[Show abstract][Hide abstract] ABSTRACT: We hypothesized that lung cancer patient's circulating microparticles (Lc-MPs) could promote angiogenesis, blood flow in ischemic zone and ischemic recovery in rat critical limb ischemia (CLI).
To investigate the impact of MP therapy on reversing the setting of CLI, adult-male Sprague-Dawley rats (n=50) equally randomized into sham control (SC) (group 1), SC-Lc-MPs (1.0 x 10(7) particles) (group 2), CLI (group 3), CLI-Hs-MPs (MPs from healthy-subject) (group 4), and CLI-Lc-MPs (group 5) were sacrificed by post-CLI day-14.
In vitro study showed that Lc-MPs enhanced VEGFR2 expression, angiogenesis, nitric-oxide production, and endothelial cell proliferation (all p<0.005). By days 7 and 14, Laser Doppler showed significantly higher ischemic/normal blood-flow ratio in groups 1 and 2 compared with group 3, and was significantly higher in group 4 and further elevated in group 5 (p<0.0001). Numbers of small vessels and endothelial markers (CD31(+) and vWF(+) cells) and protein expressions (eNOS, CD31) exhibited a pattern identical to Lasre Doppler among the five groups (all p<0.001). Pro-angiogenic factors (VEGF, CXCR4, SDF-1α, HGF) at cellular and protein levels showed a significant step-wise increase from groups 1 and 2 to groups 3, 4, and 5 (all p<0.001). Protein expressions of fibrotic (Smad3, TGF-β) and apoptotic (mitochondrial Bax, cleaved caspase 3, and PARP) biomarkers displayed an opposite pattern compared to that of Laser Doppler, whereas the protein expressions of anti-fibrotic (Smad1/5, BMP-2) and anti-apoptotic (Bcl-2) biomarkers showed an identical pattern compared with that of Laser Doppler among groups 1 to 3, and 5 (all p<0.001).
Administration of Lc-MPs augmented angiogenesis and restored blood flow in a rat of CLI.
Journal of Translational Medicine 12/2015; 13(1). DOI:10.1186/s12967-015-0381-8 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO.
This was a prospective, randomized, placebo-controlled trial that was conducted between October 2008 and March 2010 in a tertiary referral center. IS stroke patients who were eligible for EPO therapy were enrolled into the study.
The results showed that long-term recurrent stroke and mortality did not differ between group 1 (placebo-control; n = 71) and group 2 (EPO-treated; n = 71). Long-term Barthel index of <35 (defining a severe neurological deficit) was lower in group 2 than group 1 (P = 0.007). Multiple-stepwise logistic-regression analysis showed that EPO therapy was significantly and independently predictive of freedom from a Barthel index of <35 (P = 0.029). Long-term major adverse neurological event (MANE; defined as: death, recurrent stroke, or long-term Barthel index < 35) was lower in group 2 than group 1 (P = 0.04). Log-Rank test showed that MANE-free rate was higher in group 2 than group 1 (P = 0.031). Multiple-stepwise Cox-regression analysis showed that EPO therapy and higher Barthel Index at day 90 were independently predictive of freedom from long-term MANE (all P <0.04).
EPO therapy significantly improved long-term neurological outcomes in patients after IS.
ISRCTN71371114 . Registered 10 October 2008.
Critical Care 12/2015; 19(1). DOI:10.1186/s13054-015-0761-8 · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: The aim of this study was to evaluate the clinical effects of different strategies for preventing coronary microvascular obstruction in ST elevation myocardial infarction (STEMI) patients with a high thrombus-burden plaque. Methods: Between January, 2007 and December, 2012, 354 patients suffering from STEMI with high thrombus-burden were enrolled and divided into three groups as the first group received a GP IIb/IIIa inhibitor, and the second group received a distal protective device, and the third group was treated with primary PCI alone. Results: A high percentage of patients in the GP IIb/IIIa inhibitor (96.8% and 90.5%), distal protective device (99.3% and 87.6%) had better thirty-day and one-year symptom-free outcomes when compared with PCI only group (91.6% and 65.6%) (P = 0.008 and P < 0.001; respectively). Conclusions: Treatment with intracoronary GP IIb/IIIa inhibitor injection or distal protection device to prevent coronary microvascular obstruction was demonstrated to increase the occurrences of thirty-day and one-year symptom-free outcomes; thus, these treatments can help decrease post-MI medical care costs.
Heart and Lung The Journal of Acute and Critical Care 11/2015; 44(6):487-493. DOI:10.1016/j.hrtlng.2015.08.003 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The management of ostial lesions is one of the challenges of percutaneous coronary intervention (PCI) in recent medicine. Although stent implantation has increased the accuracy of the results and improved long-term outcomes, in-stent restenosis (ISR) occurs more frequency following the treatment of ostial lesions than the treatment of non-ostial lesions. When additional stenting is not desirable, PCI with drug-eluting balloons (DEBs) has emerged as an adjunctive strategy. However, little data regarding the effects of DEBs in ostial ISR lesions are available. Our study aimed to assess the efficacy of the use of DEBs in coronary ostial instent restenotic lesions.
[Show abstract][Hide abstract] ABSTRACT: This study tested for the benefits of early administration of carvedilol as protection againstdoxorubicin-induced cardiomyopathy. Thirty male-adult B6 mice were categorized into group 1 (untreated control), group 2 [doxorubicin (15 mg/every-other-day for 2-weeks, I.P.], and group 3 [carvedilol (15 mg/kg/day, from day-7 after doxorubicin for 28 days)] and euthanized by day 35 after doxorubicin treatment. By day 35, the left-ventricular injection fraction (LEVF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the LV end-diastolic and LV end-systolic dimensions showed an opposite pattern to LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA-damage (γ-H2AX), oxidative-stress (oxidized protein), mitochondrial-damage (cytosolic cytochrome-C), heart failure (BNP), hypertrophic (β-MHC) biomarkers of LV myocardium showed an opposite pattern to LVEF among the three groups. The protein expressions of anti-fibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas, numbers of γ-H2AX+ and 53BP1+ cells in LV myocardium, exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31+, vWF+) markers showed an identical pattern to LVEF among the three groups. Cardiac stem cell markers (C-kit+, Sca-1+ cells) were significantly progressively increased from group 1 to group 3. Additionally, The in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1+, CD90/53BP1+ and r-H2AX+ cells) damage. Early carvedilol therapy protected against doxorubicin-induced DNA-damage and cardiomyopathy.
Journal of Pharmacology and Experimental Therapeutics 10/2015; 355(3). DOI:10.1124/jpet.115.225375 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Emergency department and hospital crowding have become an increasing problem. The clinical outcomes of prolonged emergency department (ED) length of stay in acute ST-segment elevation myocardial infarction (STEMI) patients after reperfusion are still unknown. Between January 2008 and December 2011, 432 consecutive patients with STEMI undergoing primary PCI were recruited. Patients were divided into two groups: the immediate admission group (length of ED stay <8 h; IA group) and the prolonged ED stay group (length of ED stay ≧8 h; PS group). The median lengths of ED stay of the patients in both groups were 29.97 h in the PS group (n = 145, 33.6 %) and 1.78 h in the IA group (n = 287, 66.4 %), respectively. The age, gender, risk factors of coronary artery disease, characteristic of coronary angiography, and TIMI risk score did not differ between the two groups. During nearly 4-year clinical follow-up, the short-term and long-term clinical outcomes were similar between the two groups. B-blocker and statins were used infrequently in the ED. In addition, patients with high TIMI risk score in the PS group had higher incidence of 1-year re-MI (6.8 vs. 1.8 %; p = 0.045). In the era of primary PCI for STEMI patients after reperfusion, prolonged ED length of stay may not influence clinical outcomes. Patients with high TIMI risk score in the PS group still had a trend toward worse clinical outcome after long ED stays.
Internal and Emergency Medicine 10/2015; DOI:10.1007/s11739-015-1330-5 · 2.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to evaluate the effects of adipose-derived mesenchymal stem cells (ADMSCs) exosomes on hepatocellular carcinoma (HCC) in rats using apparent diffusion coefficient (ADC), natural killer T-cell (NKT-cell) responses, and histopathological features. ADMSC-derived exosomes appeared as nanoparticles (30–90 nm) on electron microscopy and were positive for CD63, tumor susceptibility gene-101, and
-catenin on western blotting. The control (
) and exosome-treated (
) rats with N1S1-induced HCC underwent baseline and posttreatment day 10 and day 20 magnetic resonance imaging and measurement of ADC. Magnetic resonance imaging showed rapidly enlarged HCCs with low ADCs in the controls. The exosome-treated rats showed partial but nonsignificant tumor reduction, and significant ADC and ADC ratio increases on day 10. On day 20, the exosome-treated rats harbored significantly smaller tumors and volume ratios, higher ADC and ADC ratios, more circulating and intratumoral NKT-cells, and low-grade HCC (
for all comparisons) compared to the controls. The ADC and volume ratios exhibited significant inverse correlations (
). ADMSC-derived exosomes promoted NKT-cell antitumor responses in rats, thereby facilitating HCC suppression, early ADC increase, and low-grade tumor differentiation. ADC may be an early biomarker of treatment response.
Stem cell International 09/2015; 2015:1-11. DOI:10.1155/2015/853506 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of shock wave (SW) on brain-infarction volume (BIV) and neurological function in acute ischemic stroke (AIS) by left internal carotid artery occlusion in rats.
SD rats (n=48) were divided into group 1 [sham-control (SC)], group 2 [SC-ECSW (energy dosage of 0.15 mJ/mm(2)/300 impulses)], group 3 (AIS), and group 4 (AIS-ECSW) and sacrificed by day 28 after IS induction. In normal rats, caspase-3, Bax and TNF-α biomarkers did not differ between animals with and without ECSW therapy, whereas Hsp70 was activated post-ECSW treatment. By day 21 after AIS, Sensorimotor-functional test identified a higher frequency of turning movement to left in group 3 than that in group 4 (P<0.05). By day 28, brain MRI demonstrated lager BIV in group 3 than that in group 4 (P<0.001). Angiogenesis biomarkers at cellular (CD31, α-SMA+) and protein (eNOS) levels and number of neuN+ cells were higher in groups 1 and 2 than those in groups 3 and 4, and higher in group 4 than those in group 3, whereas VEGF and Hsp70 levels were progressively increased from groups 1 and 2 to group 4 (all P<0.001). Protein expressions of apoptosis (Bax, caspase 3, PARP), inflammation (MMP-9, TNF-α), oxidative stress (NOX-1, NOX-2, oxidized protein) and DNA-damage marker (γ-H2AX), and expressions of γ-H2AX+, GFAP+, AQP-4+ cells showed an opposite pattern compared to that of angiogenesis among the four groups (all P<0.001).
ECSW therapy was safe and effective in reducing BIV and improved neurological function.
American Journal of Translational Research 08/2015; 7(6):976-94. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that autologous adipose-derived mesenchymal stem cells (ADMSCs) embedded in platelet-rich fibrin (PRF) can significant promote myocardial regeneration and repair after acute myocardial infarction (AMI).
With avoiding the needle-related complications, PRF-embedded autologous ADMSCs graft provides a new effective stem cell-based therapeutic strategy for myocardial repair.
Adult male Sprague-Dawley rats were equally divided (n = 8 per group) into group 1 (sham-operated), group 2 (AMI by ligating left coronary artery), group 3 (AMI+ PRF), and group 4 (AMI+PRF-embedded autologous ADMSCs). RPF with or without ADMSCs was patched on infarct area 1h after AMI induction. All animals were sacrificed on day 42 after echocardiography.
Left ventricular (LV) dimension and infarct/fibrotic areas were lowest in group 1, highest in group 2, in group 3 higher than in group 4, whereas LV performance and wall thickness exhibited a reversed pattern in all groups (all p < 0.001). Protein expressions of inflammatory (MMP-9, IL-1β), oxidative, apoptotic (Bax, cleaved PARP), fibrotic (Smad 3, TFG-β), hypertrophic (β-MHC), and heart failure (BNP) biomarkers displayed an identical pattern in infarct/fibrotic areas, whereas the protein expressions of anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), anti-fibrotic (Smad1/5, BMP-2) biomarkers and α-MHC showed an opposite pattern (all p < 0.01). Angiogenic activities (c-Kit+, Sca-1+, CD31+, SDF-1α+, CXCR4+ cells; protein expressions of SDF-1α, CXCR4, VEGF) were highest in group 4 and lowest in group 1 (all p < 0.001).
ADMSCs embedded in PRF offered significant benefit in preserving LV function and limiting LV remodeling after AMI.
American Journal of Translational Research 07/2015; 7(5):781-803. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that peripheral blood-derived endothelial progenitor cell (PBDEPC) therapy can impede the deterioration of chronic kidney disease (CKD) induced by 5/6 nephrectomy in rats.
Adult-male rats (n = 30) were equally categorized into group 1 (sham control), group 2 (CKD only) and group 3 [CKD + PBDEPC (left intra-arterial (3.3 × 10(5)) and penile vein (6.7 × 10(5)) injections by day 14 after CKD induction]. By day 60, kidney blood flow (KBF) was significantly lower in group 2 than that in groups 1 and 3, and significantly lower in group 3 than that in group 1, whereas the levels of serum creatinine, and kidney injury score and size showed an opposite pattern compared to that of KBF among all groups (all p < 0.001). Protein expressions of apoptotic (caspase 3, PARP), inflammatory (TNF-α, MMP-9), oxidative-stress (oxidized protein, NOX-1), fibrotic (Smad3, TGF-β), and hypoxic/ischemic cell-stress (HIF-1α, p-Akt) biomarkers showed an opposite pattern, whereas angiogenesis at protein (eNOS, CD31) and cellular (CD31+, CXCR4+) levels showed an identical pattern compared to that of blood flow in all groups (all p < 0.01). Other pro-angiogenic biomarkers (SDF-1α, CXCR4, VEGF) at protein and cellular levels and antioxidants (HO-1+, NQO 1, GR+) at cellular level showed progressive significant increase from groups 1 to 3 (all p < 0.001).
The results support that PBDEPC therapy effectively inhibits the propagation of CKD and the deterioration of renal function through enhancement of angiogenesis, blood flow, and anti-oxidative capacity as well as suppression of inflammation, oxidative stress, apoptosis, and fibrosis in a rodent model.
American Journal of Translational Research 07/2015; 7(5):804-24. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that intra-coronary transfusion of circulation-derived autologous CD34+ cells can improve ischemia-related left ventricular dysfunction in patients with severe diffuse coronary artery disease refractory to medication and unsuitable for coronary intervention.
A prospective, randomized, double-blinded phase I clinical trial.
Tertiary care center.
Thirty-eight patients with severe diffuse coronary artery disease were randomized into group 1 and group 2 receiving CD34+ cell infusion with dosages of 1.0 x 107 and 3.0 x 107 cells/vessel, respectively, after subcutaneous G-CSF injection (5 μg/kg twice a day for 4 d).
Cardiac catheterization and intra-coronary administration of CD34+ cells.
This clinical trial was to test effectiveness and safety of these two different dosages of CD34+ cells in the setting of severe diffuse coronary artery disease. Blood samples were collected for endothelial progenitor cell culture before and after granulocyte colony-stimulating factor injection for matrigel-assay and comparison of levels of soluble angiogenesis factors (vascular endothelial growth factor, epithelial growth factor, hepatocyte growth factor, angiopoietin-1, and transforming growth factor-β). Procedural safety was 100% with all patients uneventfully discharged. The numbers of endothelial progenitor cells in blood samples from coronary sinus after transfusion were higher than those in circulation, and the circulatory level was higher after granulocyte colony-stimulating factor treatment (all p < 0.001). Cardiac MRI and three-dimensional echocardiography at 6 month and angiographic follow-up at 9 month showed improvement in left ventricular ejection fraction (p < 0.001) and consistent increase in neovascularization (p < 0.001), respectively, in both groups. Despite good correlation in angiogenesis between 9-month angiography and matrigel-assay (p < 0.001), no significant correlation was noted in of soluble angiogenesis factor levels. Angina and heart failure were improved in both groups at 12-month follow-up (all p < 0.001). The survival rate at 18.5-month follow-up was 94.7 % (n = 36).
CD34+ cell therapy was safe and efficacious in improving heart function for patients with severe diffuse coronary artery disease unsuitable for coronary intervention and with poor response to pharmacotherapy.
Critical care medicine 07/2015; 43(10). DOI:10.1097/CCM.0000000000001138 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that exendin-4 protects against critical limb ischemia (CLI) in obese mice undergoing hypoxic stress (H). B6 mice were categorized into aged-matched control (C)-H (group 1-A), obesity (induced by high-fat diet) (O)-H (group 1-B), C-H-CLI (group 2-A), O-H-CLI (group 2-B), C-H-CLI-exendin-4 (group 3-A) and O-H-CLI-exendin-4 (group 3-B). Animals were sacrificed by day 14 after CLI procedure. By day 14, laser Doppler results showed that blood flow in CLI area was higher in group 3-A than group 2-A, higher in group 3-B than group 2-B, highest in groups 1-A and 1-B, higher in group 2-A than in group 2-B, and higher in group 3-A than in group 3-B (all p<0.001), but not significantly different between groups 1-A and 1-B. Furthermore, circulating numbers of endothelial progenitor cells (EPCs) (c-kit/CD31+, Sca-1/KDR+) showed an identical pattern of blood flow in CLI area among groups 2-A, 2-B, 3-A and 3-B, except that these biomarkers were lowest in groups 1-A and 1-B (all p<0.001). Protein and cellular levels of angiogenesis factors (VEGF, CXCR4, SDF-1α) exhibited an identical pattern of circulating EPC numbers among all groups (all p<0.001). Protein levels of apoptotic (cytosolic cytochrome-C, mitochondrial Bax, cleaved caspase 3 and PARP) and fibrotic (Samd 3, TGF-β) biomarkers showed an opposite pattern of blood flow in CLI area among groups 2-A, 2-B, 3-A and 3-B, but were lowest in groups 1-A and 1-B (all p<0.001). This finding suggests exendin-4 protected against CLI in obese mice undergoing hypoxic stress mainly through enhancing angiogenesis and inhibiting apoptosis.
American Journal of Translational Research 06/2015; 7(3):445-59. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study hypothesized that combined serum-deprived (Sd) and healthy (He) adipose-derived mesenchymal stem cell (ADMSC) therapy is superior to either alone in reducing acute lung ischemia-reperfusion injury (ALIRI).
Adult male Sprague-Dawley (SD) rats (n = 30) were equally randomized into group 1 (sham control), group 2 (ALIRI + culture medium), group 3 (ALIRI + intravenous autologous 1.2 × 10(6) He-ADMSCs at 30 minute, 6 h, and 24 h following lung ischemia/reperfusion for 45 minutes/72 hours, respectively), group 4 (ALIRI + 1.2 × 10(6) Sd-ADMSCs at identical time points after ischemia/reperfusion), and group 5 (ALIRI + 1.2 × 10(6) combined Sd-ADMSC/He-ADMSC 1:1).
Blood oxygen saturation (%) was lowest in group 2, lower in groups 3 to 5 than in group 1, and lower in group 5 than in group 1, whereas right ventricular systolic pressure (RVSP) showed a reverse pattern among the five groups (all p < 0.001). Additionally, changes in histological scoring of lung parenchymal damage, inflammatory and apoptotic biomarkers showed identical pattern compared to that of RVSP in all groups (all p < 0.001). Protein expressions of VCAM-1, ICAM-1, oxidative stress, TNF-α, nuclear factor-κB, and number of CD68 + cells were highest in group 2, higher in groups 3 to 5 than in group 1, and higher in groups 3 and 4 than in group 5, whereas NQO-1 and HO-1 activities and number of CD31 + and vWF + cells showed opposite changes compared with those of inflammatory biomarkers (all p < 0.001).
Combined Sd-ADMSC/He-ADMSC therapy offered superior benefit to either option alone in minimizing rodent ALIRI through suppressing oxidative stress and inflammatory reaction.
American Journal of Translational Research 04/2015; 7(2):209-31. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
We tested the hypothesis that transfusion of autologous peripheral blood-derived endothelial progenitor cells (PBDEPC) via the internal carotid artery could reduce brain-infarct zone (BIZ) and neurological deficit in rats following acute ischemic stroke (IS) induced by 50-min left middle cerebral artery occlusion.
Adult male Sprague-Dawley rats (n=60) were equally divided into group 1 [sham control (SC)], group 2 [SC-PBDEPC (5.7×10(6)/kg)], group 3 (IS), group 4 [IS-low-dose PBDEPC (1.7×10(6)/kg)], group 5 [IS-high-dose PBDEPC (5.7×10(6)/kg)]. Groups 2 to 5 received G-CSF (35μg/kg subcutaneously) for 4days before drawing blood for PBDEPC culture.
Measurements and main results:
By day 90, BIZ determined by histopathology (area) and brain MRI (volume) were highest in group 3, lowest in groups 1 and 2, higher in group 4 than in group 5 (all p<0.0001), and not significantly different between groups 1 and 2. Sensorimotor functional results exhibited an opposite pattern of BIZ among groups 3 to 5 (p<0.005). Angiogenesis biomarkers (SDF-1α, CXCR4, VEGF, angiopoietin-1) significantly increased progressively from groups 1 and 2 to group 5 (all p<0.0001). Oxidative-stress (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), inflammatory (MMP-9, TNF-α, AQP-4, GFAP, iNOS), and brain-damaged (cytosolic cytochrome-C) biomarkers showed an identical pattern, whereas anti-inflammatory (Bcl-2), mitochondrial preservation (mitochondrial cytochrome-C, PGC-1α), and endothelial function (CD31+, vWF+, eNOS) biomarkers, and vessel density showed an opposite pattern of BIZ among these five groups (all p<0.001).
Higher-dose was superior to lower-dose EPC treatment for reducing BIZ and improving neurological functional outcome.
International Journal of Cardiology 03/2015; 201. DOI:10.1016/j.ijcard.2015.03.137 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to evaluate the feasibility and safety of routine transradial approach (TRA) percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions using the sheathless technique with standard guiding catheters.
[Show abstract][Hide abstract] ABSTRACT: Sitagliptin, a new antidiabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effects of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS).
Thirty C57BL/6 mice were divided into three groups: sham control (n = 10), CHP (n = 10) and CHP-sitagliptin (orally 600 mg/kg/day) (n = 10). Working memory was assessed with novel-object recognition test. MRI was performed at day 0 and day 90 after BCAS procedure prior to sacrifice.
Immunohistochemical (IHC) staining showed significantly enhanced white matter lesions, microglia activation and astrocytosis of white matter in CHP group than in sham control, but the changes were significantly suppressed after sitagliptin treatment (all P < 0.01). The mRNA expressions of inflammatory [tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein (MCP-1) and matrix metalloproteinase (MMP)-2] and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (interleukin, IL-10) and antiapoptotic (Bcl-2) biomarkers showed an opposite pattern compared with that of IHC among all groups (all P < 0.01). The protein expressions of oxidative stress (NOX-I, NOX-II, nitrotyrosin, oxidized protein), inflammatory [nuclear factor-kappa B (NF-κB), TNF-α and MMP-2], apoptotic [mitochondrial Bax, cleaved poly(ADP-ribose) polymerase (PARP)] and DNA-damage (γ-H2AX) markers showed an identical pattern, while expression pattern of antiapoptotic marker (Bcl-2) was opposite to that of IHC (all P < 0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from sham control to CHP-sitagliptin (P < 0.01). The short-term working-memory loss and MRI/diffusion tensor imaging (DTI) showed a pattern identical to that of IHC in all groups (all P < 0.01).
Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model.
Journal of Hypertension 02/2015; 33(5). DOI:10.1097/HJH.0000000000000529 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We tested the hypothesis that Lipofectamine siRNA delivery to deplete transient receptor potential cation channel (TRPC) 1 protein expression can suppress hypoxia-induced pulmonary arterial hypertension (PAH) in mice. Adult male C57BL/6 mice were equally divided into group 1 (normal controls), group 2 (hypoxia), and group 3 (hypoxia + siRNA TRPC1). By day 28, right ventricular systolic pressure (RVSP), number of muscularized arteries, right ventricle (RV), and lung weights were increased in group 2 than in group 1 and reduced in group 3 compared with group 2. Pulmonary crowded score showed similar pattern, whereas number of alveolar sacs exhibited an opposite pattern compared to that of RVSP in all groups. Protein expressions of TRPCs, HIF-1α, Ku-70, apoptosis, and fibrosis and pulmonary mRNA expressions of inflammatory markers were similar pattern, whereas protein expressions of antifibrosis and VEGF were opposite to the pattern of RVSP. Cellular markers of pulmonary DNA damage, repair, and smooth muscle proliferation exhibited a pattern similar to that of RVSP. The mRNA expressions of proapoptotic and hypertrophy biomarkers displayed a similar pattern, whereas sarcomere length showed an opposite pattern compared to that of RVSP in all groups. Lipofectamine siRNA delivery effectively reduced TRPC1 expression, thereby attenuating PAH-associated RV and pulmonary arteriolar remodeling.
Stem cell International 12/2014; 2014:316214. DOI:10.1155/2014/316214 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.
Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.
Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.
Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.