lactate dehydrogenase activity
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2021 ◽  
Author(s):  
Mei-Ling Zhang ◽  
Meng Wang ◽  
Jian Chen ◽  
Yan-Jie Liu ◽  
Xiao-Hui Zheng ◽  
...  

Abstract BackgroundThe pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms.MethodsPretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse pyroptosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro.ResultsAs revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. ConclusionsPretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.


2021 ◽  
Author(s):  
Mei-Ling Zhang ◽  
Meng Wang ◽  
Jian Chen ◽  
Yan-Jie Liu ◽  
Xiao-Hui Zheng ◽  
...  

Abstract Background: The pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms.Methods: Pretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse propotosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro.Results: As revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. Conclusions: Pretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.


2021 ◽  
Vol 4 (12) ◽  
pp. 287
Author(s):  
Ryo Okada ◽  
Hazuki Abe ◽  
Tetsuya Okuyama ◽  
Yuto Nishidono ◽  
Toshinari Ishii ◽  
...  

Background: The roots of Angelica dahurica Bentham et Hooker filius ex Franchet et Savatier (Apiaceae) have traditionally been used for inflammatory skin diseases. A. dahurica roots (Byakushi) contain furanocoumarins, such as imperatorin and byakangelicin. To elucidate which constituents are responsible for the anti-inflammatory effects, we evaluated the potency of crude A. dahurica root extract fractions by monitoring the production of the inflammatory mediator nitric oxide (NO) in hepatocytes.Methods: The dried roots of A. dahurica were collected in South Korea and extracted with methanol. The resulting extract was fractionated into ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions. Primary cultured rat hepatocytes were treated with interleukin (IL)-1β and each fraction for 8 h, and then the NO production and lactate dehydrogenase activity in the medium were measured. The expression of inducible nitric oxide synthase (iNOS) was detected by Western blotting, and its mRNA expression level was measured by quantitative reverse transcription-polymerase chain reaction.Results: Among the three fractions, the EtOAc-soluble fraction markedly suppressed NO production without showing cytotoxicity and decreased iNOS expression in hepatocytes. From this hydrophobic fraction, we isolated five furanocoumarins: isoimperatorin, imperatorin, phellopterin, oxypeucedanin, and oxypeucedanin methanolate. Phellopterin and oxypeucedanin methanolate significantly suppressed NO production and reduced the mRNA expression of iNOS and tumor necrosis factor α. In contrast, the other three constituents did not affect NO production. Comparison of their chemical structures suggests that a methoxy group at carbon 5 and a side chain at carbon 8 in the furanocoumarin skeleton may be essential for NO production suppression.Conclusion: These data imply that phellopterin and oxypeucedanin methanolate, which are hydrophobic furanocoumarins, may contribute to the anti-inflammatory effects of A. dahurica roots by suppressing iNOS gene expression.Keywords: Inflammation, nitric oxide, hepatocyte, coumarin, Kampo medicine


2021 ◽  
Vol 12 (4) ◽  
pp. 745-752
Author(s):  
O. M. Marenkov ◽  
O. O. Izhboldina ◽  
M. M. Nazarenko ◽  
R. V. Mylostyvyi ◽  
O. M. Khramkova ◽  
...  

Anthropogenic load on aquatic ecosystems leads to increased inputs of heavy metals, which can have a toxic effect on aquatic organisms. Some of the most appropriate objects for research are short-cycle fish species. This article considers the results of studies on the adaptive reactions of the stone moroko Pseudorasbora parva (Temminck et Schlegel, 1846) to Mn, Pb, Ni heavy metal ions, which exceeded the reference values in the reservoir by 1.7, 1.5 and 2.0 times, respectively. Changes in morphological parameters of the blood and histocytological pattern of the hepatopancreas of the experimental species under the influence of toxicants, as well as changes in biochemical parameters, were determined. It was noted that the influence of Mn caused pathological changes in the form of poikilocytosis. The morphometric parameters of erythrocytes (the cell area and the nuclear area) reached 67.48 ± 0.67 and 13.97 ± 0.22 µm2 respectively (4.0% and 13.8% less compared to the control). The influence of Ni resulted in an increased number of leukocytes and immature forms of erythrocytes. The area of erythrocytes was 0.9% smaller than that of the control group, and the area of the nucleus was 4.5% smaller than in the control. The effect of Pb as well as Mn consisted in poikilocytosis. The area of red blood cells and nuclei was smaller by 6.5% and 8.3%, respectively, compared to the control. The percentage of white blood cells in fish exposed to Ni and Pb tended to increase. In the experiment with nickel, the percentage of white blood cells was 10.2% of the number of formed elements; in the experiment with lead – 11.3%; with manganese – 6.1%, while in the control, the number of white blood cells compared to the total number of formed elements of fish was only 1.2%. Cytometric studies have revealed that there are significant differences in the shape, size, and location of hepatocytes in different experimental fish. The structural components of the liver for histological specimens were stained differentially with different intensities and different colours. The hepatocytes on histological specimens of the liver of the stone moroko exposed to Ni and Mn ions did not have clearly defined boundaries, there was a large number of destroyed cells, which indicates the toxic effect of these heavy metals. The hepatocytes exposed to Pb had the largest area of cells and nuclei and the highest nuclear-cytoplasmic ratio is typical for hepatocytes under the influence of Mn. The nuclei had the largest size and occupied 12.7% of the internal contents of the cells. It is shown that under the impact of the studied concentrations of Mn, Ni and Pb, lactate dehydrogenase activity increased by 1.22, 1.14 and 1.48 times compared to the control, respectively. In contrast, there was a 3.27-fold decrease in succinate dehydrogenase activity under the impact of Mn. Besides that, the activity of the enzyme decreased by 1.48 and 1.68 times under the action of Ni and Pb. Subsequently, we found an increase in the activity of alkaline phosphatase in muscle tissue by 3.25–3.94 times under the influence of the studied toxicants. Muscle protein levels under the impact of Mn were 1.14 times lower than in the control, the most distinct decrease in protein was found under the impact of Ni (1.53 times). The obtained data of physiological and biochemical reactions of the stone moroko to the influence of heavy metals provide an opportunity to predict changes in the species composition of fish fauna under conditions of excessive toxic pollution of ecosystems.


Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1703
Author(s):  
Viktoria Pevna ◽  
Georges Wagnières ◽  
Veronika Huntosova

Glioblastoma is one of the most aggressive types of tumors. Although few treatment options are currently available, new modalities are needed to improve prognosis. In this context, photodynamic therapy (PDT) is a promising adjuvant treatment modality. In the present work, hypericin-mediated PDT (hypericin-PDT, 2 J/cm2) of U87 MG cells is combined with (2 min, 15 mW/cm2 at 808 nm) photobiomodulation (PBM). We observed that PBM stimulates autophagy, which, in combination with PDT, increases the treatment efficacy and leads to apoptosis. Confocal fluorescence microscopy, cytotoxicity assays and Western blot were used to monitor apoptotic and autophagic processes in these cells. Destabilization of lysosomes, mitochondria and the Golgi apparatus led to an increase in lactate dehydrogenase activity, oxidative stress levels, LC3-II, and caspase-3, as well as a decrease of the PKCα and STAT3 protein levels in response to hypericin-PDT subcellular concentration in U87 MG cells. Our results indicate that therapeutic hypericin concentrations can be reduced when PDT is combined with PBM. This will likely allow to reduce the damage induced in surrounding healthy tissues when PBM-hypericin-PDT is used for in vivo tumor treatments.


Blood ◽  
2021 ◽  
Author(s):  
Steven de Maat ◽  
Chantal Clark ◽  
Arjan D. Barendrecht ◽  
Simone Smits ◽  
Nadine D van Kleef ◽  
...  

Thrombotic microangiopathies are hallmarked by attacks of disseminated microvascular thrombosis. In thrombotic thrombocytopenic purpura (TTP), this is caused by a rise in thrombogenic ultra-large von Willebrand factor (VWF) multimers because of ADAMTS13 deficiency. We previously reported that systemic plasminogen activation is therapeutic in a TTP mouse model. In contrast to its natural activators (i.e. tPA and uPA), plasminogen can directly bind to VWF. For optimal efficacy and safety, we aimed to focus and accelerate plasminogen activation at sites of microvascular occlusion. We here describe the development and characterization of Microlyse, a fusion protein consisting of a high-affinity VHH targeting the CT/CK domain of VWF and the protease domain of uPA, for localized plasminogen activation on microthrombi. Microlyse triggers targeted destruction of platelet-VWF complexes by plasmin on activated endothelial cells and in agglutination studies. At equal molar concentrations, Microlyse degrades microthrombi 7-fold more rapidly than blockade of platelet-VWF interactions with a bivalent humanized VHH (caplacizumab*). Finally, Microlyse attenuates thrombocytopenia and tissue damage (reflected by increased plasma lactate dehydrogenase activity, as well as PAI-1 and fibrinogen levels) more efficiently than caplacizumab* in an ADAMTS13-/- mouse model of TTP, without affecting hemostasis in a tail-clip bleeding model. These findings show that targeted thrombolysis of VWF by Microlyse is an effective strategy for the treatment of TTP and might hold value for other forms of VWF-driven thrombotic disease.


Author(s):  
Anna Kopińska ◽  
Anna Koclęga ◽  
Tomasz Francuz ◽  
Grzegorz Helbig

AbstractThymus and activation-regulated chemokine (TARC) is expressed on Reed-Sternberg cells of patients with classical Hodgkin lymphoma (HL) and may serve as a marker in response assessment. In our study, we correlated serum TARC levels with early response to treatment measured by PET/CT in 19 newly diagnosed patients with HL who received ABVD (Adriblastin, Bleomycin, Vinblastine, Dacarbazine) regimen. Finally, 17 patients were analyzed and six of them (35%) achieved PET/CT negativity defined as Deauville (D) 1 or 2 after 2 cycles of ABVD; 11 pts (65%) had D3 on PET/CT. None of the patients presented D 4/5. Median serum TARC levels at diagnosis were significantly higher when compared with healthy controls: 5718 pg/ml vs 76.1 pg/ml (p < 0.001). All study patients were treated with ABVD regimen and there was a significant decrease of baseline serum TARC levels after 2 cycles of therapy. No significant difference of baseline serum TARC levels was demonstrated between patients with D1/2 and D3 whereas levels were significantly decreased after 2 cycles of ABVD in patients D1/2 vs D3; p = 0.049. There was a tendency to higher baseline serum TARC levels in patients with an increased LDH (lactate dehydrogenase) activity (p = 0.08) and in those who progressed when compared with those who maintained response (p = 0.09). Serum TARC levels decrease after chemotherapy and may serve as a marker of response assessment.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1851
Author(s):  
Sabna Kotta ◽  
Hibah Mubarak Aldawsari ◽  
Shaimaa M. Badr-Eldin ◽  
Lenah S. Binmahfouz ◽  
Rana Bakur Bakhaidar ◽  
...  

Excessive architectural re-modeling of tissues in pulmonary fibrosis due to proliferation of myofibroblasts and deposition of extracellular matrix adversely affects the elasticity of the alveoli and lung function. Progressively destructive chronic inflammatory disease, therefore, necessitates safe and effective non-invasive airway delivery that can reach deep alveoli, restore the surfactant function and reduce oxidative stress. We designed an endogenous surfactant-based liposomal delivery system of naringin to be delivered as an aerosol that supports pulmonary mechanics for the management of pulmonary fibrosis. Phosphatidylcholine-based liposomes showed 91.5 ± 2.4% encapsulation of naringin, with a mean size of 171.4 ± 5.8 nm and zeta potential of −15.5 ± 1.3 mV. Liposomes with the unilamellar structure were found to be spherical and homogeneous in shape using electron microscope imaging. The formulation showed surface tension of 32.6 ± 0.96 mN/m and was able to maintain airway patency of 97 ± 2.5% for a 120 s test period ensuring the effective opening of lung capillaries and deep lung delivery. In vitro lung deposition utilizing Twin Stage Impinger showed 79 ± 1.5% deposition in lower airways, and Anderson Cascade Impactor deposition revealed a mass median aerodynamic diameter of 2.35 ± 1.02 μm for the aerosolized formulation. In vivo efficacy of the developed formulation was analyzed in bleomycin-induced lung fibrosis model in rats after administration by the inhalation route. Lactate dehydrogenase activity, total protein content, and inflammatory cell infiltration in broncho-alveolar lavage fluid were substantially reduced by liposomal naringin. Oxidative stress was minimized as observed from levels of antioxidant enzymes. Masson’s Trichrome staining of lung tissue revealed significant amelioration of histological changes and lesser deposition of collagen. Overall results indicated the therapeutic potential of the developed non-invasive aerosol formulation for the effective management of pulmonary fibrosis.


Author(s):  
SHWETA R. GOPHANE ◽  
SAGAR R. JADHAO ◽  
PREETI B. JAMDHADE

Objective: Bergenia ciliata (family-Saxifragaceae) is a well-known herb for kidney stone. The main objective of the study was the identification of flavonoids along with ADME profile. Another supportive objective was to check inhibition of enzymes which perform active role in oxalate synthesis. Methods: The hydromethanolic extract was fractionated by liquid-liquid extraction to obtain ethyl acetate and ethyl ether fractions. The chemical structures of the purified compounds were identified by gas chromatography-mass spectrometry. Results: A total of 12 volatile chemical compounds belonging to hydrocarbons, esters, alcohols, fatty acids, ketones, etc. were identified and characterized in ethyl acetate fraction through GC-MS analysis Fractions enriched in flavonoids showed glycolate oxidase and lactate dehydrogenase enzyme inhibition with IC50 value (µg/ml) 65.76 and 69.84 respectively. The kinetic behaviour of the extracts that inhibit the Glycolate oxidase and Lactate dehydrogenase activity was determined by the Lineweaver-Burk plot. The mode of inhibition of the studied plant extract was type of a non-competitive inhibition. ADMET screening of compounds successfully passed all the parameters of screening. Conclusion: On the basis of the results, it was found that Bergenia ciliata (rhizome) may serve as a novel and rich source of therapeutic compounds and it can be further explored for urolithiasis treatment purposes.


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