Search Results (92)

Arteriogenesis, the growth of pre-existing arterioles into functional collateral arteries, represents a key adaptive response to severe arterial stenosis. This process is driven by hemodynamic forces and a tightly coordinated inflammatory cascade. Here, we investigated the effects of pharmacological stimulation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway using the phosphodiesterase-5 (PDE5) inhibitor Sildenafil on collateral vessel growth in a murine model of femoral artery ligation (FAL). Flow cytometric analyses revealed that Sildenafil treatment significantly enhanced platelet–leukocyte aggregate formation, a prerequisite for the subsequent initiation of a localized perivascular inflammation. Histological and immunofluorescence analyses further demonstrated a marked increase in mast cell recruitment and degranulation at early time points (days 1 and 3 post-FAL). In addition, Sildenafil promoted perivascular macrophage accumulation on days 3 and 7, with a pronounced shift toward an M2-like pro-regenerative polarization state, ultimately resulting in the enhanced proliferation of vascular cells and the enlargement of collateral diameters. Together, these findings identify Sildenafil as a potent enhancer of arteriogenesis through coordinated immune cell activation, stimulating vascular cell proliferation along with positive collateral outward remodeling. Thus, Sildenafil emerges as a promising therapeutic candidate to promote collateral artery growth in cardiovascular occlusive diseases. Full article

Acute respiratory distress syndrome (ARDS) is a fatal inflammatory lung disorder with few effective treatments. Hyaluronan (HA), a major extracellular matrix component, exhibits diverse biological activities depending on its molecular weight. This study aimed to evaluate the therapeutic potential of HA of various molecular weights in a rat model of ARDS. ARDS was induced in rats via the intratracheal instillation of 5 mg of bleomycin. Seven days later, when ARDS symptoms developed, low (LHA), medium (MHA), high (HHA), and mixed (MIX HA) hyaluronan were intratracheally administered seven times from Days 7 to 28. On Day 7, arterial oxygen saturation (SpO₂) and the partial pressure of oxygen (PaO₂) decreased, carbon dioxide levels increased, the respiratory rate increased, and extensive lung cell infiltration was observed, confirming successful ARDS induction. LHA and MIX HA improved the SpO₂ and PaO₂, and the latter increased lung and alveolar volume, reduced infiltration, and normalized breathing. All HA types attenuated collagen deposition and M1 macrophage activity, while MIX HA enhanced M2 polarization and upregulated MMP-2, MMP-9, and TLR-4. LHA increased VEGF and EGF expression. These findings demonstrate that different-weight HAs provide partial ARDS protection via distinct mechanisms. MIX HA shows synergistic effects, restoring and improving lung structure and function, respectively, representing a promising ARDS therapy. Full article

Inflammation plays a pivotal role in the pathogenesis of acute coronary syndromes (ACS), contributing to plaque instability, thrombosis, and myocardial injury. This review aims to comprehensively examine the inflammatory mechanisms underlying ACS and evaluate current and emerging anti-inflammatory therapeutic strategies. We conducted a comprehensive literature review examining the role of inflammatory pathways in ACS pathophysiology, including innate and adaptive immune responses, key inflammatory mediators, and cellular mechanisms. We analyzed current evidence for anti-inflammatory therapies and their clinical outcomes in ACS management. Inflammatory processes in ACS involve complex interactions between innate immune cells (neutrophils, macrophages, monocytes) and adaptive immune cells (T lymphocytes, B cells). Key mechanisms include neutrophil extracellular trap (NET) formation, macrophage polarization, T cell subset imbalances (Th1/Th17 predominance with regulatory T cell dysfunction), and complement activation. Inflammatory biomarkers such as C-reactive protein, interleukin-6, and NET-specific markers demonstrate prognostic value. Anti-inflammatory therapies including colchicine, canakinumab (IL-1β inhibition), and methotrexate have shown cardiovascular benefits in clinical trials. Emerging targets include NET inhibition, T cell modulation, and precision inflammatory profiling approaches. Inflammation represents a critical therapeutic target in ACS beyond traditional risk factor modification. While colchicine and IL-1β inhibition have demonstrated clinical efficacy, future strategies should focus on precision medicine approaches targeting specific inflammatory pathways based on individual patient profiles. Integration of anti-inflammatory therapy with lipid management and antithrombotic strategies offers promise for improving ACS outcomes through comprehensive targeting of the multifactorial pathophysiology underlying coronary artery disease. Full article

Efferocytosis, the process by which macrophages clear apoptotic cells, plays a vital role in maintaining immune homeostasis. This study explores the influence of inflammatory cytokines—tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β)—on efferocytosis dysregulation in coronary artery disease (CAD). Peripheral blood samples were collected from 27 non-obstructive and 29 obstructive CAD patients to isolate monocytes, which were then differentiated into M1 and M2 macrophages using specific cytokine stimuli. These macrophages were transfected with TNF-α and TGF-β siRNA to assess cytokine impact on efferocytosis. Expression levels of the efferocytosis receptor MERTK and its regulatory protease ADAM17 were quantified via qPCR. Statistical analysis revealed significantly higher MERTK expression in M2 macrophages compared to M1 (p = 0.002). Notably, TNF-α silencing enhanced efferocytosis in M2 macrophages, with increased clearance of early apoptotic bodies in non-obstructive CAD and late apoptotic bodies in obstructive CAD (both p < 0.001). These findings suggest that macrophage phenotype, apoptotic stage, and cytokine environment influence efferocytosis efficiency and may involve pathways beyond MERTK-ADAM17. They offer preliminary mechanistic insights into cytokine-mediated modulation of efferocytosis in CAD. Further in vivo studies are needed to confirm these observations and evaluate their relevance for future therapeutic strategies. Full article

Background/Objectives: The efficacy of ST909, an innate immune cGAS/STING/IRF3 pathway regulator, against ischemic brain injury was investigated, and its pharmacological mechanism was elucidated. Methods: The efficacy and pharmacological mechanism of ST909 in ischemic brain injury were evaluated using the middle cerebral artery occlusion (MCAO) rat model, with brain tissue staining, MRI, behavioral tests (balance beam, screen), and ELISA detection of brain injury markers (neuron-specific enolase [NSE], homocysteine [Hcy], and S100β). Results: ST909 significantly reduces cerebral ischemic area, restores blood–brain barrier integrity, and improves neuronal function, outperforming clinical drugs (3-n-butylphthalide and edaravone) in preclinical models. ST909 markedly reduces neuroinflammation while upregulating neurotrophic factors (e.g., BDNF, NGF) in brain tissue. Through PI3K/Akt pathway activation in microglia, ST909 induces M1-to-M2 phenotype polarization, rebalances the M1/M2 ratio, and enhances secretion of anti-inflammatory cytokines and neurotrophic factors, thereby reducing chronic inflammation and promoting neurological recovery. These findings elucidate ST909’s potential pharmacological mechanism against ischemic brain injury, involving microglial polarization via STING/IRF3 and PI3K/Akt pathway. Conclusions: ST909 has a significant pharmacological effect on improving the ischemic area of the brain and repairing the function of the brain neuronal tissues. Targeting the STING/IRF3 pathway, ST909 exhibits neurorestorative potential in post-ischemic brain injury recovery. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) remains a major challenge in the treatment of ischemic stroke, characterized by intertwined oxidative stress and neuroinflammation. Existing monotherapies often fail to address this dual pathology effectively. We developed PLSCZ, a biomimetic nanoplatform integrating a catalytic core of imidazolate framework-8 (ZIF-8)-encapsulated superoxide dismutase (SOD) and catalase (CAT) enzymes with a hybrid platelet membrane shell. This design strategically employs metal–organic frameworks (MOFs) to effectively overcome the critical limitations of enzyme instability and provide a cascade catalytic environment, while the biomimetic surface modification enhances targeting capability, thereby enabling dual-pathway intervention against CIRI. Methods: PLSCZ was engineered by co-encapsulating SOD and CAT within a ZIF-8 core to form a cascade antioxidant system (SCZ). The core was further coated with a hybrid membrane composed of rapamycin-loaded phospholipids and natural platelet membranes. The nanoparticle was characterized by size, structure, enzyme activity, and targeting capability. In vitro and in vivo efficacy was evaluated using oxygen–glucose deprivation/reoxygenation (OGD/R) models and a transient middle cerebral artery occlusion/reperfusion (tMCAO/r) rat model. Results: In vitro, PLSCZ exhibited enhanced enzymatic stability and cascade catalytic efficiency, significantly scavenging reactive oxygen species (ROS) and restoring mitochondrial function. The platelet membrane conferred active targeting to ischemic brain regions and promoted immune evasion. PLSCZ effectively polarized microglia toward the anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine levels, restored autophagic flux, and preserved blood–brain barrier integrity. In vivo, in tMCAO/r rats, PLSCZ markedly targeted the ischemic hemisphere, reduced infarct volume, improved neurological function, and attenuated neuroinflammation. Conclusions: By synergistic ROS scavenging and anti-inflammatory action, the PLSCZ nanozyme overcomes the limitations of conventional monotherapies for CIRI. This biomimetic, multi-functional platform effectively reduces oxidative stress, modulates the phenotype of microglia, decreases infarct volume, and promotes neurological recovery, offering a promising multi-mechanistic nanotherapeutic for CIRI and a rational design model for MOF-based platforms. Full article

Peripheral artery disease is a common manifestation of atherosclerosis, characterized by insufficient tissue perfusion and chronic ischemia. Arteriogenesis and angiogenesis are essential endogenous mechanisms to restore blood flow and limit ischemic injury. The metalloprotease ADAMTS13, known for cleaving ultra-large von Willebrand factor, has been implicated in thrombotic and inflammatory regulation. However, its role in ischemic vascular remodeling remains unclear. Using a murine hind limb ischemia model, we investigated the effect of ADAMTS13 deficiency on arteriogenesis and angiogenesis by comparing male ADAMTS13^−/− and wild-type control mice. Perfusion recovery, vascular cell proliferation, immune cell infiltration, and thrombotic activity were evaluated using laser Doppler measurements, immunohistochemical analysis of adductor and gastrocnemius muscle tissues, and in vivo microscopy. ADAMTS13 deficiency did not impair perfusion recovery, collateral artery growth, or capillarization. While platelet adhesion was slightly increased in ADAMTS13^−/− mice, no thrombotic occlusions were observed. Inflammatory responses, including macrophage and neutrophil infiltration as well as macrophage polarization, were largely unaffected. Despite previous in vitro evidence indicating an angiogenic role for ADAMTS13, its absence did not compromise angiogenesis in vivo. Our findings suggest that ADAMTS13 does not play a critical role in ischemia-related angiogenesis and arteriogenesis under sterile conditions and may be relevant only in contexts involving acute and sufficiently strong thromboinflammatory stimuli. Full article

Background: Lipoprotein(a) [Lp(a)]-induced inflammation contributes to coronary artery spasm (CAS) by the contraction of vascular smooth muscle cells. However, the interaction between Lp(a) and soluble CD36 (sCD36)/interleukin (IL)-6/RAS Homolog Family Member A (RhoA)-GTP signaling pathway has not been evaluated. Methods: We investigated the relevance of Lp(a)/CD36 signaling in CAS patient monocyte-derived macrophages (PMDMs) and a human coronary artery smooth muscle cell (HCASMC) line using expression profile correlation analyses, molecular docking, RNA sequencing, flow cytometry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. Results: Plasma Lp(a) and sCD36 levels in 41 CAS patients were significantly higher (p = 0.001) and positively correlated (r² = 0.3145, p < 0.001), a trend not observed in 36 non-CAS controls. RNA sequencing indicated a significant co-overexpression of CD36 and RhoA in Lp(a)-treated CAS PMDMs and HCASMCs, of which the mRNA and protein expression of CD36 and RhoA were significantly enhanced (p < 0.001) dose-dependently. Lp(a) rather than LDL preferentially induced CD80+ PMDM (M1) polarization. In HCASMCs, the CD36 knockdown using either short hairpin RNA or natural biflavonoid amentoflavone suppressed Lp(a)-upregulated protein expression of CD36, RhoA-GTP, IL-6, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, and CD80; however, overexpressed CD36 increased their levels. Lp(a) decreased and amentoflavone increased the epigenetic expression of CD36 inhibitors, miR-335-5p, and miR-448, respectively. Reciprocally, an miRNA inhibitor or mimic could magnify or diminish Lp(a)-induced CD36, TNF-α, NF-κB and IL-6 expressions in HCASMCs, respectively. Conclusions: Elevated Lp(a) levels upregulate the CD36-dependent TNF-α/NF-κB/IL-6/RhoA-GTP signaling pathway in CAS PMDMs and HCASMCs, indicating that Lp(a)/CD36 inflammatory signaling, HCASMC activation, and macrophage M1 polarization mediate CAS development. Full article

Background and Objectives: In the current era of solid organ transplantation, the gap between available donors and patients on the waiting list is widening. Worldwide, surgeons are confronted with the challenge of optimizing the utilization of renal grafts, including the presence of multiple renal arteries (MRA), occurring in 20% to 30% of cases. The presence of a lower polar artery (LPA), which provides a significant vascular contribution to both the lower renal parenchyma and the upper urinary tract, constitutes an additional challenge, but its preservation is fundamental for the outcome of the kidney transplant (KT). The end-to-end (E/E) anastomosis with the recipient’s inferior epigastric artery (IEA) has been rarely reported in the literature, with variable results. The aim of this study is to report on technical aspects as well as on short- and long-term outcomes of this reconstruction in KT. Materials and Methods: A retrospective three-centre analysis was conducted on 13 KTs in which the graft’s LPA was anastomosed E/E with the recipient’s IEA. Results: Following an average follow-up period of 84 months, the patient and graft survival rate was 100%. Neither vascular nor urological complications were observed. Conclusions: In the event of KT with LPA, an E/E anastomosis with IEA performed with microsurgical technique is safe and provides excellent long-term results. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

Mesenchymal stem cell (MSC) transplantation has emerged as a potential therapeutic strategy for systemic sclerosis (SSc), a rare autoimmune disease characterized by inflammation, fibrosis, and vasculopathy. Recent evidence suggests that the therapeutic benefits of MSCs do not depend directly on their ability to proliferate but rather on their capacity to release extracellular nanovesicles known as exosomes (MSC-Exos). MSC-Exos are rich in bioactive molecules such as microRNAs, which can modulate gene expression and trigger significant biological responses, playing a central role in modulating immune responses, inhibiting fibrotic pathways and promoting tissue repair and angiogenesis. Preclinical studies have demonstrated that MSC-Exos can attenuate fibrosis, modulate macrophage polarization, suppress autoreactive lymphocyte activity, and even reverse pulmonary arterial hypertension in animal models of SSc. Compared to cell-based therapies, MSC-Exos offer several advantages, including lower immunogenicity and better safety profile. This review provides an overview of the immunomodulatory, antifibrotic, and angiogenic properties of MSC-Exos and explores their potential as novel cell-free therapy for SSc. Full article

The enzyme transglutaminase 2 (TG2) has an open conformation with transamidase activity which crosslinks matrix proteins contributing to fibrosis development. LDN-27219 promotes the closed conformation of TG2, which can enhance vasodilation, but its effects in renal tissue are unknown. We investigated whether LDN-27219 treatment affects albuminuria and markers of renal fibrosis as well as ex vivo vasodilatation. Male C57BL/6 mice (n = 48) underwent unilateral nephrectomy plus insertion of a deoxycorticosterone acetate pellet (DOCA group) or nephrectomy only (sham group). Both groups were randomized to intraperitoneal treatment with either LDN-27219 (8 mg/kg twice daily) or vehicle for 2 weeks. Urine albumin excretion was evaluated by metabolic cages. Kidney tissue fibrosis markers were assessed by qPCR and Western blotting, while the TG2 conformational state was evaluated using native gel electrophoresis. Collagen staining was performed using Picrosirius red and quantified under circularly polarized light. Mesenteric arteries were mounted in wire myographs for evaluation of vasorelaxation. DOCA mouse developed significant albuminuria (p < 0.001 vs. sham), but neither TG2 mRNA nor protein expression was upregulated in the kidney. However, the relative amount of TG2 in the closed conformation was higher in DOCA mice. LDN-27219 did not affect albuminuria, but LDN-27219-treated DOCA mice showed less urine production and less collagen staining than vehicle-treated DOCA mice. LDN-27219 did not affect TG2 mRNA or TG2 protein expression or mRNA of fibrosis markers. LDN-27219-treated mice had enhanced vasorelaxation to the nitric oxide donor sodium nitroprusside. In conclusion, LDN-27219 treatment in the one-kidney DOCA–salt model did not affect renal TG2 mRNA and protein expression or albuminuria but still exerted beneficial effects in terms of reduced kidney fibrosis and urine production in addition to enhanced vasodilatation. Full article

Diabetic foot ulcers (DFUs) are among the most common and debilitating complications of diabetes mellitus (DM), affecting approximately 15–25% of patients and contributing to over 85% of non-traumatic amputations. DFUs impose a substantial clinical and economic burden due to high recurrence rates, prolonged wound care, and frequent hospitalizations, accounting for billions in healthcare costs worldwide. The multifactorial pathophysiology of DFUs involves peripheral neuropathy, peripheral arterial disease, chronic inflammation, and impaired tissue regeneration. Recent studies underscore the importance of immune dysregulation—specifically macrophage polarization imbalance, regulatory T cell dysfunction, and neutrophil impairment—as central mechanisms in wound chronicity. These immune disruptions sustain a pro-inflammatory environment dominated by cytokines, such as TNF-α, IL-1β, and IL-6, which impair angiogenesis and delay repair. This review provides an updated synthesis of DFU pathogenesis, emphasizing immune dysfunction and its therapeutic implications. We examine emerging strategies in immunomodulation, regenerative medicine, and AI-based wound technologies, including SGLT2 inhibitors, biologics, stem cell therapies, and smart dressing systems. These approaches hold promise for accelerating healing, reducing amputation risk, and personalizing future DFU care. Full article

Background/Objectives: During retroperitoneal surgery, awareness of the anatomic variants of renal arteries (RAs) is essential. We aimed to determine the prevalence of early-branched (short) Ras, the bilateral morphologies of RAs in such cases, and to check for significant correlations regarding gender or side. Short RAs may be regarded as false multiple RAs and should be distinguished from true RAs. Methods: For the study, 185 archived angioCT files were randomly selected and evaluated for <1.5 cm RAs (106 male and 79 female cases). Simple regression and multiple regression tests, alongside ANOVA, were used for the statistical analysis. Results: Short RAs were found in 15/185 cases, 12 males and 3 females (8.1%), with short RAs found on the right side (2.7%), left side (4.86), and bilaterally (one case, 0.54%). The mean length was 9.46 mm. Short RAs were bifurcated in most cases and trifurcated in one case. In four other cases, peculiar RA anatomical patterns were found. They included a right RA origin of the right inferior phrenic artery, variable polar RAs, malrotated and ptotic kidneys, anteriorly dehiscent renal sinuses, and multiple RAs, including five right RAs, with the three inferior ones having precaval courses. Short RAs were not significantly related to gender (p > 0.05). There was a significant correlation between gender and right short RAs (p < 0.05). Conclusions: During renal transplant surgery, distinguishing between true and false multiple RAs is essential. While true multiple RAs may cause surgical discomfort, short RAs may be used as single RAs, but they should be carefully documented before donor nephrectomies. Full article

Noninvasive blood pressure (NIBP) device performance in dogs may be influenced by extreme pressures and altered systemic vascular resistance (SVR). This study evaluated the agreement of two NIBP devices (HDO and petMAP) with invasive blood pressure (IBP) measurements, compliance with hypertension consensus statement criteria, and their trending ability (TA) across varying blood pressure and SVR ranges in awake and anesthetized dogs. Seven healthy Beagles were studied, with IBP recorded from the dorsal metatarsal artery and NIBP cuffs placed randomly on the front limb, hind limb, or base of the tail. Cardiac output was determined by thermodilution, and the systemic vascular resistance index (SVRI) was calculated by a standard formula. Bland–Altman, concordance rate, and polar plot analyses were used for statistical analysis. A total of 752 and 640 paired measurements were obtained for HDO and petMAP, respectively. Both devices showed good agreement with IBP for mean arterial pressure (MAP) at low blood pressure and the SVRI. At high blood pressure and the SVRI, agreement weakened, with substantial underestimation of systolic arterial pressure (SAP). Both devices demonstrated moderate to good TA for MAP and SAP. Overall, the best agreement was observed for MAP at a low SVRI, while agreement was moderate at hypertension (petMAP) and a high SVRI (petMAP, HDO). Full article