scholarly journals Synthetic hydrogel nanoparticles for sepsis therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hiroyuki Koide ◽  
Anna Okishima ◽  
Yu Hoshino ◽  
Yuri Kamon ◽  
Keiichi Yoshimatsu ◽  
...  
Keyword(s):  
Lethal Dose ◽  
Intervention Strategy ◽  
High Capacity ◽  
Multiple Organs ◽  
Synthetic Hydrogel ◽  
Threatening Condition ◽  
Sepsis Therapy ◽  
Life Threatening ◽  
And Migration

AbstractSepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

scholarly journals Synthetic hydrogel nanoparticles for sepsis therapy

2021 ◽  
Author(s):  
Kenneth Shea ◽  
Hiroyuki Koide ◽  
Anna Okishima ◽  
Yu Hoshino ◽  
Yuri Kamon ◽  
...  
Keyword(s):  
Lethal Dose ◽  
Intervention Strategy ◽  
High Capacity ◽  
Multiple Organs ◽  
Synthetic Hydrogel ◽  
Threatening Condition ◽  
Sepsis Therapy ◽  
Life Threatening

Abstract Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protected mice against a lethal dose of histones through the inhibition of platelet migration into the lungs. In vivo administration in murine sepsis model mice resulted in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

Protein Phosphatase 2A Activation via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Haiyan Chu ◽  
Anastasia Sacharidou ◽  
An Nguyen ◽  
Chun Li ◽  
Ken L Chambliss ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Protein Phosphatase ◽  
In Vivo Studies ◽  
Hypertensive Disorder ◽  
Fetal Demise ◽  
Maternal Hypertension ◽  
Life Threatening ◽  
Phosphatase 2A ◽  
And Migration

Rationale: Preeclampsia (PE) is a potentially life-threatening, placenta-based hypertensive disorder during pregnancy, and the antiphospholipid syndrome (APS) frequently leads to PE. APS pregnancies are also complicated by fetal demise and intrauterine growth restriction (IUGR). Objective: Here we determined how the circulating antiphospholipid antibodies (aPL) characteristic of APS alter placental trophoblast function to cause PE and also endanger the fetus. Methods and Results: Experiments were performed in mice, in cultured human trophoblasts, and in human placenta samples. Effects of aPL and IgG from healthy subjects were compared. Based on prior findings in culture, in vivo studies were done in mice deficient in apolipoprotein E receptor 2 (ApoER2) in trophoblasts. Endpoints in tissues and cells were determined by enzymatic assay, Q-PCR, ELISA or immunoblotting. Whereas in wild-type mice aPL caused maternal hypertension and proteinuria, fetal demise and IUGR, mice lacking trophoblast ApoER2 were protected. In culture aPL attenuated trophoblast proliferation and migration via an ApoER2-related protein complex comprised of the protein phosphatase PP2A, Dab2, and JIP4. Via trophoblast ApoER2 in mice and in culture, aPL stimulated PP2A activity, leading to MMP14 and HIF1alpha upregulation and increased soluble endoglin (sEng) production. HIF1alpha and sEng upregulation was related to PP2A desphosphorylation of PHD2. In mice PP2A inhibition prevented aPL-induced maternal hypertension and proteinuria, and fetal demise and IUGR. Placentas from APS patients displayed PP2A hyperactivation, PHD2 dephosphorylation and HIF1α upregulation, and these findings were generalizable to placentas of women with PE from causes other from APS. Conclusions: In APS pregnancies trophoblasts are the critical cell target of aPL, and via ApoER2-dependent PP2A activation, aPL cause PE through MMP14 upregulation and PHD2 dephosphorylation leading to HIF1 and sEng upregulation. Moreover, parallel processes may be operative in PE in non-APS patients. Interventions targeting PP2A may provide novel means to combat APS-related PE and PE unrelated to APS.

Encapsulation of Astragaloside with Matrix Metalloproteinase-2-Responsive Hyaluronic Acid End-Conjugated Polyamidoamine Dendrimers Improves Wound Healing in Diabetes

2020 ◽  
Vol 16 (8) ◽  
pp. 1229-1240
Author(s):  
Dongping Zhang ◽  
Qiang Huang
Keyword(s):  
Wound Healing ◽  
Hyaluronic Acid ◽  
Wound Repair ◽  
Average Diameter ◽  
Matrix Metalloproteinase 2 ◽  
Impaired Wound Healing ◽  
Polyamidoamine Dendrimers ◽  
Life Threatening ◽  
And Migration

Impaired wound healing that occurs in diabetics can result in many life-threatening complications associated with excessive expression of matrix metalloproteinases (MMPs), which mediate the proteolysis of major matrix constituents. In this study, the dendrimer polyamidoamine (PAMAM) and the polysaccharide hyaluronic acid (HA) were connected through the substrate polypeptide (Gly-PLGLAG-Cys) of MMP-2 to obtain the MMP-2-responsive nanocarrier HA-pep-PAMAM. Insoluble astragaloside (ASI) was encapsulated in this nanocarrier to achieve controlled release at the site of intractable wounds. The HA-pep-PAMAM-ASI was successfully prepared with an average diameter of 142.3 ± 28.9 nm. Immunohistochemical staining of the skin revealed that the hard-to-heal wounds of diabetic mice showed stronger expression of MMP-2 than the wounds of normal mice. HA-pep-PAMAM-ASI achieved 73.9% release in the presence of MMP-2, but only 13.5% in PBS. A dose-dependent effect of H2O2 on the proliferation of BJ and HaCaT cells was observed, and HA-pep-PAMAM-ASI treatment had the best antioxidant capacity with MMP-2 pretreatment. HA-pep-PAMAM-ASI significantly increased GSH levels and reduced reactive oxygen species (ROS) levels to achieve antioxidant effects. The MMP-2-pretreated HA-pep-PAMAM-ASI group showed more improved cell proliferation and migration abilities. Compared with ASI group, the expression of all wound-repair-related genes in the group of HA-pep-PAMAM-ASI was significantly increased, and HA-pep-PAMAM-ASI showed a pronounced in vivo therapeutic effect. Therefore, our results revealed that enzyme-responsive MMP-2-loaded PAMAM nanoparticles could promote wound healing in diabetes and may be a promising biomaterial for treatment.

scholarly journals Proteomic atlas of organ vasculopathies triggered by Staphylococcus aureus sepsis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alejandro Gómez Toledo ◽  
Gregory Golden ◽  
Alexandre Rosa Campos ◽  
Hector Cuello ◽  
James Sorrentino ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Responses ◽  
High Resolution Mass Spectrometry ◽  
Vascular Dysfunction ◽  
Microbial Infection ◽  
Chemical Labeling ◽  
Vascular Cell ◽  
Multiple Organs ◽  
Threatening Condition

Abstract Sepsis is a life-threatening condition triggered by a dysregulated host response to microbial infection resulting in vascular dysfunction, organ failure and death. Here we provide a semi-quantitative atlas of the murine vascular cell-surface proteome at the organ level, and how it changes during sepsis. Using in vivo chemical labeling and high-resolution mass spectrometry, we demonstrate the presence of a vascular proteome that is perfusable and shared across multiple organs. This proteome is enriched in membrane-anchored proteins, including multiple regulators of endothelial barrier functions and innate immunity. Further, we automated our workflows and applied them to a murine model of methicillin-resistant Staphylococcus aureus (MRSA) sepsis to unravel changes during systemic inflammatory responses. We provide an organ-specific atlas of both systemic and local changes of the vascular proteome triggered by sepsis. Collectively, the data indicates that MRSA-sepsis triggers extensive proteome remodeling of the vascular cell surfaces, in a tissue-specific manner.

scholarly journals In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

2021 ◽  
Vol 7 (12) ◽  
pp. 1012
Author(s):  
Sana Jemel ◽  
Jacques Guillot ◽  
Kalthoum Kallel ◽  
Grégory Jouvion ◽  
Elise Brisebard ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Galleria Mellonella ◽  
Lethal Dose ◽  
Dose Assessment ◽  
Suitable Model ◽  
Invasive Infection ◽  
Larval Hemolymph ◽  
Life Threatening ◽  
Dose Dependent

Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus.

In Vitro Efficacy of Recombinant ADAMTS13 in Acquired TTP Patients with Anti-ADAMTS13 Inhibitory Antibody.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2295-2295
Author(s):  
Barbara Plaimauer ◽  
Claudia Juno ◽  
Friedrich Scheiflinger
Keyword(s):  
Current Treatment ◽  
Activity Level ◽  
Inhibitory Antibody ◽  
Multiple Organs ◽  
Life Threatening ◽  
The Individual ◽  
Von Willebrand ◽  
Functional Deficiency

Abstract Thrombotic thrombocytopenic purpura (TTP) is associated with a severe functional deficiency of the ADAMTS13 metalloprotease resulting in accumulation of highly adhesive ultra-large von Willebrand factor (ULVWF) multimers. ULVWF promote spontaneous platelet clumping eventually leading to life-threatening widespread microvascular thrombosis in multiple organs. Inhibitory and non-inhibitory anti-ADAMTS13 autoantibodies that result in functional deficiency and/or accelerated in vivo clearance of ADAMTS13 have been detected in patients suffering from acquired idiopathic TTP. Current treatment with plasma exchange therapy is considered to remove the autoantibodies and to replenish plasma with the deficient protease. While researching therapeutic recombinant ADAMST13 (rADAMTS13) as a possible treatment modality for TTP patients, we investigated the in vitro potency of rADAMTS13 to overwhelm and neutralize circulating anti-ADAMTS13 antibodies and concurrently to reinstate plasma ADAMTS13 to normal. Mixing and incubating patient plasma with normal reagent plasma and subsequent FRETSVWF73 activity analysis was used to calculate the individual anti-ADAMTS13 inhibitor titers in 36 untreated idiopathic TTP patient plasma samples with severe ADAMTS13 deficiency (<10% of normal). The inhibitor titers (IU/ml) ranged from 1.5 to 85IU/ml (median of 3.75 IU/ml). To compare the performance of the different patient samples at equal inhibitor titers, we diluted each sample to predefined inhibitor titers (e.g. in patient samples with inhibitor titers <10IU/ml we diluted to 1, 3, 6 and 9IU/ml). Then, incrementally increasing concentrations of purified rADAMTS13 derived from stably transfected CHO cells were added to each pre-set inhibitor titer done for each of the 36 patient samples. Complex formation of rADAMTS13 and anti-ADAMTS13 patient antibody was allowed and the remaining ADAMTS13 activity was analyzed. The input of rADAMTS13 required to saturate circulating inhibitors and to elevate the activity level up to 1U/ml in the plasma was calculated by regression analysis. Our data indicate a linear correlation between supplemented rADAMTS13 and anti-ADAMTS13 antibody titer (for titers <10IU/ml) suggesting that rADAMTS13 should be further investigated as a possible treatment of acquired TTP.

scholarly journals Adenovirus vectored IFN-α protects mice from lethal challenge of Chikungunya virus infection

2020 ◽  
Vol 14 (12) ◽  
pp. e0008910
Author(s):  
Huixin Chen ◽  
Nyo Min ◽  
Luyao Ma ◽  
Chee-Keng Mok ◽  
Justin Jang Hann Chu
Keyword(s):  
Single Dose ◽  
Chikungunya Virus ◽  
Lethal Dose ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Chikv Infection ◽  
Lethal Challenge ◽  
Virus Challenge ◽  
Multiple Organs

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that is responsible for numerous large and geographical epidemics, causing millions of cases. However, there is no vaccine or therapeutics against CHIKV infection available. Interferon-alpha (IFN-α) has been shown to produce potent antiviral responses during viral infection. Herein we demonstrated the use of an adenovirus-vectored expressed mouse IFN-α (mDEF201) as a prophylactic and therapeutic treatment against CHIKV in vivo. 6-day-old BALB/c mice were pre- or post-treated intranasally with single dose of mDEF201 at 5 x 106 PFU per mouse and challenged with lethal dose of CHIKV. Complete survival protection was observed in mice upon a single dose of mDEF201 administration 1 days prior to virus challenge. Viral load in the serum and multiple organs were significantly reduced upon mDEF201 administration in a dose dependent manner as compare with adenovirus 5 vector placebo set. Histological analysis of the mice tissue revealed that mDEF201 could significantly reduce the tissue morphological abnormities, mainly infiltration of immune cells and muscle fibre necrosis caused by CHIKV infection. In addition, administration of mDEF201 at 6 hours post CHIKV challenge also showed promising inhibitory effect against viral replication and dissemination. In conclusion, single-dose of intranasal administration with mDEF201 as a prophylactic or therapeutic agent within 6 hours post CHIKV infection is highly protective against a lethal challenge of CHIKV in the murine model.

May-Thurner syndrome – Are we aware enough?

VASA ◽  
2019 ◽  
Vol 48 (5) ◽  
pp. 381-388 ◽  
Author(s):  
Katalin Mako ◽  
Attila Puskas
Keyword(s):  
Contraceptive Use ◽  
Iliac Vein ◽  
Common Iliac Vein ◽  
Vein Thrombosis ◽  
Compression Syndrome ◽  
Threatening Condition ◽  
Life Threatening ◽  
Iliac Vein Compression ◽  
Iliac Vein Compression Syndrome ◽  
The Right

Summary. Iliac vein compression syndrome (May-Thurner syndrome – MTS) is an anatomically variable clinical condition in which the left common iliac vein is compressed between the right common iliac artery and the underlying spine. This anatomic variant results in an increased incidence of left iliac or iliofemoral vein thrombosis. It predominantly affects young women in the second or third decades of life with preponderance during pregnancy or oral contraceptive use. Although MTS is rare, its true prevalence is underestimated but it can be a life-threatening condition due to development of pulmonary embolism (PE). In this case based review the authors present three cases of MTS. All patients had been previously confirmed with PE, but despite they were admitted to hospital, diagnosed and correctly treated for PE and investigated for thrombophilia, the iliac vein compression syndrome was not suspected or investigated. With this presentation the authors would like to emphasize that MTS is mostly underdiagnosed, and it needs to be ruled out in left iliofemoral vein thrombosis in young individuals.

Consumption of Hageman Factor Activity in the Generalized Shwartzman Reaction Induced by Liquoid

1970 ◽  
Vol 23 (02) ◽  
pp. 386-404 ◽  
Author(s):  
G Müller-Berghaus ◽  
H. G Lasch
Keyword(s):  
Partial Thromboplastin Time ◽  
Lethal Dose ◽  
Control Group ◽  
Factor V ◽  
Consumption Coagulopathy ◽  
Factor Activity ◽  
Hageman Factor ◽  
Intravascular Coagulation ◽  
Shwartzman Reaction

SummaryThe role of Hageman factor in triggering intravascular coagulation has been studied in rabbits injected intravenously with Liquoid. Besides changes of coagulation parameters characteristic of consumption coagulopathy (e.g. decrease in platelet counts, fibrinogen levels, factor V activity), a pronounced drop in Hageman factor activity was observed after injection of Liquoid. Likewise, the partial thromboplastin time became prolonged.The activation of Hageman factor in vivo could be prevented by intravenous infusion of lysozyme. Twenty min after starting the lysozyme infusion, the partial thromboplastin time became prolonged from a mean of 29 sec to 108 sec. Animals infused with lysozyme and injected with a lethal dose of Liquoid did not develop a consumption coagulopathy. In the same manner, none of 10 animals treated with lysozyme developed the generalized Shwartzman reaction, whereas in the control group 19 out of 20 animals showed fibrin thrombi in the glomerular capillaries.From the present study it may be concluded that the intravascular coagulation process after intravenous injection of Liquoid is triggered by Hageman factor activation.

Severe Alveolar Hemorrhage – What’s in it for the Gastroenterologist?

2016 ◽  
Vol 25 (4) ◽  
pp. 555-558
Author(s):  
Alina Popp
Keyword(s):  
Celiac Disease ◽  
International Normalized Ratio ◽  
Gluten Free Diet ◽  
Alveolar Hemorrhage ◽  
Severe Anemia ◽  
Gluten Free ◽  
Pulmonary Infiltrates ◽  
Pulmonary Hemosiderosis ◽  
Threatening Condition ◽  
Life Threatening

Background: Alveolar hemorrhage is a potentially life-threatening condition which is usually managed by the pulmonologist. When considering its etiology, there is a rare association that sets the disease into the hands of the gastroenterologist. Case presentation: We report the case of a 48 year-old female who was admitted to the intensive care unit for severe anemia and hemoptysis. On imaging, diffuse pulmonary infiltrates suggestive of alveolar hemorrhage were detected and a diagnosis of pulmonary hemosiderosis was made. She received cortisone therapy and hematologic correction of anemia, with slow recovery. In search of an etiology for the pulmonary hemosiderosis, an extensive workup was done, and celiac disease specific serology was found positive. After confirmation of celiac disease by biopsy, a diagnosis of Lane-Hamilton syndrome was established. The patient was recommended a gluten-free diet and at 6 months follow-up, resolution of anemia and pulmonary infiltrates were observed. Conclusion: Although the association is rare, celiac disease should be considered in a patient with idiopathic pulmonary hemosiderosis. In our case, severe anemia and alveolar infiltrates markedly improved with glucocorticoids and gluten-free diet. Abbreviations: APTT: activated partial thromboplastin time; BAL: bronchoalveolar lavage; CD: celiac disease; Cd: crypt depth; GFD: gluten-free diet; GI: gastrointestinal; IEL: intraepithelial lymphocyte; INR: international normalized ratio; IPH: idiopathic pu

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