two distinct channels (emission filter: 450/50 nm for the blue channel, 525/50 nm for the green channel) using a 60× immersion-oil objective. Generalized polarization (GP) was calculated as follows: GP = Iblue − G Igreen/Iblue + G Igreen, where Iblue and Igreen are the intensities for the blue and green channels, respectively, and G is a calibration factor that depends on the experimental setup. GP is a measure of membrane fluidity. (<b>B</b>) Longitudinal section of an erythrocyte. (<b>C</b>) Description of the main components of the erythrocyte membrane.</p>
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11 pages, 595 KiB  
Case Report
The Long-Term Cardiovascular Risks of Duloxetine Use in Older Adults: A Retrospective Medical Record-Based Adverse Drug Reaction Assessment
by Yuqi Cui, Sayed Aliul Hasan Abdi, Jeanne Wei and Gohar Azhar
J. Clin. Med. 2024, 13(24), 7595; https://doi.org/10.3390/jcm13247595 - 13 Dec 2024
Viewed by 303
Abstract
Background: Duloxetine, a Serotonin–Norepinephrine Reuptake Inhibitor (SNRI), is frequently used to treat diabetic peripheral neuropathy, depression, and fibromyalgia. However, its long-term cardiovascular implications in older individuals remain underexplored, particularly in those with pre-existing cardiovascular diseases. This medical record assessment aimed to evaluate the [...] Read more.
Background: Duloxetine, a Serotonin–Norepinephrine Reuptake Inhibitor (SNRI), is frequently used to treat diabetic peripheral neuropathy, depression, and fibromyalgia. However, its long-term cardiovascular implications in older individuals remain underexplored, particularly in those with pre-existing cardiovascular diseases. This medical record assessment aimed to evaluate the potential cardiovascular risks of duloxetine use in older persons after prolonged use. Methods: We evaluated adverse drug reactions (ADRs) using six medical records from elderly individuals (aged 70–79) with cardiovascular comorbidities who received duloxetine (≥60 mg daily) for anxiety, depression, and chronic pain. ADRs were assessed using the Naranjo ADR Probability Scale, the Modified Hartwig and Siegel Severity Scale, and the Karch and Lasagna Algorithm. Clinical outcomes were assessed before and after duloxetine dose reduction or withdrawal. Results: All the patients had cardiovascular-related ADRs, such as peripheral cyanosis, vasoconstriction, atrial fibrillation, and hypertensive episodes. Five of the six patients experienced mild cognitive impairment [Montreal Cognitive Assessment (MoCA) scores of 11–24/30]. A positive dechallenge (symptom resolution) was observed in all medical records after decreasing or discontinuing duloxetine. It is interesting to note that four medical records demonstrated significant improvement in cyanosis, blood pressure, and anxiety after decreasing or discontinuing duloxetine use. There was no rechallenge in this study. The causality was considered probable (Naranjo Scale), and ADRs were categorized as moderately severe (Hartwig and Siegel Scale) in all the medical records. However, with adequate monitoring, the ADRs were considered preventable (Schumock and Thornton Scale). Conclusions: Long-term duloxetine use could cause significant cardiovascular problems in older individuals, particularly those who already have cardiovascular difficulties. Regular monitoring of cardiovascular function and early steps such as dose adjustment or drug withdrawal of duloxetine may reduce the prognosis of ADRs. More studies are required to create safer treatment strategies for managing depression and anxiety in older people with cardiovascular issues. Full article
(This article belongs to the Section Cardiovascular Medicine)
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<p>Physiological impacts and potential toxic effects of duloxetine on the brain and cardiovascular system. Red arrows denote increase in Serotonin and Norepinephrine enhancing the cellular and physiological responses outlined in the adjacent boxes, respectively.</p>
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24 pages, 370 KiB  
Review
The Role of Behavioral Factors on Chronic Diseases—Practice and Knowledge Gaps
by Valentina Rahelić, Tomislav Perković, Lucija Romić, Pavo Perković, Sanja Klobučar, Eva Pavić and Dario Rahelić
Healthcare 2024, 12(24), 2520; https://doi.org/10.3390/healthcare12242520 - 12 Dec 2024
Viewed by 323
Abstract
Background: Behavioral factors, such as smoking, alcohol consumption, stress, poor diet, and physical inactivity, but also sleep deprivation and negative social connections, play a critical role in the development and progression of major chronic diseases. These include cardiovascular diseases, diabetes, chronic respiratory conditions, [...] Read more.
Background: Behavioral factors, such as smoking, alcohol consumption, stress, poor diet, and physical inactivity, but also sleep deprivation and negative social connections, play a critical role in the development and progression of major chronic diseases. These include cardiovascular diseases, diabetes, chronic respiratory conditions, and cancers. Methods: The objective of this review is to explore the influence of these modifiable risk factors on the global burden of chronic diseases and assess the potential impact of public health interventions and policy changes. Results: The evidence highlights a significant association between behavioral risk factors and increased morbidity and mortality from chronic diseases. Public health interventions and policy changes targeting these modifiable behaviors have shown substantial potential in reducing the prevalence and impact of chronic conditions. Strategies such as smoking cessation programs, dietary improvements, physical activity promotion, and stress reduction are critical in mitigating these risks. Conclusions: Addressing modifiable behavioral factors is essential for the prevention and control of chronic diseases. Bridging the gap between current knowledge and effective implementation of interventions is crucial for improving population health outcomes. Public health strategies focused on modifying key behavioral risks can significantly reduce the burden of chronic diseases, thereby improving overall health and reducing healthcare costs. Full article
11 pages, 789 KiB  
Review
Hemodynamic Effects of SGLT2 Inhibitors in Patients with and Without Diabetes Mellitus—A Narrative Review
by Roxana Brata, Andrei Vasile Pascalau, Ovidiu Fratila, Ioana Paul, Mihaela Mirela Muresan, Andreea Camarasan and Tiberia Ilias
Healthcare 2024, 12(23), 2464; https://doi.org/10.3390/healthcare12232464 - 6 Dec 2024
Viewed by 495
Abstract
Background: The current review aims to present the beneficial effects of SGLT2 inhibitors (dapagliflozin and empagliflozin) on several hemodynamic parameters such as blood pressure, filtration pressure at the level of the glomerular capillaries, and the improvement of the preload and afterload of [...] Read more.
Background: The current review aims to present the beneficial effects of SGLT2 inhibitors (dapagliflozin and empagliflozin) on several hemodynamic parameters such as blood pressure, filtration pressure at the level of the glomerular capillaries, and the improvement of the preload and afterload of heart muscle. In order to stop chronic kidney disease (CKD) from progressing, SGLT2 inhibitors have become an important disease-modifying treatment. Materials and methods: Recent clinical studies have shown the success of these drugs in treating heart failure, reducing the risk of cardiovascular events, hospitalization, and mortality. Results: The hemodynamic effects of SGLT2 inhibitors include a diuretic effect, due to reduced sodium reabsorption. Also, at this level, numerous studies have confirmed the beneficial effect of dapagliflozin in patients with chronic kidney disease, associated with a 44% reduced risk of progression in this pathology. SGLT2 inhibitors are associated with a reduction in blood pressure and weight loss, because of their diuretic effect, especially empagliflozin, which can explain the beneficial effects in patients with heart failure. In addition, mainly empagliflozin reduces stiffness and arterial resistance. Conclusions: Although the exact mechanism of action is unknown, SGLT2 inhibitors reduce the interstitial volume by blocking the tubular reabsorption of glucose. This leads to reduced blood pressure and enhanced endothelial function. Consequently, there have been improvements in hospitalization and fatality rates. Because of their beneficial effects, these medications have been guidelines for managing heart failure and chronic kidney disease. Full article
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<p>Flow-chart of article selection for study inclusion.</p>
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<p>Beneficial hemodynamic effects of SGLT2 inhibitors (F developed with Office Developer Tools) based on data in the article. The upper part of the image, represented by the kidney diagram, suggests that the patients with CKD (chronic kidney disease) treated with SGLT2 inhibitors, regardless of the presence or absence of DM (Diabetes Mellitus), have obtained better results regarding glomerular filtration pressure, natriuresis, and diuresis. The lower image, represented by the heart diagram, suggests that the patients with heart failure treated with SGLT2 inhibitors, regardless of the presence or absence of DM (Diabetes Mellitus), have obtained an improvement in arterial stiffness, preload and afterload reduction, and blood pressure.</p>
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12 pages, 284 KiB  
Article
The 100-Days: Physical Exercise and Challenges to Assess, Maintain and Improve Physical Fitness During Lockdown
by Tommaso Di Libero, Annalisa D’Ermo, Beatrice Tosti, Stefano Corrado, Pierluigi Diotaiuti and Angelo Rodio
Sports 2024, 12(12), 337; https://doi.org/10.3390/sports12120337 - 5 Dec 2024
Viewed by 488
Abstract
The COVID-19 pandemic reduced physical activity and increased sedentary behavior, raising health risks. To combat this, a 100-day training program was designed to maintain and improve fitness during lockdown. This program, which included a challenge with physical assessments and online sessions, aimed to [...] Read more.
The COVID-19 pandemic reduced physical activity and increased sedentary behavior, raising health risks. To combat this, a 100-day training program was designed to maintain and improve fitness during lockdown. This program, which included a challenge with physical assessments and online sessions, aimed to enhance fitness and motivation. Methods: Twenty participants (mean age 45.2 ± 12.7 years) with good baseline fitness completed strength, endurance, coordination, and flexibility exercises over 100 days, with monthly challenges. Fitness was assessed at baseline (T0), mid-program (T1), and completion (T2). Results: Males initially showed higher BMI and mild cardiovascular risks. Flexibility improved for both genders, with females increasing from 12.5 ± 4.51 cm to 14.8 ± 6.65 cm and males from 4.4 ± 6.33 cm to 8.8 ± 10.69 cm. Males’ vertical jump height increased from 20.7 ± 13.05 cm to 28.2 ± 10.49 cm. In the challenge, push-up repetitions rose for both genders, achieving excellent scores (>24 reps for females, >25 for males). Males advanced in the repeated crunch test, while females consistently excelled in the repeated squat. Weight and BMI reductions were also observed, particularly in overweight males. Conclusions: The 100-day training program, combined with the challenge, effectively sustained physical fitness and motivation among participants during pandemic-related restrictions. Notable strength and endurance improvements were observed across both genders, reinforcing the potential of interactive, remote training programs to promote physical health in periods of limited activity. Full article
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<p>The three months program is described in this image. We indicated as TEST the battery test used to evaluate the sample. This battery was performed at the beginning and the end of the program; as PUCRUSQUA, we indicated the three motor tasks: push up, crunch and squat; the PUCRUSQUA was conducted at the end of each month; the 7 days program indicated, was repeated for each week of the three months; PUCRUSQUA was conducted on a separate day, every 15th of the month, the same for the last test session.</p>
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23 pages, 2077 KiB  
Review
IgA Nephropathy: What Is New in Treatment Options?
by Roberto Scarpioni and Teresa Valsania
Kidney Dial. 2024, 4(4), 223-245; https://doi.org/10.3390/kidneydial4040019 - 3 Dec 2024
Viewed by 550
Abstract
IgA nephropathy (IgAN), first described in 1968, is one of the most common forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in 25 to 30 percent of patients within 20 to 25 years from the onset. It is histologically characterized [...] Read more.
IgA nephropathy (IgAN), first described in 1968, is one of the most common forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in 25 to 30 percent of patients within 20 to 25 years from the onset. It is histologically characterized by mesangial proliferation with prominent IgA deposition. The prognosis may be difficult to predict, but important risk factors for disease progression of kidney disease have been recognized: usually proteinuria above 0.75–1 g/day with or without hematuria, hypertension, high-risk histologic features (such as crescent formation, immune deposits in the capillary loops, mesangial deposits, glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular disease), and a reduced Glomerular Filtration Rate (GFR). In the absence of reliable specific biomarkers, current standards of care are addressed to decrease proteinuria, as a surrogate endpoint, and control blood pressure. For a long time, corticosteroids have been considered the only cure for proteinuric patients or those at risk of progression to ESKF; however, unfortunately, like other immunosuppressive agents, they are burdened with high collateral risks. Therefore, optimal treatment remains a challenge, even if, to date, clinicians have many more options available. Here, we will review the main therapies proposed, such as the stronghold of RAAS inhibition and the use of SGLT2 inhibitors; it is expected that ongoing clinical trials may find other therapies, apart from corticosteroids, that may help improve treatment, including both immunosuppressive monoclonal antibodies and other strategies. At the current time, there are no disease-specific therapies available for IgAN, because no largescale RCTs have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapy. Full article
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<p>The 4-Hit hypothesis of IGAN.</p>
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<p>Mechanism of action of SGLT2. SGLT2 inhibition affects multiple sites in the nephron. This figure summarizes the effect of SGLT2i on a single nephron. In the diabetic kidney, glomerular hyperfiltration, dependent on increased intraglomerular capillary pressure, is a detrimental process that leads to the loss of the permselective properties of the glomerular barrier to proteins, resulting in albuminuria and ESKF. In T2D patients, because of a high filtered load of glucose, reabsorption of glucose and sodium is increased in the proximal tubule via SGLT2 by up to 50%, resulting in the diminished delivery of sodium to the macula densa. Legend: ATPase = adenosine triphosphatase; GLUT2 = glucose transport 2; ESKF end-stage kidney failure; T2D: type 2 diabetes.</p>
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<p>ALGORITHM for the TREATMENT of IgAN nephropathy. LEGEND: acei: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; SGLT2: Sodium–GLucose coTransporter-2 inhibitor; AT1: angiotensin II receptor; Pozzi-Locatelli [<a href="#B39-kidneydial-04-00019" class="html-bibr">39</a>] or Manno [<a href="#B101-kidneydial-04-00019" class="html-bibr">101</a>] scheme, MASP: mannan-associated lectin-binding serine protease; MMF: Mycophenolate mofetil; C5: complement component C5 (the initiator of the effector terminal phase of the complement system); APRIL: A PRoliferation-Inducing Ligand; MEST-C: Oxford classification* (excluding crescents: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). Higher MEST-C scores, mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents. (* the Oxford Classification has not been validated as a tool for treatment selection).</p>
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12 pages, 973 KiB  
Article
Retrospective Study on Short-Term Reverse Cardiac Remodeling in Obese Patients Undergoing Sleeve Gastrectomy
by Carmine Izzo, Valeria Visco, Alessandra Cirillo, Davide Bonadies, Giuseppe Caliendo, Maria Rosaria Rusciano, Nicola Virtuoso, Francesco Loria, Alessia Bramanti, Eleonora Venturini, Paola Di Pietro, Vincenzo Pilone, Luigi Schiavo, Albino Carrizzo, Carmine Vecchione and Michele Ciccarelli
J. Cardiovasc. Dev. Dis. 2024, 11(12), 389; https://doi.org/10.3390/jcdd11120389 - 3 Dec 2024
Viewed by 481
Abstract
Severe obesity is closely associated with an increased risk of comorbidities and alterations in cardiac structure and function. The primary objective of this study was to investigate cardiovascular (CV) risk factors and ventricular remodeling in individuals from an obese population eligible for bariatric [...] Read more.
Severe obesity is closely associated with an increased risk of comorbidities and alterations in cardiac structure and function. The primary objective of this study was to investigate cardiovascular (CV) risk factors and ventricular remodeling in individuals from an obese population eligible for bariatric surgery. The secondary objective was to evaluate changes in anthropometric, clinical laboratory, and echocardiographic measurements 12 weeks after surgery compared to baseline values. This retrospective observational cohort study involved patients from a single specialized bariatric surgery center. A total of 35 patients were included (mean age 41.5 ± 10.3 years; BMI 43.4 ± 6.6 kg/m2), of whom 34.2% had a family history of coronary artery disease (CAD), 5.7% had a prior history of CAD, 8 had essential hypertension, 11.4% had dyslipidemia, 20% were smokers, and 8.6% were former smokers. Approximately 57% of the patients exhibited concentric left ventricular remodeling, and 14% had grade I diastolic dysfunction. At 12 weeks post-surgery, with an average weight loss of 25 kg and a mean BMI reduction of 8.5 kg/m2, 14% of the patients still exhibited concentric left ventricular remodeling, and about 11% had grade I diastolic dysfunction. Bariatric surgery contributes to the improvement of cardiac function and structure over time as a result of significant weight loss. Full article
(This article belongs to the Special Issue Risk Factors and Prevention of Cardiovascular Diseases)
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<p>Contingency retrospective data (Fisher’s exact test).</p>
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<p>BMI and RWT with simple linear regression (<span class="html-italic">p</span>-value 0.0179 * and Pearson R 0.2822). “*” stands for statistically significant.</p>
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<p>BMI and LVMI/BSA with simple linear regression (<span class="html-italic">p</span>-value 0.803 and Pearson R 0.030).</p>
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<p>Age and RWT with simple linear regression (<span class="html-italic">p</span>-value 0.037 * and Pearson R 0.249). “*” stands for statistically significant.</p>
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10 pages, 1148 KiB  
Article
Effectiveness and Predictors of Long-Term Treatment Response to Tofacitinib in Rheumatoid Arthritis Cohort: General Analysis and Focus on High-Cardiovascular-Risk Subgroup—A Multicenter Study
by Marta Priora, Andrea Becciolini, Eleonora Celletti, Myriam Di Penta, Alberto Lo Gullo, Marino Paroli, Elena Bravi, Romina Andracco, Valeria Nucera, Francesca Ometto, Federica Lumetti, Antonella Farina, Patrizia Del Medico, Matteo Colina, Viviana Ravagnani, Palma Scolieri, Maddalena Larosa, Elisa Visalli, Olga Addimanda, Rosetta Vitetta, Alessandro Volpe, Alessandra Bezzi, Francesco Girelli, Aldo Biagio Molica Colella, Rosalba Caccavale, Eleonora Di Donato, Giuditta Adorni, Daniele Santilli, Gianluca Lucchini, Eugenio Arrigoni, Emanuela Sabatini, Ilaria Platè, Natalia Mansueto, Aurora Ianniello, Enrico Fusaro, Maria Chiara Ditto, Vincenzo Bruzzese, Dario Camellino, Gerolamo Bianchi, Francesca Serale, Rosario Foti, Giorgio Amato, Francesco De Lucia, Ylenia Dal Bosco, Roberta Foti, Massimo Reta, Alessia Fiorenza, Guido Rovera, Antonio Marchetta, Maria Cristina Focherini, Fabio Mascella, Simone Bernardi, Gilda Sandri, Dilia Giuggioli, Carlo Salvarani, Veronica Franchina, Francesco Molica Colella, Giulio Ferrero, Alarico Ariani and Simone Parisiadd Show full author list remove Hide full author list
Medicina 2024, 60(12), 1982; https://doi.org/10.3390/medicina60121982 - 2 Dec 2024
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Abstract
Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying [...] Read more.
Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Safety concerns, particularly related to cardiovascular and cancer risks, prompted a need for additional investigation in real-world clinical settings. This study aimed to evaluate the long-term effectiveness and predictors of response to TOFA in two subpopulations of RA patients, categorized by differing cardiovascular risk profiles. Materials and Methods: This was a retrospective, multicenter observational study conducted as part of the BIRRA project, involving 23 Italian rheumatological referral centers. A total of 213 patients diagnosed with RA and treated with TOFA were included, with data collected on baseline demographics, clinical history, disease activity, and comorbidities. Patients were divided into high-risk and low-risk cardiovascular groups based on age (≥65 years) and the presence of at least one cardiovascular risk factor. Disease activity was assessed at baseline, 6 months, and 12 months using DAS28-ESR and DAS28-CRP. Treatment response was evaluated using intention-to-treat (ITT) and per-protocol (PP) approaches. Predictors of low disease activity (LDA) and remission were assessed through logistic regression, and clustering analyses were used to identify subgroups of patients with different therapeutic responses. Results: The study included 213 patients, with 129 classified as high-risk. For the overall cohort, patients achieving LDA and remission at 6 months were 20% and 12%, respectively, for the ITT analysis, and 29% and 14% for the PP analysis. At 12 months, 26% of patients reached LDA, and 17% achieved remission according to ITT, while for the PP analysis, these rates were 30% and 19%, respectively. No significant differences in remission or LDA rates were observed between the high-risk and low-risk groups. In the high-risk subgroup, 17% of patients reached LDA and 9% achieved remission at 6 months (ITT analysis), while these rates increased to 22% and 13%, respectively, in the PP analysis. At 12 months, 22% achieved LDA and 13% achieved remission in the ITT analysis, while 28% and 17% did so in the PP analysis. The reduction in DAS28-ESR and DAS28-CRP scores was significant (p < 0.001) across all time points for both high-risk and low-risk patients. Logistic regression analyses revealed that none of the baseline characteristics—including age, sex, comorbidities, rheumatoid factor, anti-citrullinated protein antibody (ACPA) positivity, initial disease severity, or treatment history—were significant predictors of remission or LDA at 6 or 12 months. The clustering analysis suggested that older patients, particularly those with worse baseline DAS28 scores, tended to show a less favorable response to treatment, potentially indicating impacts of age-related factors such as immunosenescence on therapeutic outcomes. Conclusions: Tofacitinib demonstrated similar effectiveness in both high- and low-risk cardiovascular subgroups of RA patients, with significant reductions in disease activity observed at both 6 and 12 months. Despite safety concerns related to cardiovascular risk, TOFA remained an effective treatment option across patient subgroups, with no significant differences in remission or LDA rates based on cardiovascular risk profiles. Age appeared to negatively impact treatment response, highlighting the role of immunosenescence in RA management. These findings support the use of TOFA as a personalized therapeutic option for RA, emphasizing the need for careful evaluation of cardiovascular and age-related risks in clinical decision-making. Full article
(This article belongs to the Special Issue Recent Advances in Autoimmune Rheumatic Diseases: 2nd Edition)
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<p>Patients achieving remission (REM), low disease activity (LDA), high/moderate (H/M) disease activity (Percentage) at T1 (6 months) and T2 (12 months). Intention to treat (ITT) and per protocol (PP) analysis.</p>
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<p>High-risk patients achieving remission (REM), low disease activity (LDA), high/moderate (H/M) disease activity (Percentage) at T1 (6 months) and T2 (12 months). Intention to treat (ITT) and per protocol (PP) analysis.</p>
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<p>Comparison of the DAS28 ESR and DAS28 CRP trend between a group of high-risk patients (according to EMA) and overall at T0 (baseline), T1 (6 months) and T2 (12 months).</p>
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17 pages, 4225 KiB  
Article
Integrating Metabolomics Domain Knowledge with Explainable Machine Learning in Atherosclerotic Cardiovascular Disease Classification
by Everton Santana, Eliana Ibrahimi, Evangelos Ntalianis, Nicholas Cauwenberghs and Tatiana Kuznetsova
Int. J. Mol. Sci. 2024, 25(23), 12905; https://doi.org/10.3390/ijms252312905 - 30 Nov 2024
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Abstract
Metabolomic data often present challenges due to high dimensionality, collinearity, and variability in metabolite concentrations. Machine learning (ML) application in metabolomic analyses is enabling the extraction of meaningful information from complex data. Bringing together domain-specific knowledge from metabolomics with explainable ML methods can [...] Read more.
Metabolomic data often present challenges due to high dimensionality, collinearity, and variability in metabolite concentrations. Machine learning (ML) application in metabolomic analyses is enabling the extraction of meaningful information from complex data. Bringing together domain-specific knowledge from metabolomics with explainable ML methods can refine the predictive performance and interpretability of models used in atherosclerosis research. In this work, we aimed to identify the most impactful metabolites associated with the presence of atherosclerotic cardiovascular disease (ASCVD) in cross-sectional case–control studies using explainable ML methods integrated with metabolomics domain knowledge. For this, a subset from the FLEMENGHO cohort with metabolomic data available was used as the training cohort, including 63 patients with a history of ASCVD and 52 non-smoking controls matched by age, sex, and body mass index from the same population. First, Partial Least Squares Discriminant Analysis (PLS-DA) was applied for dimensionality reduction. The selected metabolites’ correlations were analyzed by considering their chemical categorization. Then, eXtreme Gradient Boosting (XGBoost) was used to identify metabolites that characterize ASCVD. Next, the selected metabolites were evaluated in an external cohort to determine their effectiveness in distinguishing between cases and controls. A total of 56 metabolites were selected for ASCVD discrimination using PLS-DA. The primary identified metabolites’ superclasses included lipids, organic acids, and organic oxygen compounds. Upon integrating these metabolites with the XGBoost model, the classification yielded a test area under the curve (AUC) of 0.75. SHAP analyses ranked cholesterol, 3-methylhistidine, and glucuronic acid among the most impactful features and showed the diversity of metabolites considered for building the ASCVD discriminator. Also using XGBoost, the selected metabolites achieved an AUC of 0.93 in an independent external validation cohort. In conclusion, the combination of different metabolites has the potential to build classifiers for ASCVD. Integrating metabolite categorization within the SHAP analysis further enhanced the interpretability of the model, offering insights into metabolite-specific contributions to ASCVD risk. Full article
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<p><b>The selected metabolites’ (A) superclass distribution and (B) Spearman’s correlation network.</b> In the network, the nodes correspond to the metabolites and the edges depend on the strength of their Spearman’s correlation between two nodes. Thicker and darker edges indicate a higher pairwise correlation, whereas thinner and lighter colors indicate a lower correlation. Red edges correspond to negative correlations and blue edges to positive ones. The node colors specify the metabolite superclass, and its size increases according to the absolute strength of the edges connected to it. Metabolites marked with * represent those available also in the external validation dataset. For visualization purposes, the correlations were powered to 4 but kept the original signal. In this figure, CA stands for caproic acid.</p>
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<p>Metabolites’ superclass-informed Shapley analysis (SHAP) of the eXtreme Gradient Boosting model in the FLEMENGHO cohort with the 56 selected features. Positive SHAP values are positively associated with the ASCVD classification. Metabolites marked with * represent those that are also available in the external validation dataset. The colors of the metabolites correspond to their superclasses, as shown in <a href="#ijms-25-12905-f001" class="html-fig">Figure 1</a>.</p>
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<p><b>Shapley analysis (SHAP) of eXtreme Gradient Boosting per the metabolite’s superclass in the training FLEMENGHO set.</b> Positive SHAP values are positively associated with the ASCVD classification. Other superclasses in the panel include organoheterocyclic compounds (pink); organic nitrogen compounds (grey); nucleosides, nucleotides, and analogues (blue); homogeneous non-metal compounds (purple); and alkaloids and derivatives (red). The values in the subtitles correspond to the weighted ROC AUC during cross-validation of the training set and after hyperparameter optimization of the test set. Metabolites marked with * represent those that are also available in the external validation dataset.</p>
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<p><b>Analysis pipeline.</b> In the training cohort (FLEMENGHO), we first identified relevant metabolites to distinguish between atherosclerotic cardiovascular disease (ASCVD) cases and controls. The metabolites were selected from Partial Least Squares Discriminant Analysis (PLS-DA) and then used in eXtreme Gradient Boosting (XGBoost). Next, explainable machine learning of Shapley values (SHAP) with metabolites’ categorization was explored. After that, in an external cohort, we evaluated the same metabolites to distinguish between ischemic heart disease (IHD) cases and controls. In the figure, M stands for the number of metabolites.</p>
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14 pages, 1823 KiB  
Article
Curcumin Protects Against PM2.5−Induced Pulmonary Inflammatory and Oxidative Stress Responses by Blocking VEGFA and Renin−Angiotensin System (RAS) Components Expression
by Huan Xu, Haoyang Wang, Chongchong Zhang, Zhihui Liu, Qing Wen and Lun Song
Atmosphere 2024, 15(12), 1440; https://doi.org/10.3390/atmos15121440 - 30 Nov 2024
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Abstract
Fine particulate matter (PM) 2.5 is the main component of air pollution causing pathological responses primarily in the respiratory and cardiovascular systems. Therefore, it is urgent to explore valid strategies to inhibit the adverse reactions induced by PM2.5. In our previous studies, we [...] Read more.
Fine particulate matter (PM) 2.5 is the main component of air pollution causing pathological responses primarily in the respiratory and cardiovascular systems. Therefore, it is urgent to explore valid strategies to inhibit the adverse reactions induced by PM2.5. In our previous studies, we have revealed that intratracheal instillation of PM2.5 evoked airway remodeling, pulmonary inflammatory, and oxidative stress responses in rat lungs by upregulating VEGFA levels in bronchial epithelial cells and by activating ANGII/AT1R axis activation in vascular endothelial cells. The same results were obtained when human bronchial epithelial cells (Beas−2B) and human umbilical vein endothelial cells (HUVECs) cells were exposed to PM2.5 in vitro. Curcumin is a dietary polyphenol with protective properties, including anti−inflammatory and antioxidant effects. This study aims to determine the potential role of curcumin in protecting against PM2.5−induced adverse responses in the bronchial epithelium and vascular endothelium and the mechanism involved. To this end, we pretreated cells with curcumin (diluted 1000 times in sterile saline) for 2 h and then exposed them to PM2.5. Our results from RT−PCR, a luciferase reporter assay, and ELISA indicated that curcumin pretreatment effectively inhibited PM2.5−induced VEGFA elevation in Beas−2B cells by over 60% via blocking HIF1α accumulation and HIF1 transactivity, Moreover, curcumin also exerted a protective role in suppressing PM2.5−induced ANGII/AT1R axis components expression in HUVEC by over 90% via targeting the transcriptional factors, AP−1 and HIF1. Under the same conditions, curcumin pretreatment also blocked the downstream signaling events following ANGII/AT1R pathway activation, the increase in chemokines and cell adhesion molecules (sICAM−1, VCAM−1, E−Selectin, P−Selectin, IL−8, MCP−1) that drive monocyte−endothelial cell adhesion, as well as the elevated production of oxidative stress mediators (ROS and MDA) in HUVECs according to the data from immunofluorescence and flow cytometric assays. Most importantly, administration of curcumin resulted in an 80% reduction of the HIF1− and AP−1−dependent upregulation of VEGFA and AGT/AT1R axis components and impeding the resultant pro−inflammatory and oxidative responses in the lung of the rats exposed to PM2.5. Taking these data together, we disclosed the important role and mechanism of curcumin in protecting against PM2.5−induced adverse reactions in the bronchial epithelium and vascular endothelium. Curcumin might be used as a feasible and safe dietary agent to reduce the health risk of PM2.5. Full article
(This article belongs to the Special Issue Cutting-Edge Developments in Air Quality and Health)
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<p>Curcumin pretreatment inhibited PM2.5−induced VEGFA expression by suppressing HIF1 transactivities in Beas−2B cells. (<b>A</b>,<b>B</b>) Beas2B cells were pre−treated with curcumin (20 μM) or its vehicle (DMSO) followed by exposure to PM2.5. Then the protein and mRNA levels of VEGFA were detected by western−blot and RT−PCR assays at 24 h after PM2.5 exposure, respectively. (<b>C</b>) Beas−2B cells were transfected with VEGFA promoter−driven luciferase reporter plasmid followed by exposure to PM2.5 in the absence or presence of curcumin. Then the luciferase activity was detected at 24 h after PM2.5 exposure. (<b>D</b>) Beas−2B cells were treated with PM2.5 alone or curcumin + PM2.5 as described in (<b>A</b>). Then VEGFA levels in the supernatants of Beas−2B cells were determined with ELISA at 24 h after PM2.5 exposure. (<b>E</b>) Beas−2B cells were treated with PM2.5 alone or curcumin + PM2.5 as described in (<b>A</b>). Then activation status of STAT3 and the expression level of HIF−1α were detected at 24 h after PM2.5 exposure. (<b>F</b>) Beas−2B cells were transfected with HRE−driven luciferase reporter plasmid followed by exposure to PM2.5 in the absence or presence of curcumin. Then the luciferase activity was detected at 24 h after PM2.5 exposure.</p>
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<p>Curcumin inhibited PM2.5−induced RAS component expression by suppressing AP−1 and HIF1 transactivities in HUVECs, (<b>A</b>,<b>B</b>) HUVECs were pre−treated with curcumin (20μM) or its vehicle (DMSO) followed by exposure to PM2.5. Then the protein and mRNA levels of AGT and AT1R were detected by western−blot and RT−PCR assays at 24 h after PM2.5 exposure, respectively. (<b>C</b>) HUVECs were treated with PM2.5 alone or curcumin + PM2.5 as described in (<b>A</b>). Then ANGII levels in the supernatants of HUVECs were determined with ELISA at 24 h after PM2.5 exposure. (<b>D</b>) HUVECs were treated with PM2.5 alone or curcumin + PM2.5 as described in (<b>A</b>). Then the activation status of AP−1 components (c−Jun and ATF2), and the expression levels of XBP1s and HIF1α were detected at 24 h after PM2.5 exposure. (<b>E</b>,<b>F</b>) HUVECs were transfected with AP−1 or HRE−driven luciferase reporter plasmid, respectively, followed by exposure to PM2.5 in the absence or presence of curcumin. Then the luciferase activity was detected at 24 h after PM2.5 exposure.</p>
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<p>Curcumin inhibited PM2.5−induced inflammatory and oxidative stress responses in HUVECs. HUVECs were treated with PM2.5 alone or curcumin + PM2.5 as described in <a href="#atmosphere-15-01440-f002" class="html-fig">Figure 2</a> (<b>A</b>). Then (<b>A</b>) sICAM−1 levels in the supernatants of HUVECs were determined with ELISA at 24 h after PM2.5 exposure. (<b>B</b>–<b>D</b>) Cell surface levels of VCAM−1, E−selectin, and P−selectin were determined with flow cytometric assays at 24 h after PM2.5 exposure. (<b>E</b>,<b>F</b>) IL−8 and MCP−1 levels in the supernatants of HUVECs were determined with ELISA at 24 h after PM2.5 exposure. (<b>G</b>,<b>H</b>) Co−cultures of BCECF/AM−labeled U937 cells with PM2.5 or curcumin + PM2.5−treated HUVECs were performed for 12 h. Then the induced adhesion of U937 monocytes to HUVECs was detected under confocal microscopy or evaluated quantitatively with flow cytometric assay. (<b>I</b>,<b>J</b>) ROS and MDA were detected at 24 h after PM2.5 exposure.</p>
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<p>Curcumin alleviated PM2.5−induced pro−inflammatory and oxidative stress responses in the rat lung. (<b>A</b>,<b>B</b>) SD rats were left untreated or exposed to sterile saline or curcumin every 2 days starting from day 0, while the treatment of PM2.5 was carried out every 2 days starting from day 1. On day 7, the lung tissue was harvested. The pulmonary expression of VEGFA, AGT, and AT1R was analyzed using western blot assay (<b>A</b>) or in situ immunofluorescence assay (<b>B</b>), respectively. (<b>C</b>) The activation status of the AP−1 components (c−Jun and ATF2) and the accumulation of HIF1α in control, PM2.5− or PM2.5 + curcumin−treated rat lung was analyzed using western blot assay. (<b>D</b>) The expression levels of VCAM−1, P−Selectin, and E−Selectin in the vascular endothelium of rat lung were detected with in situ immunofluorescence assay. (<b>E</b>,<b>F</b>). The expression levels of chemokines (IL−8 and MCP−1) in the rat alveolar lavage fluid were determined with ELISA. (<b>G</b>) The pro−inflammatory responses in the rat lung were analyzed by H&amp;E assay. The arrows indicated monocyte adhesion and infiltration to the pulmonary bronchial epithelium and vascular endothelium. (<b>H</b>) MDA levels in the rat alveolar lavage fluid were determined. (N = 6).</p>
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20 pages, 3261 KiB  
Article
Long-Term Pentoxifylline Therapy Is Associated with a Reduced Risk of Atherosclerotic Cardiovascular Disease by Inhibiting Oxidative Stress and Cell Apoptosis in Diabetic Kidney Disease Patients
by Jie-Sian Wang, Ping-Hsuan Tsai, Kuo-Feng Tseng, Cheng-Li Lin, Fang-Yu Chen, Chiz-Tzung Chang and Ming-Yi Shen
Antioxidants 2024, 13(12), 1471; https://doi.org/10.3390/antiox13121471 - 29 Nov 2024
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Abstract
There is limited understanding of the optimal duration and dosage of pentoxifylline (PTX) therapy required to achieve significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk, particularly in patients with diabetic kidney disease (DKD). This study aimed to evaluate the impact of long-term PTX [...] Read more.
There is limited understanding of the optimal duration and dosage of pentoxifylline (PTX) therapy required to achieve significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk, particularly in patients with diabetic kidney disease (DKD). This study aimed to evaluate the impact of long-term PTX therapy on the risk of ASCVD in patients with DKD who do not have pre-existing cardiovascular disease, while also exploring potential vascular protective mechanisms. This retrospective cohort study included data from Taiwan’s Ministry of Health and Welfare’s Health and Welfare Data Science Center. In 2008–2019, we identified and analyzed a specific sample of 129,764 patients with DKD without established cardiovascular disease. Participants were categorized according to their PTX treatment regimen. Short-term PTX users (<763 days) had a greater risk of developing ASCVD than non-PTX users. However, those who used PTX for >763 days (long-term PTX treatment) had a significantly lower risk of ASCVD, with a 47% lower cumulative incidence. A dose-dependent reduction in apoptosis was observed via Klotho treatment in cultured human aortic endothelial cells following PTX treatment. Long-term PTX treatment (24 h) caused a higher reduction in H2O2-induced reactive oxygen species production and cell apoptosis than short-term PTX treatment (2 h). In the DKD mice model experiments, PTX reduced the ASCVD risk by increasing the Klotho levels to inhibit endothelial cell damage. These findings suggest that the cardiovascular and renoprotective benefits of PTX may be extended to primary prevention strategies for people with DKD. Full article
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<p>Flowchart for the study population. DM, diabetes mellitus; CKD, chronic kidney disease; ASCVD, atherosclerotic cardiovascular disease.</p>
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<p>Cumulative incidence of ASCVD and use of pentoxifylline medication. ASCVD, atherosclerotic cardiovascular disease.</p>
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<p>Pentoxifylline reduces endothelial cell apoptosis in a dose-dependent manner. (<b>A</b>) Viability of PTX (0–500 μM)-treated endothelial cells for 24 h based on the WST-1 assay. (<b>B</b>) PTX protects HAECs treated with H<sub>2</sub>O<sub>2</sub>. Viability of endothelial cells treated with H<sub>2</sub>O<sub>2</sub> (100 µM) and PTX based on WST-1 assay. (<b>C</b>) Level of intracellular ROS measured using DCFH<sub>2</sub>-DA staining. (<b>D</b>) Hoechst 33342 and Calcein-AM staining showing cell apoptosis. (Scale bar = 10 μm.) White arrows: HAECs with condensed, fragmented nuclei were considered to be undergoing apoptosis. (<b>E</b>) Quantification of apoptotic cells. (<b>F</b>) PTX facilitates protein–protein interactions. The line size is proportional to the combined fraction of interactions. (<b>G</b>) mRNA level of Klotho. (<b>H</b>) Protein levels of Klotho, cleaved-caspase 3 (CC3), and β-actin. HAECs were exposed to PTX (6.25, 12.5, and 25 μM) before H<sub>2</sub>O<sub>2</sub> (100 μM) treatment for 24 h. (<b>I</b>) intracellular ROS levels were measured. (<b>J</b>) Cell viability. HAECs pretreated with si-Klotho with or without PTX (25 μM) prior to a 24 h treatment with H<sub>2</sub>O<sub>2</sub> (100 μM). Data are presented as mean ± SD (<span class="html-italic">n</span> = 3). The <span class="html-italic">p</span>-values were determined using a Student’s <span class="html-italic">t</span>-test. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001 vs. control group or 0 μM group; # <span class="html-italic">p</span> &lt; 0.05, ## <span class="html-italic">p</span> &lt; 0.01, ### <span class="html-italic">p</span> &lt; 0.001, #### <span class="html-italic">p</span> &lt; 0.0001 vs. H<sub>2</sub>O<sub>2</sub> group; <sup>++</sup> <span class="html-italic">p</span> &lt; 0.01 vs. PTX + H<sub>2</sub>O<sub>2</sub> group. ROS: reactive oxygen species; PTX: pentoxifylline; ctrl; control; NAC: N-acetyl cysteine; SD: standard deviation; Calcein-AM: calcein acetoxymethyl ester; HAECs: human aortic endothelial cells; DCFH<sub>2</sub>-DA: 2′,7′-dichlorofluorescein diacetate; WST-1: water-soluble tetrazolium salt; LM: light microscopy.</p>
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<p>Protective effects of short- or long-term PTX exposure on H<sub>2</sub>O<sub>2</sub>-induced endothelial cell apoptosis. HAECs were exposed to PTX (25 μM) for 2 h or 24 h before H<sub>2</sub>O<sub>2</sub> (100 μM) treatment for 24 h. (<b>A</b>) Viability of H<sub>2</sub>O<sub>2</sub> (100 μM) and PTX (25 μM)-treated endothelial cells based on the WST-1 assay. (<b>B</b>) Intracellular ROS levels in H<sub>2</sub>O<sub>2</sub> and PTX-treated cells (2 h or 24 h) were measured using DCFH<sub>2</sub>-DA staining. N-acetyl cysteine (NAC, 5 mM) as an antioxidant [<a href="#B29-antioxidants-13-01471" class="html-bibr">29</a>]. (<b>C</b>) Hoechst 33342 and Calcein-AM staining showed cell apoptosis. White arrows: HAECs with condensed, fragmented nuclei were considered to be undergoing apoptosis. (<b>D</b>) Quantification of apoptotic cells. (<b>E</b>) mRNA level of Klotho. (<b>F</b>) Protein levels of Klotho, cleaved-caspase 3, and β-actin. Data are expressed as mean ± SD (<span class="html-italic">n</span> = 3–4). The <span class="html-italic">p</span>-values were determined using a Student’s <span class="html-italic">t</span>-test. * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001 vs. control or 0 µM group; # <span class="html-italic">p</span> &lt; 0.05, ## <span class="html-italic">p</span> &lt; 0.01, ### <span class="html-italic">p</span> &lt; 0.001 vs. H<sub>2</sub>O<sub>2</sub> group. <sup>†</sup> <span class="html-italic">p</span> &lt; 0.05, <sup>††</sup> <span class="html-italic">p</span> &lt; 0.01, <sup>†††</sup> <span class="html-italic">p</span> &lt; 0.001 vs. H<sub>2</sub>O<sub>2</sub> + PTX 2 h group. PTX: pentoxifylline; ctrl; control; NAC: N-acetyl cysteine; SD: standard deviation; HAECs: human aortic endothelial cells; Calcein-AM: calcein acetoxymethyl ester; DCFH<sub>2</sub>-DA, 2′,7′-dichlorofluorescein diacetate; WST-1, water-soluble tetrazolium salt; LM: light microscopy.</p>
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<p>Pentoxifylline decreases plaque formation and cell apoptosis in DKD mice. (<b>A</b>) Schematic illustration of the experimental mouse model. (<b>B</b>) Representative images of the aorta from mice in each group stained with Oil Red O. (<b>C</b>) Quantification of the aortic root lesion sizes. (<b>D</b>) MDA levels in the aorta. (<b>E</b>) MDA levels in the kidneys. (<b>F</b>) MDA levels in plasma. (<b>G</b>) Representative images of the aorta from mice in each group stained with H&amp;E and TUNEL (Scale bar = 50 μm). (<b>H</b>) Quantification of aorta thickness. (<b>I</b>) Quantification of TUNEL-positive cells in the aorta. (<b>J</b>) mRNA levels of Klotho. (<b>K</b>) Protein levels of Klotho, cleaved-caspase 3, and β-actin in the aorta of experimental mice. Data are expressed as mean ± SD (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001 vs. sham group; # <span class="html-italic">p</span> &lt; 0.05, ## <span class="html-italic">p</span> &lt; 0.01, ### <span class="html-italic">p</span> &lt; 0.001 vs. DM group; <sup>†</sup> <span class="html-italic">p</span> &lt; 0.05, <sup>††</sup> <span class="html-italic">p</span> &lt; 0.01, <sup>†††</sup> <span class="html-italic">p</span> &lt; 0.001, <sup>††††</sup> <span class="html-italic">p</span> &lt; 0.0001 vs. DKD group. DM group: STZ-induced mice; DKD group: 5/6Nx in STZ-induced mice. DKD, diabetic kidney disease; MDA, malondialdehyde; H&amp;E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; STZ, streptozotocin; SD: standard deviation; PTX, pentoxifylline; Ctrl, control; 5/6 Nx, 5/6 nephrectomy; DM, diabetes mellitus; SD, standard deviation.</p>
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16 pages, 1589 KiB  
Review
Pleiotropic Effects of PCSK9 Inhibitors on Cardio-Cerebrovascular Diseases
by Zhenzhen Li, Lin Zhu, Yeqiong Xu, Yiting Zhang, Yukai Liu, Huiling Sun, Shuo Li, Meng Wang, Teng Jiang, Junshan Zhou and Qiwen Deng
Biomedicines 2024, 12(12), 2729; https://doi.org/10.3390/biomedicines12122729 - 28 Nov 2024
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Abstract
Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates [...] Read more.
Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates the risk of both cardiac and cerebral vascular events, thereby enhancing patient prognosis. Consequently, LDL-C reduction remains a pivotal therapeutic strategy for CVD and IS. However, despite intensive statin therapy, a significant proportion of high-risk hypercholesterolemic patients fail to achieve sufficient reductions in LDL-C levels. In response to this challenge, an inhibitor targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed as a therapeutic intervention for hyperlipidemia. Numerous randomized controlled trials (RCTs) have conclusively demonstrated that the combination of PCSK9 inhibitors and statins significantly enhances prognosis not only in patients with CVD, but also in those afflicted with symptomatic intracranial artery stenosis (sICAS). PCSK9 inhibitors significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with LDLRs. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Besides significantly reducing LDL-C levels, PCSK9 inhibitors also demonstrate anti-inflammatory and anti-atherosclerotic properties while promoting plaque stabilization and inhibiting platelet aggregation and thrombosis. This article aims to provide a comprehensive review based on the relevant literature regarding the evolving understanding of pleiotropic effects associated with PCSK9 inhibitors, particularly focusing on their impact on the cardiovascular system and central nervous system. Full article
(This article belongs to the Section Cell Biology and Pathology)
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<p><b>Timeline of research on PCSK9.</b> In 2001, PCSK9 was initially discovered. In 2007, the structure of PCSK9 was revealed binding to LDLR. In 2015, PCSK9 mAbs was first approved by FDA/EMA. Subsequently, a series of phase I, II, and III trials were conducted. In 2021, PCSK9 siRNA was approved by FDA/EMA. Abbreviations: PCSK9, proprotein convertase subtilisin-kexin type 9. LDLR, low-density lipoprotein cholesterol receptor. PCSK9 KO, PCSK9 knockout. PCSK9 mAbs, monoclonal antibodies against PCSK9. FDA, the Food and Drug Administration. EMA, the European Medicines Agency. PCSK9 siRNA, PCSK9 small interfering RNA. The figure was created with BioRender.com.</p>
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<p><b>PCSK9 inhibitors in lipid metabolism and anti-atherosclerotic and anti-inflammatory effects.</b> First, PCSK9 binds to the LDLR, leading to a reduction in LDLR expression. Consequently, the ability to eliminate LDL-C diminishes. PCSK9 mAbs significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with the LDLR. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Second, PCSK9 siRNA effectively inhibits endothelial cell apoptosis by reducing the expression of pro-apoptotic proteins such as Bax, Caspase3, and Caspase9. Conversely, it is observed that the level of anti-apoptotic protein Bcl-2 is increased, ultimately reducing the development of atherosclerosis. Third, PCSK9 mAbs effectively suppress monocyte adhesion to endothelial cells through reducing the expression of NF-κB, eNOS, and ICAM-1. Ultimately, this leads to a decrease in both the size of atherosclerotic plaques formed as well as an attenuation of the inflammatory response. In addition, macrophage inflammatory responses induced by ox-LDL play a pivotal role in the pathogenesis of atherosclerosis. PCSK9 may accelerate inflammation of atherosclerotic plaques through activating the TLR 4/NF-κB pathway and promoting interactions between SRs on macrophage surfaces. PCSK9 siRNA reduces macrophage numbers and attenuates inflammatory response triggered by ox-LDLs in macrophages. Consequently, there is a subsequent decrease in the expression of vascular inflammation regulators such as TNF-α, IL-1β, and MCP-1. Abbreviations: PCSK9, proprotein convertase subtilisin-kexin type 9. LDL, low-density lipoprotein cholesterol. LDLR, low-density lipoprotein cholesterol receptor. PCSK9 mAbs, monoclonal antibodies against PCSK9. siRNA, small interfering RNA. NF-κB, nuclear factor kappa-B. eNOS, endothelial nitric oxide synthase. ICAM-1, intercellular cell adhesion molecule-1. ox-LDL, oxidized low-density lipoprotein. TLR 4, Toll-like receptor 4. TNF-α, tumor necrosis factor-alpha. IL-1β, interleukin 1 beta. MCP-1, monocyte chemoattractant protein-1. The figure was created with BioRender.com.</p>
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<p><b>PCSK9 inhibitors in antiplatelet aggregation and antithrombosis</b>. PCSK9 activates CD36 and LOX-1 receptors in platelets, thereby enhancing platelet activation. The interaction between CD36 and ox-LDL triggers signaling pathways, leading to the expression of P-selectin and activation of integrin αIIb β3 (the receptor for fibrinogen). This promotes the formation of platelet–leukocyte complexes through P-selectin and cross-linking adjacent platelets via fibrinogen. Additionally, the binding of ox-LDL to LOX-1 triggers the activation of integrins αIIbβ3 and α2β1, subsequently inducing alterations in platelet morphology and aggregation, ultimately facilitating thrombosis. In addition, deficiency in PCSK9 is associated with protection against venous thrombosis by reducing leukocyte recruitment and NET formation at the site of thrombosis. Abbreviations: PCSK9, proprotein convertase subtilisin-kexin type 9. ox-LDL, oxidized low-density lipoprotein. CD36, platelet glycoprotein 4, a scavenger receptor (SR). LOX-1, lectin-like oxidized low-density lipoprotein receptor-1. αIIbβ3 and α2β1, the receptors for fibrinogen. The figure was created with BioRender.com.</p>
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<p><b>Pleiotropic effects of PCSK9 inhibitors on cardio-cerebrovascular diseases</b>. PCSK9 inhibitors not only influence lipid metabolism but also exert effects on the cardiovascular system, central nervous system, and other physiological processes. Abbreviations: PCSK9, proprotein convertase subtilisin-kexin type 9. CVD, cardiovascular disease. IS, ischemic stroke. The figure was created with BioRender.com.</p>
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Article
Daily Intake of Two or More Servings of Vegetables Is Associated with a Lower Prevalence of Metabolic Syndrome in Older People
by Gloria Cubas-Basterrechea, Iñaki Elío, Carolina González Antón and Pedro Muñoz Cacho
Nutrients 2024, 16(23), 4101; https://doi.org/10.3390/nu16234101 - 28 Nov 2024
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Abstract
Objectives: We sought to examine the correlation between the recommended consumption of at least two servings (400 g) of vegetables per day and the prevalence of metabolic syndrome (MetS) in an elderly population. Methods: This observational, cross-sectional, and descriptive study was conducted with [...] Read more.
Objectives: We sought to examine the correlation between the recommended consumption of at least two servings (400 g) of vegetables per day and the prevalence of metabolic syndrome (MetS) in an elderly population. Methods: This observational, cross-sectional, and descriptive study was conducted with 264 non-institutionalized people aged 65 to 79 years old. We adhered to the recommended guidelines for vegetable intake from the MEDAS-14 questionnaire, which has been validated for elderly populations at high cardiovascular risk. Diagnoses of MetS were made based on the criteria set forth by the International Diabetes Federation (IDF). Results: Among 264 individuals, who had a mean age of 71.9 (SD: 4.2) and comprised 39% men, the prevalence of MetS was 40.2%. A total of 17% of the participants adhered to the recommended vegetable consumption. Consuming the recommended amount of vegetables was correlated with a 19% reduction in the prevalence of MetS, to 24.4% from 43.4% among those with low vegetable consumption (p < 0.05). A main finding was that inadequate vegetable consumption was significantly associated with a higher prevalence of MetS (OR: 2.21; 95% CI: 1.06–4.63; p = 0.035), considering potential influences by nutritional (consumption of fruit and nuts) and socio-demographic (sex, age, and level of education) covariates. Conclusions: A beneficial inverse correlation was identified between the recommended vegetable intake and the prevalence of MetS. In contrast, inadequate vegetable consumption was revealed as an independent variable associated with the prevalence of MetS. Considering the very low adherence to the recommended vegetable intake we observed, encouraging increased vegetable consumption among older individuals, who have a high prevalence of MetS, is advisable. Full article
(This article belongs to the Special Issue Diet and Nutrition: Metabolic Diseases)
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<p>Association between the frequency of vegetable consumption and the prevalence of metabolic syndrome.</p>
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