scholarly journals Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction

2018 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Bettina Wilm ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Liver Function ◽  
Mouse Model ◽  
Organ Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Optoacoustic Tomography ◽  
Kidney Liver

AbstractCell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages.

scholarly journals A Noninvasive Imaging Toolbox Indicates Limited Therapeutic Potential of Conditionally Activated Macrophages in a Mouse Model of Multiple Organ Dysfunction

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Lauren Scarfe ◽  
Bettina Wilm ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Liver Function ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
Optoacoustic Tomography ◽  
Multiple Organs ◽  
Kidney Liver

Cell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution, and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multispectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver, and cardiac injury and the extent of functional recovery to be assessed noninvasively in a mouse model of multiorgan dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy provided limited improvement of kidney and liver function, although not significantly so, without amelioration of histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages. More importantly, we demonstrate here the utility of the imaging toolbox for assessing the efficacy of potential regenerative medicine therapies in multiple organs.

Abstract 15: Limiting GRK2 in the Ischemic Heart can Promote Cardiac Regeneration

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Maria Cecilia Scimia ◽  
Lin Zuo ◽  
Kate E Sydnes ◽  
Daniel A Zuppo ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Cardiac Repair ◽  
Functional Improvement ◽  
Coronary Artery Ligation ◽  
Therapeutic Effects ◽  
Artery Ligation ◽  
C Terminus ◽  
Independent Effects

The detrimental role of G protein-coupled receptor (GPCR) kinase (GRK2) following cardiac injury/stress has been documented over the last two decades. Importantly, our lab has shown that inhibition or deletion of GRK2 in cardiomyocytes can prevent and also rescue heart failure (HF) phenotypes. Its role in GPCR desensitization including regulation of β-adrenergic receptors (βARs) during HF development has been well characterized. However, recently our lab and others have found that GRK2 can have novel GPCR-independent effects in the heart that appear to contribute to its pathological effects and thus, inhibition of these actions of GRK2 may contribute to therapeutic effects seen. In this study we explored whether the cardiac repair observed with lower myocardial GRK2 might involve regenerative processes. In cardiac-specific GRK2 knockout (KO) mice and also transgenic mice with cardiac-targeted expression of the βARKct, a peptide inhibitor of GRK2 activation via Gβγ sequestration, we induced HF via coronary artery ligation and subsequent myocardial infarction (MI) and measured aspects of cardiac repair including potential regeneration indices. Post-MI mice (GRK2 KO, βARKct mice and wild-type and non-transgenic control mice) were treated with 5-ethynyl-2’-deoxyuridine (EdU) or Bromodeoxyuridine (BrDU) to examine indices of DNA proliferation in myocytes as well as Ki67 staining. We also quantitated c-kit+ cells and myocytes in the post-MI hearts to compare how either loss of GRK2 expression or inhibition via its C-terminus altered potential regeneration mechanisms compared to control mice with endogenous GRK2 levels and activity. We found significantly more BrDU positive myocytes in post-MI hearts with lower GRK2 and this correlated with increased myocytes that were also cKit+. Thus, it appears that the myocardial functional improvement seen in the post-MI heart with targeted lowering of GRK2 involves, to at least a certain extent, regenerative mechanisms. This adds novel insight into the therapeutic potential of GRK2 inhibition for HF.

Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats

2008 ◽  
Vol 45 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Jeng-Yuan Wu ◽  
Mei-Yung Tsou ◽  
Tai-Hao Chen ◽  
Shiu-Jen Chen ◽  
Cheng-Ming Tsao ◽  
...  
Keyword(s):  
Septic Shock ◽  
Organ Dysfunction ◽  
Multiple Organ Dysfunction Syndrome ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
Multiple Organ Dysfunction

scholarly journals Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Tatsuma Kishimoto ◽  
Waka Ishida ◽  
Ken Fukuda ◽  
Isana Nakajima ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enterococcus Faecalis ◽  
Structural Integrity ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Content Type ◽  
Viable Bacteria ◽  
Vancomycin Resistant

ABSTRACT Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

Therapeutic effects of melatonin on heatstroke-induced multiple organ dysfunction syndrome in rats

2011 ◽  
Vol 50 (4) ◽  
pp. 436-444 ◽  
Author(s):  
Xiao-Jing Lin ◽  
Gui-Ping Mei ◽  
Jian Liu ◽  
Yi-Lei Li ◽  
Dan Zuo ◽  
...  
Keyword(s):  
Organ Dysfunction ◽  
Multiple Organ Dysfunction Syndrome ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
Multiple Organ Dysfunction

scholarly journals Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yin Ho ◽  
Li Lin ◽  
I-Chun Chen ◽  
Che-Wen Tsai ◽  
Fang-Chia Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Model Potential ◽  
Temperature Tolerance ◽  
Epileptic Activity ◽  
Dravet Syndrome ◽  
Therapeutic Effects ◽  
Discharge Duration ◽  
Spontaneous Recurrent Seizures

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

scholarly journals M1 Macrophage-Derived Nanovesicles Repolarize M2 Macrophages for Inhibiting the Development of Endometriosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiuju Li ◽  
Ming Yuan ◽  
Xue Jiao ◽  
Yufei Huang ◽  
Jing Li ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tube Formation ◽  
Reproductive Age ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Social Burden ◽  
M1 Macrophage ◽  
And Migration ◽  
Gynecological Disorder

BackgroundEndometriosis is a common nonmalignant gynecological disorder that affects 10–15% women of reproductive age and causes several symptoms that result in decreased quality of life and a huge social burden. In recent decades, extracellular vesicles (EVs) have gained attention as a potential therapeutic tool; however, the therapeutic effects of EVs against endometriosis have not been reported. Accordingly, in this study, we investigated the feasibility of nanovesicles (NVs) derived from M1 macrophages (M1NVs) in treating endometriosis.MethodsM1NVs were prepared by serial extrusion. Co-culture assays were performed to investigate changes in tube formation and migration/invasion of eutopic endometrial stroma cells (ESCs) obtained from patients with endometriosis (EM-ESCs). A mouse model of endometriosis was established, and mice were treated with phosphate-buffered saline, M0NVs, or M1NVs to evaluate the efficacy and safety of M1NV for treating endometriosis.ResultsM1NVs directly or indirectly inhibited the migration and invasion of EM-ESCs and reduced tube formation. In the mouse model, M1NVs suppressed the development of endometriosis through reprogramming of M2 macrophages, without causing damage to the organs.ConclusionsM1NVs inhibit the development of endometriosis directly, or through repolarizing macrophages from M2 to M1 phenotype. Hence, administration of M1NVs may represent a novel method for the treatment of endometriosis.

scholarly journals Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

2021 ◽  
Author(s):  
Jiqing Yang ◽  
Zunyue Zhang ◽  
Zhenrong Xie ◽  
Ling Bai ◽  
Pu Xiong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Therapeutic Potential ◽  
Withdrawal Symptoms ◽  
Anxiety And Depression ◽  
Therapeutic Effects ◽  
List Type ◽  
Psychiatric Manifestations ◽  
Behavioural Deficits

ABSTRACTObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota.MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.Study HighlightsWhat is known?There are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates.Metformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei.What is new here?METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model.The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites.Inosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours.

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