[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: 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: Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain-dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS)-stimulated NF-κB signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high-dose DA reduced proliferation and induced G1 growth arrest of clone-9 hepatocytes with concomitant decreases in Bcl-2/Bax and Hsp70/Bax protein ratios and intracellular NF-κB p65. Moreover, DA pretreatment suppressed LPS-elicited I-κBα phosphorylation and subsequent NF-κB nuclear translocation, suggesting that DA may downregulate NF-κB signaling, thereby reducing expression of anti-apoptotic regulators, such as Bcl-2. Conclusion: Despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that high-dose DA may hamper the function of NF-κB signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts. This article is protected by copyright. All rights reserved.
[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 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: Skull and intracranial metastases from hepatocellular carcinoma (HCC) have seldom been reported. A skull metastasis of HCC with a tumor bleeding resulting in spontaneous subdural hematoma (SDH) is extremely unusual. We report the first case of acute spontaneous SDH in a 69-year-old woman who presented with acute onset of headache, because of tumor bleeding caused by skull metastasis of HCC.
A 69-year-old woman was referred to our hospital because of progressive headache, nausea, and vomiting for 3 days. Brain computed tomography (CT) performed in the emergency department (ED) revealed a left temporal SDH with a slight mass effect and a small left temporal bone erosion. Tri-phasic abdominal CT demonstrated a large right lobe liver tumor compatible with HCC. She experienced progressive deterioration of consciousness in the intensive care unit. Follow-up CT showed an enlargement of the SDH. An emergency craniotomy for hematoma evacuation and removal of skull tumor was performed. She regained consciousness and had no neurological deficits during the postoperative course. Pathological examination of the skull specimen indicated metastasis of a HCC.
Patients with acute SDH without a history of head injury are rarely encountered in the ED. Metastatic carcinoma with bleeding should be included as a differential diagnosis for acute spontaneous SDH. Before an operation for SDH, the possibility of metastatic lesion of the skull should be considered in the surgical planning and the origin of malignancy should be sought.
BMC Surgery 05/2015; 15(1):60. DOI:10.1186/s12893-015-0045-x · 1.40 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: 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: Obstructive sleep apnea (OSA) is an independent cardiovascular risk factor to which autonomic nervous dysfunction has been reported to be an important contributor. Ninety subjects recruited from the sleep center of a single medical center were divided into four groups: normal snoring subjects without OSA (apnea hypopnea index, AHI < 5, n = 11), mild OSA (5 <= AHI < 15, n = 10), moderate OSA (15 <= AHI < 30, n = 24), and severe OSA (AHI >= 30, n = 45). Demographic (i.e., age, gender), anthropometric (i.e., body mass index, neck circumference), and polysomnographic (PSG) data were recorded and compared among the different groups. For each subject, R-R intervals (RRI) from 10 segments of 10-minute electrocardiogram recordings during non-rapid eye movement sleep at stage N2 were acquired and analyzed for heart rate variability (HRV) and sample entropy using multiscale entropy index (MEI) that was divided into small scale (MEISS, scale 1-5) and large scale (MEILS, scale 6-10). Our results not only demonstrated that MEISS could successfully distinguish normal snoring subjects and those with mild OSA from those with moderate and severe disease, but also revealed good correlation between MEISS and AHI with Spearman correlation analysis (r = -0.684, p < 0.001). Therefore, using the two parameters of EEG and ECG, MEISS may serve as a simple preliminary screening tool for assessing the severity of OSA before proceeding to PSG analysis.
[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: Background
We investigated whether attenuating dipeptidyl peptidase-IV (DPP4) enzyme activity protected rat heart from ischemia-reperfusion (IR) injury (40-min left anterior descending coronary artery ligation followed by 72 h reperfusion).Methods and resultsAdult male Fischer 344 rats (n¿=¿24) were equally divided into sham-control (WT-SC), WT-IR, and WT-IR-Sita (oral sitagliptin 400 mg/kg/day for 3 days) groups, whereas adult male DPP4-deficiency (DPP4D) rats (n¿=¿16) were equally divided into DPP4D-SC and DPP4D-IR groups. Animals were sacrificed at 72 h after reperfusion with collection of heart specimens. Infarct area (H&E), collagen deposition (Sirius-red stain), fibrotic area (Masson's trichrome), and fluorescent-ROS intensity (H2DCFDA-labeling myocardium) of left ventricle were significantly higher in WT-IR than those in other groups, significantly higher in WT-IR-Sita and DPP4D-IR groups than in WT-SC and DPP4D-SC groups (all p¿<¿0.001), but there was no difference between the latter two groups. Protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NOX-1, NOX-2), inflammation (TNF-¿, NF-¿B, MMP-9, VCAM-1), apoptosis (mitochondrial Bax, cleaved caspase-3 and PARP), myocardial damage markers (cytosolic cytochrome-C, ¿-H2AX), and number of inflammatory cells (CD14+, CD68+, CD40+ cells) showed a pattern identical to that of histological changes among all groups (all p¿<¿0.005), whereas markers of anti-apoptosis (Bcl-2) and mitochondrial integrity (mitochondrial cytochrome-C) as well as left ventricular ejection fraction showed an opposite pattern (all p¿<¿0.001). Protein expressions of anti-oxidants (HO-1, NQO-1), angiogenesis factors (SDF-1¿, CXCR4), and glycogen-like-peptide-1-receptor were significantly higher inWT-IR-Sita and DPP4D-IR than those in other groups (all p¿<¿0.001).Conclusion
Abrogation of DPP4 activity protects against myocardial IR injury and preserved heart function.
Journal of Translational Medicine 12/2014; 12(1):357. DOI:10.1186/s12967-014-0357-0 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We applied multiscale entropy (MSE) to assess variation in crest time (CT), a parameter in arterial waveform analysis, in diagnosing patients with diabetes. Data on digital volume pulse were obtained from 93 individuals in three groups [Healthy young (Group 1, 20< age ≤40, n = 30), healthy upper-middle-aged (Group 2, age >40, n = 30), and diabetic (Group 3, n = 33) subjects]. Crest time, normalized crest time, crest time ratio (CTR), small- and large-scale MSE on CT [MSESS(CT) and MSELS(CT), respectively] were computed and correlated with anthropometric (i.e., body weight/height, waist circumference), hemodynamic (i.e., blood pressure), and biochemical parameters (i.e., serum triglyceride, high-density lipoprotein, fasting blood sugar, and glycosylated hemoglobin). The results demonstrated higher variability in CT in healthy subjects (Groups 1 and 2) compared with that in diabetic patients (Group 3) as reflected in significantly elevated MSESS(CT) and MSELS(CT) in the former (p < 0.003 and p < 0.001, respectively). MSELS(CT) also showed significant association with waist circumference and fasting blood sugar (i.e., two diagnostic criteria of metabolic syndrome) as well as glycosylated hemoglobin concentration. In conclusion, using MSE analysis for assessing CT variation successfully distinguished diabetic patients from healthy subjects. MSESS(CT) and MSELS(CT) therefore may serve as noninvasive tools for identifying subjects with diabetes and those at risk.
[Show abstract][Hide abstract] ABSTRACT: The role of nerve growth factor (NGF) in liver injury induced by bile duct ligation (BDL) remains elusive. This study aimed to investigate the relationship between inflammation and hepatic NGF expression, to explore the possible upstream molecules up-regulating NGF, and to determine whether NGF could protect hepatocytes from oxidative liver injury. Biochemical and molecular detection showed that NGF was up-regulated in cholestatic livers and plasma, and well correlated with systemic and hepatic inflammation. Conversely, systemic immunosuppression reduced serum NGF levels and resulted in higher mortality in BDL-treated mice. Immunohistochemistry showed that the up-regulated NGF was mainly localized in parenchymal hepatocytes. In vitro mechanistic study further demonstrated that TGF-β1 up-regulated NGF expression in clone-9 and primary rat hepatocytes. Exogenous NGF supplementation and endogenous NGF overexpression effectively protected hepatocytes against TGF-β1- and oxidative stress-induced cell death in vitro, along with reduced formation of oxidative adducted proteins modified by 4-HNE and 8-OHdG. TUNEL staining confirmed the involvement of anti-apoptosis in the NGF-exhibited hepatoprotection. Moreover, NGF potently induced Akt phosphorylation and increased Bcl-2 to Bax ratios, whereas these molecular alterations by NGF were only seen in the H2O2-, but not TGF-β1-treated hepatocytes. In conclusion, NGF exhibits anti-oxidative and hepatoprotective effects and is suggested to be therapeutically applicable in treating cholestatic liver diseases.
PLoS ONE 10/2014; 9(11). DOI:10.1371/journal.pone.0112113 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigated the pro-fibrogenic role of high mobility group box 1 (HMGB1) peptides in liver fibrogenesis. An animal model of carbon tetrachloride (CCl4)-induced liver fibrosis was used to examine the serum HMGB1 levels and its intrahepatic distribution. The increased serum HMGB1 levels were positively correlated with elevation of transforming growth factor-β1 (TGF-β1) and collagen deposition during fibrogenesis. The cytoplasmic distribution of HMGB1 was noted in the parenchymal hepatocytes of fibrotic livers. In vitro studies confirmed that exposure to hydrogen peroxide and CCl4 induced an intracellular mobilization and extracellular release of nuclear HMGB1 peptides in clone-9 and primary hepatocytes, respectively. An uptake of exogenous HMGB1 by hepatic stellate cells (HSCs) T6 cells indicated a possible paracrine action of hepatocytes on HSCs. Moreover, HMGB1 dose-dependently stimulated HSC proliferation, up-regulated de novo synthesis of collagen type I and α-smooth muscle actin (α-SMA), and triggered Smad2 phosphorylation and its nuclear translocation through a TGF-β1-independent mechanism. Blockade with neutralizing antibodies and gene silencing demonstrated the involvement of the receptor for advanced glycation end-products (RAGE), but not toll-like receptor 4, in cellular uptake of HMGB1 and the HMGB1-mediated Smad2 and ERK1/2 phosphorylation as well as α-SMA up-regulation in HSC-T6 cells. Furthermore, anti-RAGE treatment significantly ameliorated CCl4-induced liver fibrosis. In conclusion, the nuclear HMGB1 peptides released from parenchymal hepatocytes during liver injuries may directly activate HSCs through stimulating HSC proliferation and transformation, eventually leading to the fibrotic changes of livers. Blockade of HMGB1/RAGE signaling cascade may constitute a therapeutic strategy for treatment of liver fibrosis.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 09/2014; 1842(9):1720-32. DOI:10.1016/j.bbadis.2014.06.017. · 4.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that rosuvastatin reduces thrombus burden through inhibiting inflammation and suppressing reactive oxygen species (ROS) generation in an inferior vena cava stenosis (IVCST)-induced deep vein thrombosis (DVT) rat model.
12-week-old male Sprague–Dawley rats (n = 24) were equally divided into sham control (group 1: laparotomy only), IVCST (group 2: IVC stenosis), and IVCST + rosuvastatin (20 mg/kg/day, orally after induction of IVC stenosis) (group 3). IVC diameter was measured by days 0 and 14 and the right hindlimb thickness was measured by day 0, 7, and 14 prior to scarifying the animals.
The results showed significantly increased IVC diameter and hindlimb thickness in group 2 than in groups 1 and 3, and significantly increased in group 3 than in group 1 by day 14 after the procedure (all p < 0.001). Additionally, WBC count and prevalence of helper T cells, cytotoxic T cells, regulatory T cells, and early and late apoptotic mononuclear cells (MNCs) in circulation were significantly higher in group 2 than in group 1, and were significantly suppressed in group 3 after treatment (all p < 0.001). Furthermore, inflammation at cellular (CD68+ cells) and protein (MMP-9, TNF-α) levels, oxidative stress (oxidized protein) and reactive oxygen species (NOX-1, NOX-2) in IVC also showed similar changes as those of immune cells in circulation among the three groups (all p < 0.01).
Rosuvastatin treatment significantly reduced IVC thrombus burden through inhibiting inflammatory response and oxidative stress in a rodent model of DVT.
Journal of Inflammation 09/2014; 11(1):27. DOI:10.1186/s12950-014-0027-2 · 2.02 Impact Factor