scholarly journals Inflammasome Regulation at the Level of Cellular and Molecular Function affect by Recombinant Tissue Plasminogen Activator and Exosomes Treatment in Ischemic Stroke Animal Model

2021 ◽  
Author(s):  
Mohsen Safakhil ◽  
Mina Ramezani ◽  
Azadeh Mohamadgholi
Keyword(s):  
Animal Model ◽  
Cell Death ◽  
Combination Therapy ◽  
Functional Recovery ◽  
Therapy Group ◽  
Neuronal Cell ◽  
Cresyl Violet ◽  
Treatment Groups ◽  
Cresyl Violet Staining ◽  
All Treatment

Abstract In the current research, neuroprotection and performance improvement have been investigated in MCAO animal model treated with exosomes combined with rt-PA. Middle cerebral artery occlusion (MCAO) was induced in 25 adult male Wistar rats. Rats received rt-PA with a dose of 100 µg/kg in a single dose or drived-exosome from bone marrow MSCs. The Garcia scoring system and elevated body test were employed as behavioral tests for the functional recovery assessment. Cresyl violet staining was applied to evaluate the cell death degree in brain tissues. Immunohistochemical analysis was performed for the detection of GFAP and IBA1-positive cells. Results Cresyl violet staining revealed that the population of dark cells was significantly reduced in all treatment groups. A considerable increase (P ≤ 0.05) in catalase enzyme was observed in the combination therapy group compared whit the MCAO group (P ≤ 0.05). The amount of GPX despite the increase in all treatment groups compared to MCAO group was not statistically significant (P ≥ 0.05). Our conclusion was approved by the Nlrp1 and Nlrp3 downregulation during combination therapy in MCAO model by reduction in cell death rate. The Density of GFAP-positive cells Showed a decrease in the exosome with or without rt-PA experimental groups in comparison with the MCAO group (P < 0.05). Our observation indicated that exosomes, in combination with rt-PA, resulted in the noticeable functional recovery, neuronal regeneration, and reduction of neuronal cell death after a 7-day period of the MCAO induction. This novel therapeutic strategy could provide a better treatment option for those patients suffered from stroke.

Combination Bortezomib (PS341, Velcade) and Rituximab Treatment Affects Multiple Survival and Death Pathways To Promote Apoptosis in Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2407-2407 ◽  
Author(s):  
Navin Wadehra ◽  
Teresa Lin ◽  
Timothy Ryan ◽  
Ashley Schneider ◽  
Allison Pepple ◽  
...  
Keyword(s):  
Animal Model ◽  
Cell Death ◽  
Combination Therapy ◽  
Mantle Cell Lymphoma ◽  
Combination Treatment ◽  
Cell Lymphoma ◽  
Proteasome Inhibition ◽  
Mantle Cell ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkin’s lymphoma that is associated with an aggressive clinical course and a particularly poor prognosis. The mechanisms that contribute to resistance of MCL to chemotherapy are not clear, however, recent work examining the consequences of ubiquitin-proteasome pathway inhibition on cell cycle (p21, p27) and key survival/death networks (NFkB, p53, Bcl2) has provided rationale for exploring combination regimens that include tumor-specific reagents (rituximab) and the 26S proteasome inhibitor bortezomib. In this study, we examined the effects of combination treatment with bortezomib and rituximab on MCL patient samples and three patient-derived cell lines (Jeko, Mino, SP53). Cells treated with bortezomib (10 – 100nM) for 4 hours demonstrated proteasome inhibition that persisted for 24 hours but returned to baseline activity at 48 hours after treatment. Despite transient proteasome inhibition, combination therapy with bortezomib (10–100nM for 4hrs) and rituximab (1 mg/ml immobilized with 20 mg/ml goat anti-human IgG) resulted in synergistic induction of apoptosis that persisted for as long as 72 hours after treatment. While bortezomib (100 nM) induced apoptosis in 18.3 ± 6.5% and rituximab induced apoptosis in 24.5 ± 4.5% of MCL cells, combination treatment resulted in 57.4 ± 5.1% apoptosis at 48 hours (p ≤ 0.02). Pretreatment of MCL cells with the broad spectrum caspase inhibitor zVAD-FMK (10 mM) showed that bortezomib-induced cell death occurred by caspase-dependent mechanisms, however, when immobilized rituximab was added, cell death occurred via caspase dependent and independent pathways. Single agent bortezomib (10 nM) or rituximab treatment of Mino and Jeko lines resulted in decreased levels of nuclear NFkB complex(s) capable of binding p65 consensus oligonucleotides (28% and 21% reduction, respectively), while combination treatment resulted in enhanced reduction of detectable nuclear NFkB (36% reduction, p ≤ 0.0007). Similar trends were observed with primary MCL cells. Experiments with an IKK inhibitor (PS1145, Millenium Pharmaceuticals) resulted in nuclear NFkB reduction without equivalent induction of apoptosis which led us to hypothesize that other pro-death pathways might be operable with combination treatment. Western blot analysis of BCL2-family members revealed that combination treatment of MCL lines resulted in near complete elimination of Bcl-xL protein while Bcl-2 protein levels remained unchanged. The pro-death gene product Bax was induced in a synergistic fashion with combined bortezomib and rituximab treatment. Finally, we have developed a reliable preclinical animal model utilizing the severe combined immune deficient (SCID) mouse engrafted with three patient-derived MCL cell lines. Each cell line results in a characteristic pattern of tumor burden and highly reproducible time to develop advanced disease. We are currently evaluating combination therapy with bortezomib and rituximab in this preclinical animal model. Our preclinical evaluation provides clear rationale for pursuing combination strategies that inhibit the proteasome in combination with tumor-specific immunotherapy in patients with MCL.

scholarly journals Treatment with Linezolid or Vancomycin in Combination with Rifampin Is Effective in an Animal Model of Methicillin-ResistantStaphylococcus aureusForeign Body Osteomyelitis

2010 ◽  
Vol 55 (3) ◽  
pp. 1182-1186 ◽  
Author(s):  
Paschalis Vergidis ◽  
Mark S. Rouse ◽  
Gorane Euba ◽  
Melissa J. Karau ◽  
Suzannah M. Schmidt ◽  
...  
Keyword(s):  
Animal Model ◽  
Foreign Body ◽  
Proximal Tibia ◽  
Bacterial Load ◽  
Control Group ◽  
Treatment Groups ◽  
Titanium Wire ◽  
Experimental Rat Model ◽  
Rifampin Resistance ◽  
All Treatment

ABSTRACTRifampin monotherapy was compared to the combination of linezolid or vancomycin with rifampin in an experimental rat model of methicillin-resistantStaphylococcus aureus(MRSA) chronic foreign body osteomyelitis. MRSA was inoculated into the proximal tibia, and a titanium wire was implanted. Four weeks after infection, rats were treated intraperitoneally for 21 days with rifampin alone (n= 16), linezolid plus rifampin (n= 14), or vancomycin plus rifampin (n= 13). Thirteen animals received no treatment. At completion of treatment, qualitative cultures of the wire and quantitative cultures of the bone (reported as median values) were performed. Quantitative cultures from the control, rifampin monotherapy, linezolid-plus-rifampin, and vancomycin-plus-rifampin groups revealed 4.54, 0.71, 0.10, and 0.50 log10CFU/gram of bone, respectively. The bacterial load was significantly reduced in all treatment groups compared to that in the control group. Rifampin resistance was detected in isolates from 10, 2, and 1 animal in the rifampin, linezolid-plus-rifampin, and vancomycin-plus-rifampin groups, respectively. Cultures of the removed wire revealed bacterial growth in 1 and 2 animals in the rifampin and linezolid-plus-rifampin groups, respectively, with no growth in the vancomycin-plus-rifampin group and growth from all wires in the untreated group. In conclusion, we demonstrated that combination treatment with linezolid plus rifampin or vancomycin plus rifampin is effective in an animal model of MRSA foreign body osteomyelitis in the context of retention of the infected foreign body.

Abstract 2741: S-Nitrosoglutathione Increases Benefit of Motor Exercise on Functional Recovery and Stimulates Neurorepair Mechanisms Following Experimental Stroke in Rats

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Mushfiquddin Khan ◽  
Harutoshi Sakakima ◽  
Tajinder S Dhammu ◽  
Shunmugavel Anandakumar ◽  
Inderjit Singh ◽  
...  
Keyword(s):  
Cell Death ◽  
Functional Recovery ◽  
Neurotrophic Factors ◽  
Neuronal Cell ◽  
Male Rats ◽  
Experimental Stroke ◽  
Protective Agent ◽  
Neurobehavioral Function ◽  
Long Term Treatment

Background: Stroke is the leading cause of long-term physical disability and life-long neurologic deficits. The disability stems from acute neurovascular injury and injury-induced compromised neuroplasticity. This neuroplasticity can be restored by stimulating neurotrophic factors via two possible modalities: rehabilitation activity and neurorepair therapy. Improvement of neurologic function has been achieved following brain trauma by the neurovascular protective agent S-nitrosoglutathione (GSNO). Therefore, we investigated whether GSNO stimulates the expression neurotrophic factors and enhances the benefits of motor exercise, leading to functional recovery in a rat model of experimental stroke. Methods: Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) for 60 min followed by reperfusion in adult male rats. Injured animals were either treated with vehicle (IR group), GSNO (0.25 mg/kg, GSNO group) or underwent rotarod exercise (EX group). In the third treatment group, GSNO was combined with rotarod exercise (GSNO+EX group). The groups were compared in terms of brain infarction, neurological score, motor function, cell death, tissue structure, and the expression of the neurotrophic factors BDNF, TrKB, and myelin. Results: All three treated groups (GSNO, EX and GSNO+EX) showed reduced infarction, improved motor and neurological functions, and decreased apoptotic neuronal cell death compared to the IR group. However, the combination group GSNO+EX showed a trend toward greater recovery than the GSNO or EX group alone. All the three treated groups also showed enhanced expression of neurotrophic factors and improved tissue histology. A delayed intervention (24 h after IR) by GSNO also aided the functional recovery. Furthermore, the protective effect of GSNO and exercise was blunted in another set of animals by an inhibition of AKT activity using the PI3 kinase inhibitor LY 294002 compound. Conclusion: GSNO, like exercise, aids recovery of functions in a long-term treatment by stimulating the expression of neurotrophic factors, reducing infarctions, and decreasing cell death. A combination of exercise and GSNO shows a greater degree of improvement in neurobehavioral function. Clinical relevance of the therapy is supported by an improved functional recovery even when GSNO was administered 24 h following IR. Mechanistically, the improvements by GSNO and exercise are dependent, at least in part, on AKT activity.

scholarly journals Activity of Omadacycline in Rat Methicillin-Resistant Staphylococcus aureus Osteomyelitis

2021 ◽  
Author(s):  
Melissa J. Karau ◽  
Suzannah M. Schmidt-Malan ◽  
Scott A. Cunningham ◽  
Jayawant N. Mandrekar ◽  
Bobbi S. Pritt ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bacterial Load ◽  
Potential Treatment ◽  
Combination Therapies ◽  
Treatment Groups ◽  
Experimental Rat Model ◽  
Rifampin Resistance ◽  
All Treatment

Omadacycline, vancomycin and rifampin as well as rifampin combination therapies were evaluated in an experimental rat model of MRSA osteomyelitis. All treatment groups had less MRSA recovered than saline-treated animals. Emergence of rifampin resistance was observed in 3 of 16 animals with rifampin monotherapy, and none with rifampin combination therapy. After treatment, the median tibial bacterial load was 6.04, 0.1, 4.81 and 5.24 log 10 cfu/g for saline-, rifampin-, vancomycin- and omadacycline-treated animals. Omadacycline or vancomycin administered with rifampin yielded no detectable MRSA. Omadacycline, administered with rifampin, deserves evaluation in humans as a potential treatment for osteomyelitis.

scholarly journals Activity of Tedizolid in Methicillin-Resistant Staphylococcus epidermidis Experimental Foreign Body-Associated Osteomyelitis

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Kyung-Hwa Park ◽  
Kerryl E. Greenwood-Quaintance ◽  
Audrey N. Schuetz ◽  
Jayawant N. Mandrekar ◽  
Robin Patel
Keyword(s):  
Foreign Body ◽  
Combination Therapy ◽  
Rat Model ◽  
Staphylococcus Epidermidis ◽  
Steel Wire ◽  
Clinical Strain ◽  
Methicillin Resistant ◽  
Infection Period ◽  
Treatment Groups ◽  
All Treatment

ABSTRACT We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) foreign body-associated osteomyelitis and used it to compare tedizolid alone and in combination with rifampin against rifampin alone, vancomycin plus rifampin, and vancomycin alone. A clinical strain of MRSE was inoculated into the proximal tibia, and a stainless steel wire with a precolonized MRSE biofilm was implanted. Following a 1-week infection period, 92 rats received either no treatment (n = 17) or 14 days of intraperitoneal tedizolid (n = 15), tedizolid plus rifampin (n = 15), rifampin (n = 15), vancomycin plus rifampin (n = 15), or vancomycin (n = 15). Quantitative bone and wire cultures were performed after treatment completion and also 1 week after infection in a separate group of five rats. The median quantity of staphylococci in bone after the 1-week infection period was 4.89 log10 CFU/g bone (interquartile range, 3.83 to 5.33 log10 CFU/g bone); staphylococci were recovered from all associated wires. A median quantity of staphylococci of 3.70 log10 CFU/g bone was detected in bones of untreated control rats after 3 weeks. Quantities of staphylococci in bones of all treatment groups except the group receiving vancomycin alone (2.78 log10 CFU/g) were significantly lower than those for untreated controls, with no staphylococci being detected in the groups receiving rifampin monotherapy, tedizolid-plus-rifampin combination therapy, and vancomycin-plus-rifampin combination therapy. Quantities of staphylococci on wires from all treatment groups that included rifampin were significantly lower than those for untreated controls. No resistance to rifampin, tedizolid, or vancomycin was detected. Tedizolid combined with rifampin was active in a rat model of MRSE foreign body-associated osteomyelitis.

scholarly journals Neuroprotective Effect of Glatiramer Acetate on Neurofilament Light Chain Leakage and Glutamate Excess in an Animal Model of Multiple Sclerosis

2021 ◽  
Vol 22 (24) ◽  
pp. 13419
Author(s):  
Rina Aharoni ◽  
Raya Eilam ◽  
Shaul Lerner ◽  
Efrat Shavit-Stein ◽  
Amir Dori ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Cell Death ◽  
Glatiramer Acetate ◽  
Clinical Symptoms ◽  
Apoptotic Cell ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35–55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.

scholarly journals Near-Infrared Fluorescence Imaging of Apoptotic Neuronal Cell Death in a Live Animal Model of Prion Disease

2010 ◽  
Vol 1 (11) ◽  
pp. 720-727 ◽  
Author(s):  
Victoria A. Lawson ◽  
Cathryn L. Haigh ◽  
Blaine Roberts ◽  
Vijaya B. Kenche ◽  
Helen M. J. Klemm ◽  
...  
Keyword(s):  
Animal Model ◽  
Cell Death ◽  
Fluorescence Imaging ◽  
Prion Disease ◽  
Near Infrared ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Live Animal ◽  
Near Infrared Fluorescence ◽  
Near Infrared Fluorescence Imaging

Effects of BET inhibitor JQ1 on neurotoxicity in rat primary cortical neurons: A potential therapeutic approach in Alzheimer's disease

2016 ◽  
Vol 33 (S1) ◽  
pp. S139-S139
Author(s):  
S.H. Han ◽  
K.J. Kwon ◽  
C.Y. Shin ◽  
S.Y. Chung
Keyword(s):  
Animal Model ◽  
Cell Death ◽  
Amyloid Beta ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Primary Cortical Neurons ◽  
Bet Inhibitor ◽  
Neuro Inflammation ◽  
Pai 1

IntroductionThe neuropathological features of Alzheimer's disease (AD) are deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Among these, neuro-inflammation is a common pathological substrate of neurodegenerative disease, such as AD, and Parkinson disease.AimsHerein, we tested whether the inhibition of bromodomain and extra-terminal domain (BET) protein, a critical regulators of transcription in neurons, could attenuate the neuronal cell death and amyloid beta aggregation using rat primary cortical neurons. We also investigated whether a BET inhibitor could prevent the inflammatory processes and cognitive decline in an animal model of AD.MethodsThe effects of BET inhibition on neuronal cell death were assessed in the followings:– cell viability and reactive oxygen species generation;– enzyme activity of tPA/PAI-1 measured by casein zymography;– the signal pathways including BDNF/CREB and MAPKs using western blotting;– the effects on inflammatory responses in an animal model of AD using immunohistochemistry.ResultsJQ1, an inhibitor of Brd2/4 protein, significantly decreased the neuronal cell death in mixed cortical neurons in concentration-dependent manner but not in pure neurons. JQ1 increased the enzyme activity of tPA, which decreased the expression of Brd2 protein. JQ1 also decreased the ROS generation and decreased cleaved caspase-3 expression. Moreover, Brd2 inhibition by transfection of Brd2 siRNA reduced amyloid beta aggregation.ConclusionOur results suggested that BET inhibition might have therapeutic potential for AD. That is, Brd2 inhibition by JQ1 can prevent the neuronal cell death and neuroinflammation as well as amyloid beta aggregation through regulation of tPA/PAI-1 system.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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