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This study tested the hypothesis that Jagged2/Notches promoted the endothelial‐mesenchymal transition (endMT)‐mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA‐binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N‐cadherin/vimentin/fibronectin/α‐SMA/p‐Smad2) were significantly reduced, whereas the endothelial‐phenotype markers (CD31/E‐cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N‐cadherin/vimentin/fibronectin/α‐SMA/p‐Smad2) were significantly upregulated in TGF‐ß/monocrotaline‐treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right‐ventricular systolic‐blood‐pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham‐control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß‐MHC)/pressure‐overload (BNP)/oxidative‐stress (NOX‐1/NOX‐2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N‐cadherin/vimentin/fibronectin/TGF‐ß/α‐SMA/p‐Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged‐Notch‐GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU. [ABSTRACT FROM AUTHOR]

Background: This study tested the hypothesis that extracorporeal shockwave therapy (ECSWT) effectively rescues critical limb ischemia (CLI) in mice through the upregulation of GPR120, which protects against inflammation and angiogenesis to restore blood flow in the ischemic area., Methods and Results: Compared with the control, ECSWT-induced GPR120-mediated anti-inflammatory effects significantly suppressed the expression of inflammatory signaling biomarkers (TAK1/MAPK family/NF-κB/IL-1β/IL-6/TNF-α/MCP-1) in HUVECs, and these effects were abolished by silencing GPR120 or by the GPR120 antagonist AH7614 (all P < 0.001). C57BL/6 mice (n = 40) were equally categorized into Groups 1 (sham-operated control), 2 (CLI), 3 (CLI + ECSWT), and 4 (CLI + ECSWT + AH7614). By Days 7, 14, and 28 just prior to harvesting the quadriceps muscle, the laser Doppler results showed that the ratio of ischemia to normal blood flow (INBF) in the CLI area was highest in Group 1, lowest in Group 2, and significantly greater in Group 3 than in Group 4 (all P < 0.0001). Endothelial cell markers (CD31/vWF) and GPR120 + cells exhibited identical patterns of INBF among the groups, whereas angiogenesis biomarkers (CXCR4/SDF-1/VEGF/VEGFR2) were significantly and progressively upregulated from Groups 1 to 4 (all P < 0.0001). The protein levels of inflammation (MMP-9, IL-6, and TNF-α) and oxidative stress (NOX-1 and NOX-2) and the cellular levels of inflammation (CD68+)/DNA damage (γ-H2AX+) displayed opposite patterns, whereas the small vessel density in the CLI area displayed an identical pattern of INBF among the groups (all P < 0.0001)., Conclusions: ECSWT rescued CLI by increasing GPR120-mediated suppression of inflammation and enhancing angiogenesis via activation of VEGFR2., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We investigated whether shock wave (SW)-pretreated autologous adipocyte-derived mesenchymal stem cells (ADMSCs) seeded in the cell-sheet scaffold (CSS) could inhibit left ventricular (LV) remodeling and improve LV ejection fraction (LVEF) in old myocardial infarction (MI)., Methods: Mini-pigs ( n =20) were divided into group 1 (sham-operated control), group 2 (old MI), group 3 (old MI + autologous ADMSCs/1.0×10 7 in CSS on LV myocardium), and group 4 [old MI + SW (0.12 mJ/mm 2 for total 140 shots)-pretreated ADMSCs in CSS on LV myocardium]. Treatments started on day 28 after MI induction. In-vivo and in-vitro studies were conducted., Results: Cell viability/relative mitochondria DNA expression/mitochondrial cytochrome C/adenosine triphosphate concentration in ADMCSs and protein expressions of angiogenesis factors [vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1)/mitochondrial respiratory chain complexes I-IV/oxygen consumption rate] were higher in group 4 than in group 3 ( P <0.001). By day 180, LVEF and small vessel numbers in the peri-infarct or infarct area were highest in group 1, lowest in group 2, and significantly lower in group 3 than in group 4. In contrast, the LV dimension was opposite to the pattern of change in LVEF in all groups ( P <0.0001). The basal/middle/apical infarct and fibrotic areas were inversely related to LVEF in all groups (all P <0.0001). Protein levels of angiogenetic markers (SDF-1α/C-X-C chemokine receptor type 4/VEGF/angiopoietin-1) were significantly and persistently increased from groups 1 to 4. In contrast, protein levels of endothelial cell markers (von Willebrand factor or endothelial nitric oxide synthase) showed an identical pattern to LVEF in all groups (all P <0.0001)., Conclusion: SW pretreatment of ADMSCs seeded in CSS offered significant benefits in preserving LV performance and ameliorating LV remodeling in mini-pigs with old MI., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study tested whether combined shock wave (SW)-facilitated melatonin (Mel) delivered into endothelial progenitor cells (EPCs) (EPC SW-Mel ) plus S-nitroso-N-acetyl-DL-penicillamine (SNAP) was superior to merely one modality alone for improving critical limb ischemia (CLI) in rats., Methods: SD rats (n = 50) were equally categorized into group 1 (sham-control), group 2 (CLI), group 3 (CLI + SNAP), group 4 (CLI + EPC SW-Mel ), and group 5 (CLI + EPC SW-Mel + SNAP), and ischemia-involved quadriceps were harvested by day 14., Results: An in vitro study showed that at time points of 24/48/72 h, the cell viability/protein expression of endothelial nitric oxide synthase (eNOS)/and cellular expression of nitric oxide (NO) were highest in EPCs, lowest in EPCs + menadione, and much higher in EPC SW-Mel + Mena than in EPCs + Mena + Mel. Protein levels of oxidative-stress (NOX-1/NOX-2/oxidized protein)/early (AN-V + /PI - )/late (AN-V + /PI + ) apoptosis and total intracellular/mitochondrial reactive oxygen species ROS exhibited an antithetical trend of cell viability among the groups (all P<0.0001). Matrigel assay of angiogenesis/positively-stained NO cells showed that they were much higher in EPCs + SNAP than in EPCs only (all P<0.0001). Ex vivo angiogenesis/arterial relaxation of carotid-artery rings were highest in left-common-carotid-artery (LCCA) + SNAP, lowest in LCCA + Mena, and notably higher in LCCA than in LCCA + Mena + SNAP (all P<0.0001). Laser Doppler showed ischemic to normal-blood-flow (INBF) ratio was highest in group 1, lowest in group 2, and it progressively increased from groups 3 to 5 (all P<0.0001). The protein levels of oxidative-stress (NOX-1/NOX-4/oxidized protein)/apoptotic [cleaved-caspase-3/cleaved apoptosis/mitochondrial-damage (cytosolic-cytochrome-C/p-DRP-1)]/fibrotic (Smad3/TGF-β)/inflammatory (MMP-9/IL-1β/TNF-α/NF-κB) biomarkers, exhibited an opposite trend, whereas the protein level of endothelial-cell surface markers (CD31/vWF/eNOS) and number of small vessels exhibited an identical pattern of INBF ratio among the groups (all P<0.0001)., Conclusions: Combined EPC SW-Mel and SNAP therapy offered a synergic effect toward rescuing from CLI., Competing Interests: None., (AJTR Copyright © 2024.)

Background: The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging., Aim: To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EX AD ) and exogenous mitochondria (mito Ex ) protect the lung from ARDS complicated by SS., Methods: In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EX AD ), 4 (ARDS-SS + mito Ex ), and 5 (ARDS-SS + EX AD + mito Ex ), were included in the present study., Results: In vitro study showed an abundance of mito Ex found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels ( P < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EX AD treatment than without EX AD treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11 b/c +/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO 2 %) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO 2 % among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001)., Conclusion: Combined EX AD -mito Ex therapy was better than merely one for protecting the lung against ARDS-SS induced injury., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)