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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]

Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose‐derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti‐inflammations, especially with prion protein overexpression (PrPcOE). Therefore, this study tested whether PrPcOE‐ADMSCs therapy offered benefits in improving outcomes via regulating nod‐like‐receptor‐protein‐3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPcOE‐ADMSCs were significantly enhanced in cellular viability, anti‐oxidative stress and migration against H2O2 and lipopolysaccharide damages. Similarly, PrPcOE‐ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham‐operated‐control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPcOE‐ADMSCs). Compared with SCI group 2, both ADMSCs and PrPcOE‐ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF‐α/IL‐6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c‐caspase8/FADD/p‐NF‐κB/NEK7/NRLP3/ASC/c‐caspase1/IL‐ß) and by Day 42 the protein expressions of DAMP‐inflammatory signalling (HGMB1/TLR‐4/MyD88/TRIF/TRAF6/p‐NF‐κB/TNF‐α/IL‐1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPcOE‐ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling. [ABSTRACT FROM AUTHOR]

This study tested whether extracorporeal shock wave (ECSW) supported-exogenous mitochondria (Mito) into adipose-derived mesenchymal stem cells (ADMSCs) would preserve left-ventricular-ejection-fraction (LVEF) in doxorubicin/12 mg/kg-induced dilated cardiomyopathy (DCM) rat. Adult-male-SD rats were equally categorized into group 1 (sham-control), group 2 (DCM), group 3 (DCM + ECSW/1.5 mJ/mm2 for 140 shots/week × 3 times/since day 14 after DCM induction), group 4 (DCM + ECSW/1.5 mJ/mm2/100 shots-assisted mito delivery (500 μg) into ADMSCs/1.2 × 106 cells, then implanted into LV myocardium day 14 after DCM induction) and group 5 (DCM + ECSW-assisted mito delivery into ADMSCs/1.2 × 106 cells, then implanted into LV, followed by ECSW/1.5 mJ/mm2 for 140 shots/week × 3 times/since day 14 after DCM induction) and euthanized by day 49. Microscopic findings showed mitochondria were abundantly enhanced by ECSW into H9C2 cells. The q-PCR showed a significant increase in relative number of mitDNA in mitochondrial-transferred H9C2 cells than in control group (p < 0.01). The angiogenesis/angiogenesis factors (VEGF/SDF-1α/IG-F1) in HUVECs were significantly progressively increased by a stepwise-increased amount of ECSW energy (0.1/0.25/0.35 mJ/mm2) (all p < 0.001). The 49-day LVEF was highest in group 1 and significantly progressively increased from groups 2 to 5 (all p < 0.0001). Cardiomyocyte size/fibrosis exhibited an opposite pattern of LVEF, whereas cellular/protein levels of angiogenesis factors (VEGF/SDF-1α) in myocardium were significantly progressively increased from groups 1 to 5 (all p < 0.0001). The protein expressions of apoptotic/mitochondrial (cleaved-caspase-3/cleaved-PARP/mitochondrial-Bax/cytosolic-cytochrome-C), fibrotic (p-Smad3/TGF-ß), oxidative-stress (NOX-1/NOX-2) and pressure-overload/heart failure (BNP/ß-MHC) biomarkers exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). ECSW-assisted mitochondrial-delivery into ADMSCs plus ECSW offered an additional benefit for preserving LVEF in DCM rat. [ABSTRACT FROM AUTHOR]

Background: This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS)., Methods and Results: An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1-5 (all p<0.0001)., Conclusion: Combined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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: This study tested whether phloretin (a brain-edema inhibitors) would augment therapeutic impact of human-derived platelet-rich plasma (hPRP) on attenuating brain-hemorrhagic volume (BHV) and preserving the neurologic function in rodent following acute traumatic brain damage (TBD)., Methods: Rats (n=40) were separated into group-1 (sham-control), group-2 (TBD), group-3 [TBD + phloretin (80mg/kg/dose by intra-peritoneal administration at 30min and days 2/3 followed-by TBD), group-4 (TBD + PRP/80μL by left intra-carotid-artery injection at 3h after TBD) and group-5 (TBD + phloretin + hPRP) and cerebral tissues were harvested by day 28 after TBD., Results: The brain MRI at day 28 revealed that the BHV was lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3/4, but it was similar between groups 3/4, whereas neurological function displayed a opposite pattern of BHV among the groups (all p&amp;amp;lt;0.0001). By 72h, the protein levels of upstream (HGMB1/TLR-2/TLR-4/MyD88/Mal/TRAM/ TRIF/TRAF6/IKK-α/IKK-ß/p-NF-κB) and downstream (IL-1ß/TNF-α/iNOS) inflammation signalings, apoptosis (caspase3/PARP) and fibrosis (Smad3/TGF-ß) biomarkers and flow cytometric assessment of inflammation cells (CD11b/c+//Ly6G+/PMO+) and early (AN-V+/PI-)/late (AN-V+/PI+) mononuclear-cell apoptosis displayed a similar manner of BHV among the groups (all p&amp;amp;lt;0.0001). Cell number of inflammatory (CD68+/MMP9+) and brain-swelling/myelin-damaged (AQP4+/ GFAP+) mediators revealed a similar way, whereas the neuronal-myelin (Doublecortin+/NeuN/nestin) mediators exhibited an inverse manner of BHV among the groups (all p&amp;amp;lt;0.0001)., Conclusion: Combination of phloretin and hPRP regimen was better than just one treatment to offer synergic benefits for protecting the brain against TBD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.)

Background: We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)]., Methods: Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 10 6 cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction., Results: In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 μM) than in N2a + glucose + EMPA (150 μM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001)., Conclusions: Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN., Competing Interests: None., (AJTR Copyright © 2023.)