scholarly journals Effect of Combination Therapy with Neuroprotective and Vasoprotective Agents on Cerebral Ischemia

2018 ◽  
Vol 45 (3) ◽  
pp. 325-331
Author(s):  
Jiping Yang ◽  
Bei Yang ◽  
Baoxin Xiu ◽  
Jinchong Qi ◽  
Huaijun Liu
Keyword(s):  
Growth Factor ◽  
Combination Therapy ◽  
Water Content ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Time Window ◽  
Infarct Volume ◽  
Neural Cell ◽  
Control Group ◽  
Solution Saline

AbstractBecause most tested drugs are active against only one of the damaging processes associated with stroke, other mechanisms may cause cellular death. Thus, a combination of protective agents targeting different pathophysiological mechanisms may obtain better effects than a single agent. The major objective of this study was to investigate the effect of combination therapy with vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) after controlled ischemic brain injury in rabbits.Methods:Animals were randomly assigned to one of the following groups: sham group, saline-treated control group or NGF+VEGF-treated group. Animals received an intracerebral microinjection of VEGF and NGF or saline at 5 or 8 hours after ischemia. The two specified time points of administration were greater than or equal to the existing therapeutic time window for monoterapy with VEGF or NGF alone (3 or 5 hours of ischemia). Infarct volume, water content, neurological deficits, neural cell apoptosis and the expression of caspase-3 and Bcl-2 were measured.Results:Compared with saline-treated controls, the combination therapy of VEGF and NGF significantly reduced infarct volume, water content, neural cell apoptosis and the expression of caspase-3, up-regulated the expression of Bcl-2 and improved functional recovery (bothp<0.01) when administered 5 or 8 hours after ischemia. The earlier the administration the better the neuroprotection.Conclusions:These results showed that the combination therapy with VEGF and NGF provided neuroprotective effects. In addition, the time window of combination treatment should be at least 8 hours after ischemia, which was wider than monotherapy.RÉSUMÉ:Les effets d’une polythérapie combinant agents neuro-protecteurs et agents vasoprotecteurs dans les cas d’ischémie cérébrale.Contexte:Étant donné que la plupart des médicaments préalablement testés tendent à n’agir contre seulement un des processus de dommage associés aux AVC, il est possible que d’autres processus entraînent une mort cellulaire. À cet effet, il se pourrait qu’une combinaison d’agents protecteurs ciblant divers mécanismes physiopathologiques permette d’obtenir de meilleurs résultats qu’un simple agent. Après avoir suscité de façon contrôlée des lésions cérébrales ischémiques chez des lapins, l’objectif principal de la présente étude a donc été de se pencher sur l’impact d’une polythérapie combinant la protéine dite « facteur de croissance de l’endothélium vasculaire » (ou « VEGF » en anglais) avec le « facteur de croissance des nerfs » (ou « NGF » en anglais).Méthodes:Les animaux ont été attribués au hasard à l’un des groupes suivants : ceux ayant reçu un traitement fictif ; ceux, du groupe témoin, ayant bénéficié d’un traitement à base de solution saline ; et finalement ceux ayant été traités au moyen des VEGF et NGF. À noter que les lapins ont reçu une micro-injection intracérébrale de VEGF et de NGF ou de solution saline 5 heures ou 8 heures à la suite de leur AVC. Ces deux délais d’administration des VEGF et NGF sont équivalents ou supérieurs aux délais actuels d’administration des VEGF ou NGF à titre de monothérapie (3 heures ou 5 heures à la suite d’un AVC). Tant le volume des infarctus, le contenu en eau, les déficits neurologiques ainsi causés, l’apoptose des neurones que l’expression des protéases caspase 3 et des protéines Bcl-2 ont été mesurés.Résultats:Si on la compare au traitement à base de solution saline administré au groupe témoin, la polythérapie à base de VEGF et de NGF, lorsqu’administrée 5 heures ou 8 heures à la suite de l’AVC, a su réduire de façon notable le volume des infarctus, le contenu en eau, l’apoptose des neurones et l’expression des protéases caspase 3. Elle a également permis de réguler à la hausse l’expression des protéines Bcl-2 en plus d’entraîner une amélioration de la récupération fonctionnelle (p< 0,01 pour ces deux aspects). Ainsi donc, plus tôt l’on opte pour cette polythérapie, meilleure sera la neuroprotection encourue.Conclusions:Ces résultats démontrent que la polythérapie à base de VEGF et de NGF procure des effets neuroprotecteurs. Quant au délai d’administration de ce traitement combinatoire, il devrait être d’au moins 8 heures à la suite d’un AVC, ce qui est plus élevé que la monothérapie.

Effect of SRY-Related High Mobility Group Box 9 on Extracellular Signal-Regulated Kinase/p38 Signaling Pathway in Glioma

2021 ◽  
Vol 11 (1) ◽  
pp. 171-175
Author(s):  
Tianlong Quan ◽  
Chunhua Zhang ◽  
Xin Song ◽  
Lu Wang
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Invasion ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
High Mobility ◽  
Negative Control ◽  
Glioma Cell Line ◽  
High Mobility Group ◽  
Control Group

As a common malignant tumor in neurosurgery, glioma is characterized as high incidence rate, easy to invade, metastasize and recurrent. It is difficult to treat and has a poor prognosis. The gliomas pathogenesis is complex and has not been fully resolved. Therefore, finding effective molecular targets for glioma is beneficial to improve therapeutic effect. The SRY-related high mobility group box 9 (SOX9) gene involves in mammalian development and is significantly increased in glioma. However, SOX9’s role in gliomas is unclear. The glioma cell line U87 was assigned into control group, scramble group that was transfected with siRNA negative control, and SOX9 siRNA group that was transfected with SOX9 siRNA followed by analysis of SOX9 mRNA and protein level by qPCR and Western blot, cell proliferation by MTT assay, cell apoptosis by Caspase 3 activity assay, cell invasion by Transwell assay, and MMP-9 level by ELISA. SOX9 siRNA transfection significantly downregulated SOX9 mRNA and protein expressions, inhibited U87 cell proliferation, enhanced Caspase 3 activity, suppressed cell invasion of U87, decreased the secretion of MMP-9 in the supernatant, and reduced ERK1/2 and P38 phosphorylation levels (P < 0.05). SOX9 can regulate the progression of glioma by regulating ERK/P38 signaling pathway, promoting cell apoptosis, inhibiting cell proliferation, and restraining cell invasion.

scholarly journals Combination Therapy with a JNK Inhibitor and Hepatocyte Growth Factor for Restoration of Erectile Function in a Rat Model of Cavernosal Nerve Injury: Comparison with a JNK Inhibitor Alone or Hepatocyte Growth Factor Alone

2021 ◽  
Vol 22 (23) ◽  
pp. 12698
Author(s):  
Junghoon Lee ◽  
Soo Woong Kim ◽  
Min Chul Cho
Keyword(s):  
Growth Factor ◽  
Combination Therapy ◽  
Hepatocyte Growth Factor ◽  
Rat Model ◽  
Erectile Function ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Group I ◽  
Jnk Inhibitors ◽  
Hepatocyte Growth

We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into 5 groups: sham-surgery-group (S), CNCI (I) group, a group treated with once-daily intraperitoneal-administration of 10.0-mg/kg of JNK-inhibitors (J), a twice-weekly intracavernosal-administration of 4.2-μg HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors and 4.2-μg HGF group (J+H). We investigated erectile-responses to electrostimulation, histological-staining, caspase-3-activity-assay, and immunoblotting at two-weeks postoperatively. The three treatment groups showed improvements in erectile-responses (ICP/MAP and AUC/MAP ratios) compared to Group-I. The erectile-responses in Group-J+H were greater than those in Group-J or Group-H. The erectile-responses in Group-J+H were generally normalized. Caspase-3-activity and cJun-phosphorylation in Group-J and Group-J+H improved compared to Group-I, whereas caspase-3-activity in Group-H partially improved. Protein-expression of PECAM-1, eNOS-phosphorylation, and smooth-muscle content in Group-J+H were normalized, although those in Group-J or Group-H were partially restored. Combination therapy with JNK-inhibitors and HGF can generally normalize erectile-function through anti-apoptosis and preservation of endothelium or SM in rat CNCI model. The combined treatment appears to be superior to the respective agent alone in terms of therapeutic effects.

scholarly journals Mechano growth factor attenuates mechanical overload-induced nucleus pulposus cell apoptosis through inhibiting the p38 MAPK pathway

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Qing Xu ◽  
Haolin Fang ◽  
Liang Zhao ◽  
Cunxin Zhang ◽  
Luo Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Nucleus Pulposus ◽  
P38 Mapk ◽  
Disc Degeneration ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Mapk Pathway ◽  
P38 Mapk Pathway ◽  
Mechanical Overload

Abstract Mechanical overload is a risk factor of disc degeneration. It can induce disc degeneration through mediating cell apoptosis. Mechano growth factor (MGF) has been reported to inhibit mechanical overload-induced apoptosis of chondrocytes. The present study is aimed to investigate whether MGF can attenuate mechanical overload-induced nucleus pulposus (NP) cell apoptosis and the possible signaling transduction pathway. Rat NP cells were cultured and subjected to mechanical overload for 7 days. The control NP cells did not experience mechanical load. The exogenous MGF peptide was added into the culture medium to investigate its protective effects. NP cell apoptosis ratio, caspase-3 activity, gene expression of Bcl-2, Bax and caspase-3, protein expression of cleaved caspase-3, cleaved PARP, Bax and Bcl-2 were analyzed to evaluate NP cell apoptosis. In addition, activity of the p38 MAPK pathway was also detected. Compared with the control NP cells, mechanical overload significantly increased NP cell apoptosis and caspase-3 activity, up-regulated gene/protein expression of pro-apoptosis molecules (i.e. Bax, caspase-3, cleaved caspase-3 and cleaved PARP) whereas down-regulated gene/protein expression of anti-apoptosis molecule (i.e. Bcl-2). However, exogenous MGF partly reversed these effects of mechanical overload on NP cell apoptosis. Further results showed that activity of the p38 MAPK pathway of NP cells cultured under mechanical overload was decreased by addition of MGF peptide. In conclusion, MGF is able to attenuate mechanical overload-induced NP cell apoptosis, and the p38 MAPK signaling pathway may be involved in this process. The present study provides that MGF supplementation may be a promising strategy to retard mechanical overload-induced disc degeneration.

siRNA Interference with Notch1 Affects LPS-Induced Apoptosis of Rat Intestinal Epithelial Cells

2020 ◽  
Vol 10 (5) ◽  
pp. 640-646
Author(s):  
Jing Li ◽  
Guanming Ruan ◽  
Xiaoyan Hu ◽  
Juhui He
Keyword(s):  
Epithelial Cell ◽  
Notch Signaling ◽  
Cell Apoptosis ◽  
Intestinal Epithelial Cell ◽  
Caspase 3 ◽  
Control Group ◽  
Ros Production ◽  
Intestinal Epithelial ◽  
Colon Tissue ◽  
Epithelial Cell Apoptosis

Notch signaling is associated with the pathogenesis of ulcerative colitis (UC). This study investigated whether the Notch regulates intestinal epithelial cell apoptosis and reactive oxygen species (ROS) production. Rats were separated into UC model group and control group followed by analysis of the expression of Notch1, Hes1 and OLFM4 by real-time PCR and western blot, content of malondialdehyde (MDA), superoxide dismutase (SOD) and caspase-3 as well as cell apoptosis by flow cytometry. Under LPS stimulation conditions, IEC-6 cells were divided into LPS + siRNA-NC group and LPS + siRNA-Notch1 group and Notch1, Hes1 and OLFM4 level as well as ROS was measured. Compared with control group, the activity of caspase-3, MDA and apoptosis in colon tissue of UC model were significantly increased with decreased SOD activity and increased Notch1, Hes1 and OLFM4 expression. LPS treatment can significantly up-regulate the expression of Notch1, Hes1 and OLFM4 in IEC-6 cells, increase cell apoptosis and ROS production. Notch1 interference by siRNA significantly downregulated Notch1, Hes1, and OLFM4 in IEC cells, and increased cell apoptosis and ROS production. UC lesions can activate Notch signaling pathway in colon tissue, which may play a role in repair. Interference with Notch1 signaling may aggravate intestinal epithelial cell apoptosis and ROS production in an inflammatory environment.

scholarly journals Effects of Heme Oxygenase 1 on Brain Edema and Neurologic Outcome after Cardiopulmonary Resuscitation in Rats

2008 ◽  
Vol 109 (2) ◽  
pp. 260-268 ◽  
Author(s):  
Bing Zhang ◽  
Xia Wei ◽  
Xiaoguang Cui ◽  
Tsutomu Kobayashi ◽  
Wenzhi Li
Keyword(s):  
Cardiac Arrest ◽  
Water Content ◽  
Brain Edema ◽  
Heme Oxygenase ◽  
Caspase 3 ◽  
Neurologic Deficit ◽  
Neurologic Outcome ◽  
Control Group ◽  
Heme Oxygenase 1 ◽  
Tin Protoporphyrin

Background Heme oxygenase 1 (HO-1) has been shown to attenuate neuronal injury. Therefore, the authors examined whether HO-1 would reduce the brain damage caused by cardiac arrest. Methods Rats anesthetized with halothane were subjected to 8 min of cardiac arrest by asphyxia without any pretreatment (control group) or pretreated with an inducer of HO-1 (hemin group) or with an inhibitor of HO-1 (tin protoporphyrin group). Then, the animals were resuscitated with a standardized method. Brain water content (1 and 6 h after resuscitation), neurologic deficit score, viable neuronal counts, and caspase-3 immunostaining in the hippocampus (4 and 14 days) were evaluated. Results Water content in the hemin group was significantly reduced (mean +/- SD: 83.1 +/- 1.9% for 1 h after resuscitation; P = 0.03) and significantly greater in the tin protoporphyrin group (91.1 +/- 2.0% for 1 h after resuscitation; P = 0.035) when compared with the control group (88.2 +/- 2.4%). Water content of the cortex was nearly the same as that of the hippocampus. Neurologic deficit scores and neuronal survival were significantly better in the hemin group than in the control group on the 4th and 14th days. In rats that survived for 4 days, the amount of caspase 3-positive neurons was 27 +/- 7 in the control group, whereas the value was 14 +/- 6 in the hemin group (P &lt; 0.05). Conclusions In rats resuscitated from cardiac arrest, induction of HO-1 by hemin reduced brain edema, improved neurologic outcome, and protected neurons against apoptosis.

scholarly journals Responses of apoptosis and matrix metabolism of annulus fibrosus cells to different magnitudes of mechanical tension in vitro

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Yanhai Jiang ◽  
Lianqiang Fu ◽  
Yeliang Song
Keyword(s):  
Protein Expression ◽  
Cell Apoptosis ◽  
Annulus Fibrosus ◽  
Caspase 3 ◽  
Mechanical Load ◽  
Control Group ◽  
Mechanical Tension ◽  
Matrix Metabolism ◽  
Apoptosis Ratio

Abstract Background: Annulus fibrosus (AF) is important to confine disc nucleus pulposus (NP) tissue during mechanical load experience. However, the knowledge on AF cell biology under mechanical load is much limited compared with disc NP. Objective: The present study aimed to investigate responses of apoptosis and matrix metabolism of AF cells to different magnitudes of mechanical tension in vitro. Methods: Rat AF cells were subjected to different magnitudes (5, 10, and 20% elongations at a frequency of 1.0 Hz for 6 h per day) of mechanical tension for 7 days. Control AF cells were cultured without mechanical tension. Cell apoptosis ratio, caspase-3 activity, gene/protein expression of apoptosis-related molecules (Bcl-2, Bax, caspase-3/cleaved caspase-3 and cleaved PARP), matrix macromolecules (aggrecan and collagen I) and matrix metabolism-related enzymes (TIMP-1, TIMP-3, MMP-3, and ADAMTS-4) were analyzed. Results: Compared with 5% tension group and control group, 10 and 20% tension groups significantly increased apoptosis ratio, caspase-3 activity, up-regulated gene/protein expression of Bax, caspase-3/cleaved caspase-3, cleaved PARP, MMP-3, and ADAMTS-4, whereas down-regulated gene/protein expression of Bcl-2, aggrecan, collagen I, TIMP-1, and TIMP-3. No significant difference was found in these parameters apart from Bcl-2 expression between the control group and 5% tension group. Conclusion: High mechanical tension promotes AF cell apoptosis and suppresses AF matrix synthesis compared with low mechanical tension. The present study indirectly indicates how mechanical overload induces disc degeneration through affecting AF biology.

scholarly journals Neural Cell Apoptosis Induced by Microwave Exposure Through Mitochondria-dependent Caspase-3 Pathway

2014 ◽  
Vol 11 (5) ◽  
pp. 426-435 ◽  
Author(s):  
Hongyan Zuo ◽  
Tao Lin ◽  
Dewen Wang ◽  
Ruiyun Peng ◽  
Shuiming Wang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Caspase 3 ◽  
Neural Cell ◽  
Microwave Exposure

scholarly journals VEGF Protects Brain against Focal Ischemia without Increasing Blood–Brain Permeability When Administered Intracerebroventricularly

2005 ◽  
Vol 25 (9) ◽  
pp. 1111-1118 ◽  
Author(s):  
Dilaver Kaya ◽  
Yasemin Gürsoy-Özdemir ◽  
Muge Yemisci ◽  
Neşe Tuncer ◽  
Sevinç Aktan ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Time Window ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Hemorrhagic Transformation ◽  
Vascular Endothelial ◽  
Blood Brain ◽  
Endothelial Growth Factor

Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood–brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently of the decrease in infarct size, VEGF also reduced the number of TUNEL-positive apoptotic neurons. Phospo-Akt levels were significantly higher in ischemic hemispheres of the VEGF-treated mice. Contrary to intracerebroventricular route, intravenous administration of VEGF (15 μg/kg) enhanced the infarct volume as previously reported for the rat. In conclusion, single intracerebroventricular injection of VEGF protects brain against ischemia without adversely affecting BBB permeability, and has a relatively long therapeutic time window. This early neuroprotective action, observed well before recovery-promoting actions such as angiogenesis, possibly involves activation of the PI-3-Akt pathway.

scholarly journals Effects of Irbesartan Pretreatment on Pancreatic β-Cell Apoptosis in STZ-Induced Acute Prediabetic Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Cuihong Chen ◽  
Li Li ◽  
Haijing Qin ◽  
Zhenxing Huang ◽  
Jing Xian ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Mouse Model ◽  
Mrna Expression ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Cell Damage ◽  
Quantitative Polymerase Chain Reaction ◽  
Fasting Blood Glucose ◽  
Mitogen Activated Protein Kinase ◽  
Control Group

The current study was performed to investigate the effects and potential effects of irbesartan pretreatment on pancreatic β-cell apoptosis in a streptozotocin- (STZ-) induced acute mouse model of prediabetes. Twenty-four male BALB/C mice (18–22 g) were randomly divided into three groups: normal control group (NC, n=6), STZ group (STZ, n=8), and irbesartan + STZ group (IRB + STZ, n=10). In the IRB + STZ group, mice were administered irbesartan (300 mg/kg per day) by gavage for one week. The STZ group and IRB + STZ group received STZ (80 mg/kg by intraperitoneal (IP) injection once). The NC group received normal saline (80 mg/kg by IP injection once). Fasting blood glucose prior to STZ injection and presacrifice was analysed using samples withdrawn from the caudal vein to confirm the induction of prediabetes. Haematoxylin and eosin staining, immunohistochemical detection of insulin, and apoptosis analysis were performed. Reverse transcription-quantitative polymerase chain reaction was used to detect angiotensin II type 1 receptor (AT1R), caspase-3, and p38 mitogen-activated protein kinase (MAPK) mRNA expression. Blood glucose was significantly higher in the STZ group (9.01 ± 1.1089 vs 4.78 ± 0.7026) and IRB + STZ group (7.86 ± 1.1811 vs 4.78 ± 0.7026) compared with the NC group (P<0.05). In comparison to the STZ group, the islet cell damage was marginally improved in the IRB + STZ group, and the IRB + STZ group had a significantly lower apoptotic rate than the STZ group (22.42 ± 8.3675 vs 50.86 ± 5.3395, P<0.001). AT1R expression in the IRB + STZ group was lower than that in the STZ group (1.56 ± 1.2207 vs 3.92 ± 2.4392, P<0.05). The mRNA expression of caspase-3 in pancreatic tissue was significantly lower in the IRB + STZ group than in the STZ group (0.90 ± 0.7272 vs 1.88 ± 1.0572, P<0.05). Similarly, the IRB + STZ group also had lower p38MAPK levels than the STZ group (1.16 ± 1.0642 vs 2.55 ± 1.7925, P>0.05). In conclusion, irbesartan pretreatment improved glucose levels and insulin secretion and decreased islet β-cell apoptosis to protect islet β cells in an STZ-induced acute prediabetic mouse model.

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