scholarly journals Endothelial Glycocalyx Disorders May Be Associated With Extended Inflammation During Endotoxemia in a Diabetic Mouse Model

Author(s):  
So Sampei ◽  
Hideshi Okada ◽  
Hiroyuki Tomita ◽  
Chihiro Takada ◽  
Kodai Suzuki ◽  
...  

In diabetes mellitus (DM) patients, the morbidity of infectious disease is increased, and these infections can easily progress from local to systemic infection. Sepsis is a characteristic of organ failure related to microcirculation disorders resulting from endothelial cell injury, whose most frequent comorbidity in patients is DM. The aim of the present study was to evaluate the influence of infection on DM-induced microvascular damage on inflammation and pulmonary endothelial structure using an experimental endotoxemia model. Lipopolysaccharide (LPS; 15 mg/kg) was injected intraperitoneally into 10-week-old male C57BLKS/J Iar- +leprdb/leprdb (db/db) mice and into C57BLKS/J Iar–m + / + leprdb (db/ +) mice, which served as the littermate non-diabetic control. At 48 h after LPS administration, the survival rate of db/db mice (0%, 0/10) was markedly lower (P < 0.05) than that of the db/ + mice (75%, 18/24), whereas the survival rate was 100% in both groups 24 h after LPS administration. In control mice, CD11b-positive cells increased at 6 h after LPS administration; by comparison, the number of CD11b-positive cells increased gradually in db/db mice until 12 h after LPS injection. In the control group, the number of Iba-1-positive cells did not significantly increase before and at 6, 12, and 24 h after LPS injection. Conversely, Iba-1-positive cells continued to increase until 24 h after LPS administration, and this increase was significantly greater than that in the control mice. Expression of Ext1, Csgalnact1, and Vcan related to endothelial glycocalyx synthesis was significantly lower in db/db mice than in the control mice before LPS administration, indicating that endothelial glycocalyx synthesis is attenuated in db/db/mice. In addition, ultrastructural analysis revealed that endothelial glycocalyx was thinner in db/db mice before LPS injection. In conclusion, in db/db mice, the endothelial glycocalyx is already injured before LPS administration, and migration of inflammatory cells is both delayed and expanded. This extended inflammation may be involved in endothelial glycocalyx damage due to the attenuation of endothelial glycocalyx synthesis.

2009 ◽  
Vol 37 (02) ◽  
pp. 361-372 ◽  
Author(s):  
Ming Xiang ◽  
Jing Tang ◽  
Xiao-Lei Zou ◽  
Zeng-Yu Zhao ◽  
Yun-Yang Wang ◽  
...  

The anti-hyperglycemic and immunomodulatory activities of the ethanol extract from Paecilomyces Hepiali Chen (PHC), a Chinese medicine, were investigated in streptozotocin-induced type 1 diabetic (T1DM) mice. Male Balb/c mice, which were i.p. injected with streptozotocin (STZ, 50 mg/kg, for 5 consecutive days) on Day 7, were orally administered saline (the normal control and diabetic control group), Metformin (60 mg/kg, b.w., positive group), or the extract (100 mg/kg, b.w., PHC prevention group) from Day 1 to Day 28, Mice i.p. injected with streptozotocin (STZ, 50 mg/kg, b.w.) for 5 consecutive days prior to PHC treatment (100 mg/kg, b.w.) were used as the PHC treatment group. The effects of PHC on postprandial blood glucose concentrations, plasmatic insulin levels, morphology of pancreatic β cells and CD4+ T cells proliferation after 28-day treatment were monitored. Results showed that PHC administered 6 days before STZ induction of diabetes in mice significantly decreased blood glucose level (p < 0.01). An increase of insulin level was also observed as compared to those in the diabetic control group (p < 0.01). In addition, fewer inflammatory cells infiltrated the pancreatic islet and fewer β cells death by apoptosis within the inflamed islets were observed. More importantly, the CD4+ T cell proliferation was remarkably attenuated ex vivo in mice preventively treated with PHC (p < 0.01). In comparison to the PHC prevention group, no significant hypoglycemia, changes of insulin level and β cell protection were observed in mice treated with PHC after STZ administration. Our findings demonstrated that preventive administration of PHC protected β cells from apoptosis in type 1 diabetes induced by STZ, and the underlying mechanism may be involved in suppressing CD4+ T cells reaction, reducing inflammatory cells infiltration and protecting beta cell apoptosis in pancreatic islet.


2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Rariane Silva de Lima ◽  
Juliane Cristina de Souza Silva ◽  
Cintia Taniguti Lima ◽  
Leandro Ezequiel de Souza ◽  
Maikon Barbosa da Silva ◽  
...  

Angiotensin II plays important functions in cardiovascular system mediating actions leading to inflammatory responses such as activation of VSMC in order to produce ROS, inflammatory cytokines, chemokines, and adhesion molecules. Changes in angiotensin II production could stimulate the recruitment and activation of myeloid cells initiating local inflammatory response without effect on BP. We aimed to verify if angiotensin II induces an inflammatory response in the aorta and if it correlates with variations in BP. C57Bl/6 mice treated with saline solution (0.9%, control group) or angiotensin II (30ng/kg, Ang II group) were used. BP and HR levels were measured. Immunohistochemistry for IL1-β, TGF-β, iNOS, CD45, andα-actin was performed in the aorta. BP and HR do not change. A biphasic response was observed both for IL1-βand TGF-βexpression and also for the presence of CD45 positive cells, with an acute increase (between 30 and 60 minutes) and a second increase, between 24 and 48 hours. Positive staining for iNOS increased in the earlier period (30 minutes) in perivascular adipose tissue and in a longer period (48 hours) in tunica adventitia. Immunoblotting toα-actin showed no alterations, suggesting that the applied dose of angiotensin II does not alter the aortic VSMCs phenotype. The results suggest that angiotensin II, even at doses that do not alter BP, induces the expression of inflammatory markers and migration of inflammatory cells into the aorta of normotensive mice. Thus, angiotensin II may increase the propensity to develop a cardiovascular injury, even in normotensive individuals.


2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Maira Nilson Benatti ◽  
Alexandre Todorovic Fabro ◽  
Carlos Henrique Miranda

Abstract Background Scientific evidence indicates that endothelial glycocalyx (EG) shedding contributes to the pathophysiological installation of acute respiratory distress syndrome (ARDS) after bacterial sepsis. The aim was to evaluate the EG shedding in ARDS installation after flu syndrome. Methods This cross-sectional study included patients with flu syndrome during the influenza outbreak divided into two groups: patients with and without ARDS. Healthy subjects without flu syndrome were included in a control group. We measured EG damage biomarkers (hyaluronan, syndecan-1) and endothelial cell injury biomarker (soluble thrombomodulin) during the first medical evaluation. Histological assessment of the perimeter of the hyaline membrane and the number of neutrophils infiltrated in the alveolar septum was performed in patients who died. Results ARDS group had 30 patients (44 ± 16 years old, 57% men), the non-ARDS group had 36 patients (39 ± 17 years old, 42% men), and the control group had 35 individuals (44 ± 9 years old, 51% men). Hyaluronan levels were significantly higher in the ARDS group than the two groups [31 ng/ml (interquartile range-IQR 12–56) vs. 5 ng/ml (IQR 3–10) vs. 5 ng/ml (IQR 2–8); p < 0.0001]. Hyaluronan levels above 19 ng/ml in patients with flu syndrome were associated with a significant increase in 28-day mortality rate: relative risk (RR): 6.95; (95% confidence interval 1.88–25.67); p = 0.0017. A positive correlation was observed between hyaline membrane perimeter and soluble thrombomodulin levels (r = 0.89; p = 0.05) as well as between the number of neutrophils in the alveolar septum and hyaluronan levels (r = 0.89; p = 0.05). Conclusions Evidence of EG shedding was found in ARDS established after flu syndrome.


Author(s):  
И.Н. Пономарев ◽  
М.С. Макаров ◽  
Н.В. Боровкова ◽  
Ю.В. Андреев ◽  
М.В. Сторожева ◽  
...  

Введение. При поверхностных ожогах процесс репарации происходит благодаря активности стволовых клеток и клеток-предшественников, сохранившихся в ране. Стимуляция миграционной, пролиферативной и секреторной активности этих клеток может быть инициирована с помощью компонентов, содержащихся в гранулах тромбоцитов. Значительно повысить сохранность тромбоцитарных гранул можно путем предварительной стабилизации тромбоцитов с помощью наночастиц серебра. Цель исследования - изучение репаративного эффекта коллагеновых повязок, насыщенных тромбоцитами, при лечении мышей с поверхностными ожогами. Методика. В работе использовались 3 типа раневых покрытий: коллагеновая повязка без тромбоцитов (контроль); повязка с нативными тромбоцитами (1-я опытная группа); повязка с тромбоцитами, предварительно стабилизированными 2,5 мкМ наносеребра (2 -я опытная группа). Тромбоциты выделяли из венозной крови доноров-добровольцев, консервированной на ЭДТА. Для стабилизации тромбоцитов в исходную суспензию с тромбоцитами предварительно добавляли раствор наносеребра до достижения концентрации 2,5 мкМ и инкубировали при 22 °С в течение 1 ч. Во всех опытах общее количество тромбоцитов с гранулами (биологически полноценные тромбоциты) в повязках составило 30-31 млн. После нанесения тромбоцитов раневые покрытия экспонировали в течение 30 мин при 37 °С, затем удаляли всю жидкую фракцию с неадгезировавшими тромбоцитами. Готовые повязки хранили при -40 °С и размораживали непосредственно перед экспериментом. Результаты. Через 3 сут у животных контрольной группы наблюдалась выраженная воспалительная реакция и значительная деформация коллагеновых волокон дермы, в опытных группах эти процессы были менее выражены. Использование коллагеновых повязок с тромбоцитами существенно усиливало миграцию эпителиальных клеток из дериватов кожи, а также миграцию фибробластов из глубоких слоев дермы. Через 5 сут эпителизация раны в контроле была частичной, тогда как у опытных животных эпителий был непрерывным по всей площади раны. В опытных группах сохранялась высокая миграционная активность эпителиальных клеток и фибробластов. Структурно деформированные волокна коллагена не выявлялись в опытных группах. Декомпактизация и отечность волокон в контрольной группе наблюдалась по всей глубине дермы, тогда как в опыте отечные волокна присутствовали только в сетчатом слое дермы. Заключение. Использование коллагеновых повязок с тромбоцитами ускоряло процессы эпителизации и восстановления волокон дермы на фоне сохранения локальной инфильтрация раны воспалительными клетками. Activity of stem cells and primordial cells is the main reparative factor in healing of superficial burns. Components of platelet granules could stimulate cell migration, proliferation, and secretion. Survival of platelet granules can be enhanced by prior platelet stabilization with silver nanoparticles. The aim of this work was to study reparative effect of collagen bands, saturated with platelets, on mice with superficial burns. Methods. Three types of wound coatings were used: 1) collagen bands without platelets (control); 2) collagen bands with native platelets (1st experimental group); 3) collagen bands with platelets, prestabilized with 2.5 µM nanosilver (2nd experimental group). Platelets were harvested from venous blood of volunteer donors preserved in EDTA. Platelet were stabilized by incubation with 2.5 µM nanosilver at 22°С for 1 hr. In all experiments, the collagen bands contained 30-31 million platelets with granules, i.e., biologically normal platelets. Collagen bands were incubated with platelets at 37°С for 30 min, and then all solution with unadhered platelets was eliminated. Experimental bands were stored at -40°С and defrosted immediately before experimental treatment. Results. After three days of treatment, the control group had a pronounced inflammatory reaction and significant deformation of dermal collagen fibers. In the experimental groups, these processes were less pronounced. Collagen bands with platelets significantly increased migration of epithelial cells from the skin derivatives and migration of fibroblasts from the deep dermal layers. After five days, the epithelization of wounds in the control group was partial, while in experimental groups, epithelium covered all areas of the wound. Experimental groups maintained high migration activity of epithelial cells and fibroblasts. Structurally deformed collagen fibers were detected sporadically in the control group and were not detected in the experimental groups. Decompactization and swelling of fibers in the control group were observed throughout the depth of the derma, while in the experiment groups, swollen fibers were present only in the deep dermal layer. Conclusion. The use of collagen bands with platelets accelerated the processes of epithelialization and collagen remodeling associated with preserved local infiltration of the wound with inflammatory cells.


2017 ◽  
Vol 7 (12) ◽  
pp. 923
Author(s):  
Olubukola Sinbad Olorunnisola ◽  
Adewale Adetutu ◽  
Rasaq B POPOOLA ◽  
Abiodun Olusoji Owoade ◽  
Peter Adegbola ◽  
...  

Background: The leaves of Thaumatococcus danielli (Benth.) have been traditionally used in folk medicine to treat malaria in Nigeria. However, there is no report on whether these leaves contain Nephroprotective activity. Thus, the ethanol leaf extract was investigated for Nephron-protective activity in Streptozotocin induced diabetic rats.Methods: First, the LD50 of the leaf was determined using standard procedure. Rats were assigned to 5 groups (A-E) of five rats. Except for the control group, each group was made diabetic using Streptozotocin (65 mg/kg/b.wt. i p). The treated groups received 0.5 ml of glibenclamide (25mg/kg/b.wt, o.p), 250 and 500 mg/kg/b.wt, o.p of Thaumatococcus danielli respectively. After 14 days of treatment, animals were sacrificed under light anaesthesia. Data were expressed as Means ± S.D (n=5) and were analyzed using one-way ANOVA followed by Dunnet’s test, values were considered significant at p<0.05. Results: The plant showed a LD50 greater than 5000 mg/kg/b.wt in albino rats observed for 72 hours. A significant (p<0.05) decreased in serum Na+, Cl-, HCO-3, total protein, and an insignificant increase in K+, urea and creatinine level were observed in the diabetic group when compared with the normal group. Oral administration of plant extract and glibenclamide significantly (p<0.05) restored the electrolytes to near normal. Histological alterations such as glomerulonephritis, and tubules infiltration by inflammatory cells observed in diabetic control were also reversed.Conclusion: This study suggests renal protective ability of the plant against impairment due to hyperglycemia.Keywords: Streptozotocin, Thaumatococcus danielli, Nephroprotective, Glibenclamide, serum electrolytes.


2017 ◽  
Vol 87 (3-4) ◽  
pp. 179-190
Author(s):  
Amel Kanane ◽  
Fayrouz Rouaki ◽  
Mohamed Brahim Errahmani ◽  
Abdenour Laraba ◽  
Hayet Mesbah ◽  
...  

Abstract. The aim of this study is to evaluate the effect of α-tocopherol supplementation at two doses (600 and 1200 mg × kg–1) on kidney antioxidant status and the histopathological changes in Wistar rats after 12 weeks of exposure at different diets. Forty rats has been divided into 4 groups of 10 rats each, the control group received basal diet with 5 % fresh sunflower oil (FSO), the second group: 5 % oxidized sunflower oil (OSO), the third group: 5 % OSO supplemented with 600 mg × kg–1 α-tocopherol and the fourth group: 5 % OSO supplemented with 1200 mg × kg–1 α-tocopherol. In OSO groups, the results showed highly significant increases of LPO (from 31.3 ± 0.9 to 53.8 ± 1.2 nmol of MDA formed/min/mg protein, p < 0.0001) with a significant decrease (p < = 0.001) of the antioxidant enzymatic activities (CAT, SOD, GPX, GR and G6PDH), body weight (339 ± 9 to 290 ± 3 g) and α-tocopherol levels (13.6 ± 0.6 to 6.5 ± 0.4 μg/mg protein). In OSO groups with 600 mg × kg–1 α-tocopherol, an antioxidant effect was found, reflected by a return of the parameters to values similar to those of the control group. However, higher doses of α-tocopherol (1200 mg × kg–1) induced a depletion of antioxidant status, α-tocopherol levels (6.0 ± 0.3 μg/mg protein, p < 0.001) and a very highly significant rise (p < 0.0001) of LPO content (54.86 ± 0.01 nmol of MDA formed/min/mg protein). The kidney tissues also showed changes in glomerular, severe inflammatory cells infiltration, and formation of novel vessels. So, we can conclude that the oxidative stress is attenuated by a moderate administration of 600 mg × kg–1 α-tocopherol, while a pro-oxidant effect occurs at 1200 mg × kg–1 α-tocopherol.


Author(s):  
Nishtha R. Mahida ◽  
G. . Mandali ◽  
Vijaysinh V. Sindha ◽  
S. K. Raval

Gymnema sylvestre of the family Asclepiadaceae is one of the most important medicinal plants of the central eco-region. It is popularly known as Gurmar, which means “sugar killer”. Extract of leaves is reported to have tannins, gum, flavonoids, proteins and saponins. It has displayed a wide array of pharmacological activities. This study was aimed to investigate the antidiabetic and hypolipidemic effects of Gymnema sylvestre extract in experimentally induced diabetes in rats. Diabetes was produced in adult Wistar rats with single dose of streptozotocin (STZ) @ 60 mg/kg b.wt. intraperitoneally. After the confirmation of diabetes on 7th day (sugar >200 mg/dl), alcoholic and aqueous extracts of G. sylvestre (400 mg/kg) were administered orally to the experimental rats from 8th day and continued for 42 days thereafter. The antidiabetic and hypolipidemic activity was estimated by measuring blood glucose, lipid profile and histopathological examination of various tissues from all the groups. Administration of STZ resulted in a significant (p less than 0.01) increase in blood glucose and lipid profile and histopathological alterations in Diabetic control group as compared to healthy control group. Gymnema treatment demonstrated significant (p less than 0.01) antidiabetic effect indicated by restoration of blood glucose compared to STZ control group. The study concluded that extracts of Gymnema sylvestre improved the altered glucose and lipid profile in diabetic rats, suggesting that the Gymnema Sylvestre extracts exhibit the antidiabetic and hypolipidemic activity.


2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peng Li ◽  
Xi Liang ◽  
Shan Xu ◽  
Ye Xiong ◽  
Jianrong Huang

AbstractWe aim to determine the impact of an artificial liver support system (ALSS) treatment before liver transplantation (LT), and identify the prognostic factors and evaluate the predictive values of the current commonly used ACLF prognostic models for short-term prognosis after LT. Data from 166 patients who underwent LT with acute-on-chronic liver failure (ACLF) were retrospectively collected from January 2011 to December 2018 from the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were divided into two groups depending on whether they received ALSS treatment pre-LT. In the observation group, liver function tests and prognostic scores were significantly lower after ALSS treatment, and the waiting time for a donor liver was significantly longer than that of the control group. Both intraoperative blood loss and period of postoperative ICU care were significantly lower; however, there were no significant differences between groups in terms of total postoperative hospital stays. Postoperative 4-week and 12-week survival rates in the observation group were significantly higher than those of the control group. Similar trends were also observed at 48 and 96 weeks, however, without significant difference. Multivariate Cox regression analysis of the risk factors related to prognosis showed that preoperative ALSS treatment, neutrophil–lymphocyte ratio, and intraoperative blood loss were independent predicting factors for 4-week survival rate after transplantation. ALSS treatment combined with LT in patients with HBV-related ACLF improved short-term survival. ALSS treatment pre-LT is an independent protective factor affecting the 4-week survival rate after LT.


2021 ◽  
Vol 28 ◽  
pp. 107327482199743
Author(s):  
Ke Chen ◽  
Xiao Wang ◽  
Liu Yang ◽  
Zheling Chen

Background: Treatment options for advanced gastric esophageal cancer are quite limited. Chemotherapy is unavoidable at certain stages, and research on targeted therapies has mostly failed. The advent of immunotherapy has brought hope for the treatment of advanced gastric esophageal cancer. The aim of the study was to analyze the safety of anti-PD-1/PD-L1 immunotherapy and the long-term survival of patients who were diagnosed as gastric esophageal cancer and received anti-PD-1/PD-L1 immunotherapy. Method: Studies on anti-PD-1/PD-L1 immunotherapy of advanced gastric esophageal cancer published before February 1, 2020 were searched online. The survival (e.g. 6-month overall survival, 12-month overall survival (OS), progression-free survival (PFS), objective response rates (ORR)) and adverse effects of immunotherapy were compared to that of control therapy (physician’s choice of therapy). Results: After screening 185 studies, 4 comparative cohort studies which reported the long-term survival of patients receiving immunotherapy were included. Compared to control group, the 12-month survival (OR = 1.67, 95% CI: 1.31 to 2.12, P < 0.0001) and 18-month survival (OR = 1.98, 95% CI: 1.39 to 2.81, P = 0.0001) were significantly longer in immunotherapy group. The 3-month survival rate (OR = 1.05, 95% CI: 0.36 to 3.06, P = 0.92) and 18-month survival rate (OR = 1.44, 95% CI: 0.98 to 2.12, P = 0.07) were not significantly different between immunotherapy group and control group. The ORR were not significantly different between immunotherapy group and control group (OR = 1.54, 95% CI: 0.65 to 3.66, P = 0.01). Meta-analysis pointed out that in the PD-L1 CPS ≥10 sub group population, the immunotherapy could obviously benefit the patients in tumor response rates (OR = 3.80, 95% CI: 1.89 to 7.61, P = 0.0002). Conclusion: For the treatment of advanced gastric esophageal cancer, the therapeutic efficacy of anti-PD-1/PD-L1 immunotherapy was superior to that of chemotherapy or palliative care.


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