Functional Remodeling Research Articles

Mechanism and Treatment of Right Ventricular Failure Due to Pulmonary Hypertension in Children

Pulmonary hypertension (PH) is a progressive disorder characterized by obstructive changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance (PVR), right ventricular (RV) strain, and eventual RV failure (RVF). Despite advancements in medical therapy, PH remains associated with significant morbidity and mortality, particularly in children. RVF is a clinical syndrome resulting from complex structural and functional remodeling of the right heart, leading to inadequate pulmonary circulation, reduced cardiac output, and elevated venous pressure. Management paradigms for pediatric PH diverge significantly from those in adults, particularly due to the predominance of congenital heart disease (CHD) and the dynamic nature of pediatric cardiovascular and pulmonary development. CHD remains a principal driver of PH in children, and its associated pathophysiology demands a nuanced approach. In patients with unrepaired left-to-right shunts, elevated pulmonary blood flow can lead to progressive pulmonary vascular remodeling and increased PVR. The postoperative persistence or progression of PH may occur if irreversible vascular changes have already developed. Current PH treatments primarily focus on reducing PVR, yet distinguishing between therapeutic approaches that target the pulmonary vasculature and those aimed at improving RV function remain challenging. In pediatric patients with progressive PH despite optimal therapy, additional targeted interventions may be necessary to mitigate RV dysfunction and disease progression. This review provides a comprehensive analysis of the mechanisms underlying RVF in PH, incorporating insights from clinical studies in adults and experimental models, while highlighting the unique considerations in children. Furthermore, it explores current pharmacological and interventional treatment strategies, emphasizing the need for novel therapeutic approaches aimed at directly reversing RV remodeling. Given the complexities of RV adaptation in pediatric PH, further research into disease-modifying treatments and innovative interventions is crucial to improving long-term outcomes in affected children.

Trimethylamine N-Oxide as a Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling After STEMI.

Despite successful primary percutaneous coronary intervention (PPCI), the incidence of heart failure (HF) following ST-elevation myocardial infarction (STEMI) remains high. We investigated using Trimethylamine N-oxide (TMAO), a gut microbiota-derived biomarker, to predict adverse functional left ventricular (LV) remodeling (FLVR) and/or diastolic dysfunction (DD), which are precursors of HF post-STEMI. This prospective, observational study enrolled 204 STEMI patients with multivessel coronary artery disease after PPCI. TMAO level was collected at the baseline and 3 months. An echocardiography was performed at the baseline and at 12 months. The primary endpoints were the number of patients developing Group 4 FLVR or ≥Grade II DD at 12 months. The median age was 65 [57.00, 76.00] and 39.7% were women. The primary endpoints occurred in 47 (23.0%) patients. Three months of TMAO can discriminate patients with/without ≥Grade II LV DD and FLVR Grade 4 with areas under the curve (AUC) of the ROC of 0.72 (95% CI: 0.63-0.81; p < 0.001) and 0.77 (95% CI: 0.63-0.91), respectively. Similar results were shown in the validation cohort of 31 patients. The addition of 3 months of TMAO to traditional risk factors significantly improved the AUCs from 0.675 to 0.736 for ≥Grade II DD and from 0.793 to 0.873 for FLVR Grade 4. In multivariable logistic regression, 3 months of TMAO was independently associated with ≥Grade II DD (OR: 1.29 (1.13-1.50), p < 0.001) and FLVR Grade 4 (OR: 1.28 (1.12-1.47), p < 0.001). Three months of TMAO is strongly associated with LV DD and adverse remodeling after STEMI and may help identifying such patients for early treatment.

Smooth leaflets with curved belly and attachment edge profiles promote adaptive remodeling in tissue-engineered heart valves: an in silico study

Abstract Tissue-engineered heart valves (TEHVs) are promising valve replacements due to their potential to regenerate into living heart valves, capable of growth and adaptation. Previous TEHVs showed promising results, but often developed progressive leaflet retraction in the long term. In a prior proof-of-concept study, we demonstrated that a novel geometry with more native-like mechanical behavior could give rise to more adaptive remodeling, thereby minimizing leaflet retraction in vivo. In the current study, we aimed to systematically analyze the impact of TEHV geometry on in vivo remodeling under both pulmonary and aortic conditions. Using a bio-inspired in silico framework, we predicted cell-driven, mechano-mediated remodeling in TEHVs post-implantation. Two parameterized valve designs were evaluated under both pulmonary and aortic pressure conditions. The results indicate that a valve design with smooth leaflets, a curved belly profile, and medium to wide attachment edge effectively minimizes stress concentrations and reduces the risk of valve insufficiency in both conditions. Additionally, this design should be tailored to specific hemodynamic conditions to prevent retraction in pulmonary applications and excessive stress concentrations in aortic applications. These insights provide essential guidelines for optimizing TEHV designs, aiming to promote functional remodeling and maintain valve functionality over time, thereby advancing the development of next-generation TEHVs with enhanced long-term outcomes.

Dynamic Functional Network Connectivity Remodeling in Cervical Spondylotic Myelopathy: Insights into Postoperative Neural Recovery.

Dynamic Functional Network Connectivity Remodeling in Cervical Spondylotic Myelopathy: Insights into Postoperative Neural Recovery.

Early Pro- and Anti-Inflammatory Immune Response Induced by Probiotic Treatment After Th9 Compression: The Interplay Between Spinal Cord and Jejunum.

The aim of our study was to limit the inflammatory response after spinal cord injury (SCI) using the probiotic strain Lacticaseibacillus paracasei Ž2 (5 × 109, CFU/mL). The relationship between pro- and anti-inflammatory markers was studied in a rat model after Th9 compression (40 g/15 min) and daily application (7 or 14 days) of probiotics. The probiotic treatment strongly reduced pro-inflammatory markers specific for microglia/macrophages (CD11b), microglia (CD68, IL-6, and iNOS), astrocytes (C1q), and TLR/NF-κB signaling pathway at lesion site and to a lesser extent cranially and caudally (0.3 cm) 7 days postinjury. In the spinal cord segments, 2-week probiotic therapy affected the expression of these targets depending on the intensity of their damage (cranially > caudally > lesion site). It was also noted that the impact of 14-day probiotic therapy in the jejunum was more pronounced than after a shorter treatment. Additionally, probiotic therapy significantly boosted the neuroprotective and anti-inflammatory milieu in the spinal cord tissues. Seven days post-SCI probiotic therapy had the potential to modulate the unfavorable environment around the injury site by increasing the anti-inflammatory microglial (IL-4Rα, TGF-β, and SOCS3) and astroglial (Ptx3) transcripts and by overexpression of immunoregulatory (TLR9 and IFN-γ) markers leading to functional remodeling and mitigation of hematuria. Longer post-SCI probiotic treatment upregulates the neuroprotective molecules at the injury site and simultaneously regulates the anti-inflammatory response in the jejunum. Herein we show that probiotic strain L. paracasei Ž2 has the potential to manage inflammation induced by SCI in both the gut and affected spinal cord within both subacute phases.

Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction.

After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.

Analysis of associations of rs2305948 genotypes of KDR (VEGFR2) gene, collateral coronary blood flow degree and statin treatment dose intensity with long-term prognosis in patients with myocardial infarction

The aim of the study was to analyze the associations of rs2305948 KDR (VEGFR2) genotypes, the state of collateral coronary blood flow, as well as the intensity of statin therapy with the development of structural and functional remodeling of the left ventricle and the onset of ischemic cardiovascular events during long-term observation in patients with myocardial infarction (MI). Material and methods. The prospective observational study included 51 patients with acute MI with ST-segment elevation. All patients underwent coronary angiography and angioplasty with stenting of the coronary arteries, as well as echocardiography and laboratory diagnostics with biomarker assessment at the hospital stage and over time (36 months). Also, the rs2305948 genotypes of the KDR (VEGFR2) gene were determined using real-time polymerase chain reaction. Two groups were allocated for further observation: 1 – with poor coronary collaterals (n = 25), 2 – with good coronary collaterals (n = 26). The duration of outpatient observation and treatment of both groups of patients with registration of ischemic cardiovascular events after MI was 108 months. Results and discussion. In group 1, compared with group 2, there was a higher incidence of severe left ventricular structural and functional remodeling (LVSFR) over 36 months (p = 0.0380), the combined end point (CEP) over 108 months (p = 0.0001), carriage of genotypes C/T and T/T rs2305948 KDR (VEGFR2) (p = 0.0002), as well as the size of the acute and past MI zone (according to the value of the LV local contractility impairment index) (p = 0.0107 and p = 0.0443, respectively); at the post-infarction stage – all echocardiographic parameters of LVSFR (p &lt; 0.05). According to the logistic regression analysis, the development of LVSFR was directly affected by hypertension (p = 0.037) and inversely by the presence of good coronary collaterals in the MI zone (p = 0.024); the onset of CEP was directly determined by the comorbidity index (p = 0.041) and inversely by the presence of good coronary collaterals (p &lt; 0.0001), as well as long-term treatment with high doses of statins (p = 0.043). Conclusions. The development of LVSFR and the onset of CEP are associated with the rs2305948 genotypes of KDR (VEGFR2), the status of coronary collaterals, the size of the MI zone, as well as long-term use of high-dose statin therapy in post-infarction patients.

Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction.

After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.

A new frontier in aortic valve treatment: surgical & echocardiographic evaluation of the Ozaki procedure

BackgroundAortic valve disease (AVD) significantly impacts global health, especially in regions where rheumatic heart disease is prevalent. Traditional aortic valve replacement options have limitations, such as the need for lifelong anticoagulation with mechanical valves and limited durability of bioprosthetic valves. The Ozaki procedure, or aortic valve neo-cuspidization using autologous pericardium, offers a potential alternative. This study evaluates the Ozaki procedure as a novel frontier in aortic valve treatment by assessing its surgical feasibility, echocardiographic outcomes, and its impact on left ventricular remodeling in patients with aortic valve disease.ResultsNineteen patients with severe AVD underwent the Ozaki procedure at Mansoura University between October 2021 and February 2022. The mean age was 54.95 ± 11.39 years, and 73.7% were male. Severe aortic stenosis was present in 63.2% of patients. Preoperative mean aortic valve area increased from 1.072 ± 1.000 cm2 to 2.864 ± 0.712 cm2 postoperatively (p < 0.001). The mean trans-aortic pressure gradient decreased from 57.58 ± 27.94 mmHg to 6.89 ± 2.233 mmHg (p < 0.001). Left ventricular mass index significantly reduced, indicating favorable cardiac remodeling over a mean follow-up of 14.75 ± 7.44 months. There were no operative mortalities or conversions to traditional valve replacement. One patient (5.3%) required temporary pacemaker insertion. Patients maintained improved valve function and clinical status with a stable aortic valve area (2.66 ± 0.45 cm2) and a low mean trans-aortic pressure gradient (5.33 ± 2 mmHg). Left ventricular mass index significantly decreased from 155.07 ± 39.80 g/m2 to 93.09 ± 27.39 g/m2.ConclusionsThis technique showed potential for favorable short-term outcomes in aortic valve disease, improving valve function and left ventricular remodeling with low complication rates. It could serve as a viable alternative to conventional aortic valve replacement, particularly for patients with small aortic annuli or those seeking a biological option without long-term anticoagulation.

Chronic treatment with photobiomodulation decreases blood pressure and improves endothelial function in ovariectomized rats.

Menopause is a natural phase, related to the aging reproductive female, characterized by decreased production of hormones steroids, mainly estrogen, involved in multiple physiological process, including cardiovascular function. This estrogen decline can lead to the development of hypertension, as well as other cardiovascular diseases. Strategies therapeutics complementary he comes winning emphasis as option for management women's insurance at menopause, such as photobiomodulation. Photobiomodulation (PBM) is the application of no invasive low light sources level, normally in the forms of low level lasers therapy (LLLT) or light emitting diodes (LEDs) that present potentials benefits therapeutics in the treatment of inflammation and stress oxidative, favoring angiogenesis, improving function cardiac and remodeling tissue. The objective of this work was to evaluate the in vivo effects of photobiomodularion on cardiovascular parameters in ovariectomy-induced menopause in female rats. Twenty-six 70-day-old female Wistar rats were randomly assigned to three experimental groups: sham (SH), ovariectomized (OVX), and ovariectomized treated with photobiomodulation (OVX + PBM). The ovaries of all animals in the OVX groups were surgically removed at 12 weeks of age. The OVX + PBM group received photobiomodulation treatment with 5.6 Joules per point at six points on the abdominal region, using a power of 100mW at a wavelength of 660nm, applied twice a week for two weeks. Blood pressure was measured using tail plethysmography, and endothelial function was assessed through vascular reactivity tests. At the end of the treatment period, the mean blood pressure in the OVX + PBM group was significantly lower than in the untreated OVX group. PBM treatment also improved endothelium-dependent vasodilation in aortic rings of OVX rats compared to the untreated OVX group, with no significant difference between the OVX + PBM and Sham groups. In addition, PBM increased serum nitric oxide (NO) levels compared to the OVX group. These results suggest that PBM treatment effectively reduced blood pressure, increased serum NO levels, and reversed endothelial dysfunction in ovariectomized rats.

Diagnosing Heart Failure with Preserved Ejection Fraction in Obese Patients.

Obesity is a current pandemic that sets all affected individuals at risk of heart failure (HF), and the majority of them will develop the clinical syndrome of HF with preserved ejection fraction (HFpEF). The diagnosis of HFpEF is challenging as it is based on the detection of subtle functional and structural remodeling of the heart that leads to diastolic dysfunction with increased left ventricular (LV) filling pressures and raised natriuretic peptides (NPs). The accurate diagnosis of HFpEF is even more challenging in patients who are obese, since the echocardiographic imaging quality may be suboptimal, the parameters for the evaluation of cardiac structure are indexed to the body surface area (BSA) and thus may underestimate the severity of the remodeling, and the NPs in patients who are obese have a lower normal threshold. Moreover, patients who are obese are prone to atrial fibrillation (AF) and pulmonary hypertension (PH), making the evaluation of diastolic dysfunction more strenuous. The current review aims to offer insights on the accurate diagnosis of HFpEF in patients who are obese in different clinical scenarios-patients who are obese in different clinical scenarios-such as in sinus rhythm, in atrial fibrillation, and in the case of pulmonary hypertension-by applying multimodality imaging and clinical diagnostic algorithms.

TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction.

Organ health and function depend on communication between cell types to coordinate tissue growth and repair. Recent studies have indicated that fibroblasts are critical to this process; however, their role in regulating inflammatory responses to injury have remained ambiguous. Here, we demonstrate that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of the inflammatory cardiac fibroblast phenotype. We find that TAK1 propagates IL-1β and TNF-α signaling in cardiac fibroblasts and coordinates the synthesis and secretion of chemokines as well as inflammatory and pro-resolving lipid mediators. Deletion of TAK1 in fibroblasts decreased immune cell recruitment after MI, which was associated with improved cardiac structural and functional remodeling in male mice. Nevertheless, we found the effects of TAK1 deletion to be sexually dimorphic in nature, providing support to the idea that the protected phenotype of the female sex may be based in disparate immune and inflammatory responses. Moreover, TAK1 signaling controlled the acquisition of novel markers of the inflammatory fibroblast phenotype, having a biological basis in redox stress, chemokine and lipid mediator biosynthesis, metalloproteinase activity, and damage-associated molecular pattern recognition. Collectively, these results further resolve the nature and function of inflammatory cardiac fibroblasts in cardiac responses to injury and identify TAK1 signaling in fibroblasts as a potential target for therapy.

Frozen Shoulder as a Metabolic and Immune Disorder: Potential Roles of Leptin Resistance, JAK-STAT Dysregulation, and Fibrosis.

Frozen shoulder (FS) is a complex and multifactorial condition characterized by persistent inflammation, fibrosis, and metabolic dysregulation. Despite extensive research, the underlying drivers of FS remain poorly understood. Recent findings indicate the coexistence of pro-inflammatory and fibrosis-resolving macrophages within affected tissues, suggesting a dysregulated immune response influenced by metabolic and neuroendocrine factors. This review proposes that leptin resistance, a hallmark of metabolic syndrome and chronic inflammation, may play a central role in FS pathogenesis by impairing macrophage polarization, perpetuating inflammation, and disrupting fibrosis resolution. The JAK-STAT signaling pathway, critically modulated by leptin resistance, may further contribute to immune dysregulation by sustaining inflammatory macrophage activation and interfering with tissue remodeling. Additionally, FS shares pathogenic features with fibrotic diseases driven by TGF-β signaling, mitochondrial dysfunction, and circadian disruption, further linking systemic metabolic dysfunction to localized fibrotic pathology. Beyond immune and metabolic regulation, alterations in gut microbiota, bacterial translocation, and chronic psychosocial stress may further exacerbate systemic inflammation and neuroendocrine imbalances, intensifying JAK-STAT dysregulation and leptin resistance. By examining the intricate interplay between metabolism, immune function, and fibrotic remodeling, this review highlights targeting leptin sensitivity, JAK-STAT modulation, and mitochondrial restoration as novel therapeutic strategies for FS treatment. Future research should explore these interconnections to develop integrative interventions that address both the metabolic and immune dysregulation underlying FS, ultimately improving clinical outcomes.

GRK2 and Mitochondrial Dynamics in Cardiovascular Health and Disease

G protein-coupled receptors (GPCRs) represent a family of membrane proteins that regulate several cellular processes. Among the GPCRs, G protein-coupled receptor kinases (GRKs) regulate downstream signaling pathways and receptor desensitization. GRK2 has gained significant interest due to its cardiovascular physiology and pathological involvement. GRK2’s presence in cardiac tissue and its influence on cardiac function, β-adrenergic signaling, and myocardial remodeling underlies its involvement in cardiovascular diseases such as heart failure and ischemia. GRK2’s canonical role is receptor desensitization, but emerging evidence suggests its involvement in mitochondrial dynamics and bioenergetics, influencing processes such as oxidative phosphorylation, reactive oxygen species production, and apoptosis. Moreover, GRK2’s localization within mitochondria suggests a direct role in regulating mitochondrial health and function. Notably, while GRK2 inhibition seems to be a therapeutic approach to heart failure, its precise role in mitochondrial dynamics and pathology needs further investigation. This review explores the complex relationship between mitochondrial function and GRK2 and clarifies the implications for cardiovascular health. Cardiovascular medicine might greatly benefit from future studies that focus on understanding the processes behind GRK2–mitochondrial crosstalk to develop personalized therapies

Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function

Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery's media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1, Srebf1, Scd1, Scd2, Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.

Structural and functional remodeling for elite cyclists during exercise; pressure-volume loops and hemodynamic forces analysis.

The study was designed to investigate the pattern of intraventricular hemodynamic forces (HDFs) and myocardial performance during exercise in elite cyclists (ECs). Transthoracic stress echocardiography was performed on 19 ECs and 13 age-matched sedentary controls (SCs) at three incremental exercise intensities based on heart rate reserve (HRR). Left ventricular (LV) HDFs were computed from echocardiography long-axis datasets using a novel technique based on endocardial boundary tracking, both in apex-base and latero-septal directions. Pressure volume (PV) loops were noninvasively investigated using the single-beat approach. Differences between groups were investigated using mixed model analysis. At PV loops, EC showed a steeper increase in stroke work compared with SC, without acute changes in ventricular capacity (EDVI20). Contractility, measured as ventricular elastance (Ees), increased during exercise with no difference between groups (P = 0.625). At rest, EC had significantly lower heart rates and generated lower HDF than SC. However, during exercise, the pressure gradient developed by EC in systole, and therefore systolic HDF, was significantly higher than that developed by SC (P < 0.009), also showing a greater elastic rebound in late systole compared with SC (P < 0.032). Importantly, during early diastolic filling, EC showed lower HDF deceleration than SC (P < 0.043), indicating a facilitated relaxation of the left ventricle. Analysis of the HDF pattern during exercise shows the functional changes that occur in EC, characterized by increased HDF generation in systole, and facilitated relaxation in early diastole. This is the first time LV structural and functional remodeling is reported for elite cyclists during exercise.NEW & NOTEWORTHY Analysis of the hemodynamic forces shows that the functional changes that occur in elite cyclists during exercise are characterized by increased hemodynamic forces generation in systole, and facilitated relaxation in early diastole.

Cell death crosstalk in respiratory diseases: unveiling the relationship between pyroptosis and ferroptosis in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.

Identification of differentially expressed genes in resting human skeletal muscle of sedentary versus strength and endurance-trained individuals using bioinformatics analysis and in vitro validation

Understanding the molecular mechanisms underlying skeletal muscle adaptation to different training regimens is essential for advancing muscle health and performance interventions. The aim of this study was to investigate molecular and genetic adaptations in the resting skeletal muscle of sedentary individuals compared to strength- and endurance-trained athletes using bioinformatics and in vitro validation. Differentially expressed genes (DEG) analysis of the GSE9405 dataset was conducted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, followed by protein-protein interaction (PPI) network analysis and receiver operating characteristic (ROC) analysis. To validate the bioinformatics findings, the expression of two identified genes was assessed using real-time polymerase chain reaction (PCR) in professional athletes and age-matched non-athletes. Analysis of RNA expression profiles from the GSE9405 dataset identified 426 DEGs, with 165 upregulated and 261 downregulated in trained individuals. Enrichment analysis highlighted pathways related to metabolic efficiency, mitochondrial function, and muscle remodeling, all crucial for athletic performance. PRKACA and CALM3 were identified as key upregulated genes in trained individuals with central roles in these pathways. The area under the curve (AUC) values for CALM3 and PRKACA were 0.8558 and 0.8846, respectively, for differentiating the two groups. Validation in human samples confirmed that CALM3 expression was significantly higher in athletes (p=0.001), suggesting its critical role in muscle adaptation. However, PRKACA expression differences between the groups were not statistically significant (p=0.321). These findings provide insights into gene-level responses to long-term training, offering a basis for targeted interventions to enhance muscle health and athletic performance.

Right atrial strain in Anderson-Fabry disease.

To date, only limited data are available on right atrium (RA) morphofunctional remodeling in Fabry disease (FD). We aimed to investigate RA structural and functional remodeling in patients with FD vs. healthy controls using 2D speckle tracking echocardiography (STE) and to explore whether any differences exist in FD patients with and without left ventricular hypertrophy (LVH). We prospectively enrolled patients with FD and controls matched for age, sex, and cardiovascular risk factors. Patients with FD were divided in two groups according to the presence/absence of LVH (LVH+: left ventricular wall thickness >12 mm). All patients underwent standard echocardiography and STE analysis investigating the mechanics of all cardiac chambers, including RA reservoir, contractile and conduit strain. A total of 64 patients with FD (50% males; mean age 50 ± 17 years; 51.5% LVH+) and 64 control patients were included in the study. Focusing on right chambers, RA and right ventricular (RV) dimensions were similar between FD and controls. No differences were found for tricuspid annular plane systolic excursion (p = 0.073) and RV fractional area change (p = 0.461), while RV systolic Tissue Doppler velocity was reduced in patients with FD (p = 0.041). STE analysis revealed impaired strain values for all cardiac chambers in FD vs controls, specifically: left ventricular global longitudinal strain (LV-GLS, p < 0.001), left atrial (LA) reservoir strain (p = 0.001), conduit strain (p = 0.012), and contractile strain (p < 0.001), RV-GLS and RV free wall strain (p < 0.001). Similarly, all RA strain phases were significantly reduced in patients with FD compared with control patients (RA reservoir 27.4 ± 11.1 vs. 41.9 ± 8.3%, p < 0.001; RA contractile 9.9 ± 5.1 vs. 18.0 ± 4.9%, p < 0.001; RA conduit 19.1 ± 8.1 vs. 24.1 ± 8.1%, p = 0.001). When comparing FD patients without LVH to controls, it was found that RA reservoir and contractile strains were significantly reduced in the former (p < 0.001). In multivariable linear regression analyses, LA reservoir strain (p = 0.010) and LV-GLS (p = 0.044) emerged as independent correlates of RA mechanics after adjustments were made for RA dimensions, RV systolic function parameters and hypertrophy, and LV maximal wall thickness. In FD impaired RA strain is a common finding. RA reservoir and contractile strains are reduced in FD patients even before LVH ensues, as compared to controls. LA reservoir strain and LV-GLS show an independent correlation with RA reservoir strain.

Nitric Oxide-Producing Multiple Functional Nanoparticle Remodeling Tumor Microenvironment for Synergistic Photodynamic Immunotherapy against Hypoxic Tumor.

The treatment of pancreatic cancer faces significant challenges due to connective tissue hyperplasia and severe hypoxia. Unlike oxygen-dependent Type II photosensitizers, Type I photosensitizers can produce a substantial amount of reactive oxygen species, even under hypoxic conditions, making them more suitable for photodynamic therapy of pancreatic cancer. However, the dense extracellular matrix of pancreatic cancer limits the penetration efficiency of photosensitizers, and the presence of immunosuppressive cells in the tumor microenvironment reduces the therapeutic effect. To address these challenges, we designed the photoimmunotherapeutic M1@PAP nanoparticles composed of Type I photosensitizer and anti-PD-L1 siRNA (siPD-L1), which was encapsulated into M1 macrophage membrane vesicles. In this system, pyropheophorbide-a (PPA) was covalently conjugated to poly-l-arginine (Arg9). Notably, it was capable of generating sufficient superoxide anions under hypoxic conditions, thereby functioning as a Type I photosensitizer. Furthermore, Arg9 acted as a nitric oxide (NO) donor, enhancing the penetration efficiency of the nanophotosensitizer by inhibiting cancer-associated fibroblast (CAF) activation and decomposing the tumor extracellular matrix. Additionally, M1 macrophage membrane vesicles provided active targeting capabilities and reeducated immunosuppressed M2 macrophages. The reversal of immunosuppressive microenvironment further promoted the efficacy of anti-PD-L1 siRNA immunotherapy, showing great potential in synergistic photodynamic immunotherapy against hypoxic pancreatic tumor.