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Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.
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Objective To evaluate the in vitro synergistic antifungal activity of HDAC inhibitors in combination with azole drugs against azoles-resistant Candida strains. Methods The checkerboard microdilution method was used to evaluate the antifungal activity of the HDAC inhibitors in combination with azole drugs against clinically drug-resistant strains. The fungistatic activity and toxicity of Rocilinostat was determined through time-growth curve assay and cytotoxicity assay. Results The compound Rocilinostat combined with azole drugs showed excellent synergistic antifungal activity against a variety of azoles-resistant Candida albicans and Candida glabrata. The combination of high concentration Rocilinostat with FLC exhibited fungistatic effects. Very low toxicity was detected with Rocilinostat towards normal cells. Rocilinostat showed better HDAC inhibitory activity than SAHA. Conclusion As a fungi HDAC inhibitor, Rocilinostat has excellent in vitro synergistic antifungal activity and no severe toxicity to normal human cells.
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Aim To investigate the eorrelation between angiotensin II (Ang II ) level and clinical indicators in patients with rheumatoid arthritis ( HA) , and to determine the therapeutic effect of angiotensin receptor blockers ( ARBs).Methods Plasma samples and personal information were collected from HA patients admitted to our hospital from 2019 to 2021.The level of Ang II in plasma was determined by ELISA to elucidate the correlation between plasma Ang II level and the severity of HA.The pathological changes of synovi-al tissues and T eells subtype in different groups of HA patients were determined by pathological examination and flow cytometry.A rat model of collagen-induced arthritis (CIA) was established and the pathological examination was used to confirm that valsartan could alleviate the disease course in the CIA animal model.Results Compared with control group, the plasma level of Ang II in HA patients significantly increased.After therapy with oral ARBs plasma Ang H levels and anti - cyclic citrullinated peptide antibody ( CCP) titre were significantly lower than those untreated HA patients.The level of Ang II in plasma was positively correlated with CCP and the number of monocytes, but negatively with number of RBC and hemoglobin content.Staining of synovial tissue with HE and Masson found that patients with HA had significant synovial proliferation, pannus formation , and numerous inflammatory cell infiltrates compared with control patients.Immunohistochemical results showed significant infiltration of CD4 4 T cells in synovial tissues of HA patients.Western blot and immunofluorescence analysis showed that the expression of angiotensin type 1 receptor ( ATI R ) was significantly up-regulated in CD4 + T cells and synovial tissues of HA patients.The results of animal experiments showed that valsartan harl therapeutic effect on CIA rats and could delay the disease process of CIA.Conclusions Plasma Ang II level is positively correlated with CCP level and HA severity.ARBs can down-regualte CCP level and delay disease progression in HA patients.Animal experiments showed that valsartan blocks the combination of Ang H and ATI R and has therapeutic effect on a CIA rat model.This study provides the theoretical and experimental basis for ARBs to become the preferred antihypertensive drugs for HA patients with hypertension.
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A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N
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A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N
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Animals , Mice , Interneurons/metabolism , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nucleus Accumbens/metabolism , Parvalbumins/metabolismABSTRACT
OBJECTIVE@#To investigate the effects of emodin on inflammation and autophagy in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and reveal its underlying mechanism.@*METHODS@#3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was conducted to find the appropriate dose for emodin. RAW264.7 cells pretreated with different concentrations (0-50 μmol/L) of emodin or vehicle for 2 h prior to exposure to LPS for 16 h. Cell morphology was examined and propidium iodide staining was used to examine cell cycle. Expressions of inflammation-related proteins [nuclear factor-kappaB (NF-κ B) and I-kappaB (I κ B)α] and autophagy-related proteins [light chain (LC)3, P62/sequestosome 1, mammalian target of rapamycin (mTOR), and p-mTOR] were examined using Western blot analysis. Expression of inflammation-related cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were detected by enzyme-linked immunosorbent assay. Autophagy was examined with LC3B fluorescence intensity and aggregation. The effect of emodin on autophagy was conducted with an autophagy inhibitor, 3-methyladenine (3-MA).@*RESULTS@#The expression of NF-κ B in LPS-induced cells was significantly increased (P<0.01) and simultaneously I κ B α decreased compared with the normal cell (P<0.05). The expressions of TNF-α, IL-β, and IL-6 proteins in the LPS-induced RAW264.7 cells were significantly higher than in the normal cell (P<0.05 or P<0.01). LPS increased the percentage of cells in the G@*CONCLUSION@#Emodin could inhibit inflammation of mice RAW264.7 macrophages induced by LPS, possibly through activating autophagy.
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Autophagy is a widespread and unique degradation process in eukaryotic cells. When cells are under various stress conditions such as nutritional deficiencies, growth factor deficiencies or hypoxia, autophagy will be initiated to maintain the stability of the internal environment and ensure normal proliferation and differentiation. At present, research on autophagy-related targets is mostly focused on tumor cells. In contrast, research on fungal autophagy targets is still limited. Autophagy plays an important role in growth, development and morphological changes of fungal cells, suggesting that research on fungal autophagy as a drug target should be useful. This article reviews the signal regulation and detection strategies for autophagy in fungal cells, and provides a research basis for the screening of antifungal drugs targeting autophagy-related proteins.
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Polysaccharide from Ganoderma applanatum has the activities of anti-tumor and enhancing immune function. There were no reports on antitumor effect of its intratumoral injection. In this study, the polysaccharide was extracted from G. applanatum by water extraction and alcohol precipitation, and purified by ceramic membrane after removing protein by Sevage method. The total polysaccharide content from G. applanatum(PGA)was about 63%. The combination of PGA and paclitaxel showed synergistic effect on cytotoxicity of 4 T1 cells at lower concentrations in vitro. In addition, the growth curve of 4 T1 cells showed that PGA could retard the growth of 4 T1 cells gradually. The PGA thermosensitive gel(PGA-TG)was prepared by using poloxamer 188 and 407. The gel temperature was 36 ℃, and the PGA-TG could effectively slow down the release rate of PGA in vitro. 4 T1 breast cancer-bearing mice were used as a model to evaluate the therapeutic effect of intratumoral injection of PGA combined with tail vein injection of nanoparticle albumin-bound paclitaxel(nab-PTX). In high and low dose PGA groups, each mice was given with 2.25, 1.125 mg PGA respectively, twice in total, and the dosage of paclitaxel was 15 mg·kg~(-1), once every 3 days, for a total of five times. The tumor inhibition rate was 29.65% in the high dose PGA-TG group, 58.58% in the nab-PTX group, 63.37% in low dose PGA-TG combined with nab-PTX group, and 68.10% in high dose PGA-TG combined with nab-PTX group respectively. The inhibitory effect in high dose PGA-TG group combined with nab-PTX on tumors was significantly higher than that in nab-PTX group(P<0.05). The results showed that paclitaxel therapy combined with intratumoral injection of PGA-TG could improve the therapeutic effect for 4 T1 mice and reduce the side effects of chemotherapy.
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Animals , Mice , Breast Neoplasms , Cell Line, Tumor , Ganoderma , Neoplasms , Paclitaxel , Poloxamer , PolysaccharidesABSTRACT
<p><b>OBJECTIVE</b>To analyze the changes in endogenous small molecule metabolites after benzo[a]pyrene (B[a]P) exposure in rat cerebral cortex and explore the mechanism of B[a]P neurotoxicity.</p><p><b>METHODS</b>Five-day-old SD rats were subjected to gavage administration of 2 mg/kg B[a]P for 7 consecutive weeks. After the exposure, the rats were assessed for spatial learning ability using Morris water maze test, ultrastructural changes of the cortical neurons under electron microscope, and metabolite profiles of the cortex using GC/MS. The differential metabolites between the exposed and control rats were identified with partial least squares discriminant analysis (PLS-DA) and the metabolic pathways related with the differential metabolites were analyzed using Cytoscape software.</p><p><b>RESULTS</b>Compared with the control group, the rats exposed to B[a]P showed significantly increased escape latency (P<0.05) and decreased time spent in the target area (P<0.05). The exposed rats exhibited widened synaptic cleft, thickened endplate membrane and swollen cytoplasm compared with the control rats. Eighteen differential metabolites (VIP>1, P<0.05) in the cortex were identified between the two groups, and 9 pathways associated with B[a]P neurotoxicity were identified involving amino acid metabolism, tricarboxylic acid cycle and Vitamin B3 (niacin and nicotinamide) metabolism.</p><p><b>CONCLUSION</b>B[a]P can cause disturbance in normal metabolisms and its neurotoxicity is possibly related with disorders in amino acid metabolism, tricarboxylic acid cycle and vitamin metabolism.</p>
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<p><b>OBJECTIVE</b>In the present study, we investigated the antioxidant and anti-aging effects of Silybum marianum protein hydrolysate (SMPH) in D-galactose-treated mice.</p><p><b>METHODS</b>D-galactose (500 mg/kg body weight) was intraperitoneally injected daily for 7 weeks to accelerate aging, and SMPH (400, 800, 1,200 mg/kg body weight, respectively) was simultaneously administered orally. The antioxidant and anti-aging effects of SMPH in the liver and brain were measured by biochemical assays. Transmission electron microscopy (TEM) was performed to study the ultrastructure of liver mitochondri.</p><p><b>RESULTS</b>SMPH decreased triglyceride and cholesterol levels in the D-galactose-treated mice. It significantly elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC), which were suppressed by D-galactose. Monoamine oxidase (MAO) and malondialdehyde (MDA) levels as well as the concentrations of caspase-3 and 8-OHdG in the liver and brain were significantly reduced by SMPH. Moreover, it increased Bcl-2 levels in the liver and brain. Furthermore, SMPH significantly attenuated D-galactose-induced liver mitochondrial dysfunction by improving the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase as well as mitochondrial membrane potential (ΔΨm) and fluidity. TEM showed that the degree of liver mitochondrial damage was significantly decreased by SMPH.</p><p><b>CONCLUSION</b>The results indicated that SMPH protects against D-galactose-induced accelerated aging in mice through its antioxidant and anti-aging activities.</p>
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Animals , Male , Mice , Aging , Antioxidants , Pharmacology , Brain , Caspase 3 , Metabolism , Galactose , Toxicity , Gene Expression Regulation, Enzymologic , Glutathione Peroxidase , Metabolism , Malondialdehyde , Metabolism , Maze Learning , Silybum marianum , Chemistry , Mitochondria, Liver , Oxidative Stress , Plant Proteins , Chemistry , Pharmacology , Protective Agents , Pharmacology , Protein Hydrolysates , Chemistry , Pharmacology , Superoxide Dismutase , MetabolismABSTRACT
Objective: To analyze the metabolicomics pathway in the rats with chronic glomerulonephritis intervened by tannins from Pericarpium Granati.Methods: Signal pathway analysis was carried out using the KEGG database and molecular metabolite annotation was performed using HMDB database.The enzyme or transporter and its related properties were analyzed.The metabolite path visualization was carried out by using MetPA network software.Results: The analysis of biological metabolism pathway showed that 12 metabolites involved in 16 metabolic pathways.The pathway of tryptophan metabolism, citrate cycle, phenylalanine metabolism, cysteine and methionine metabolism showed notable changes (P<0.05).Conclusion: The changes of phenylalanine metabolism, citrate cycle, tryptophan metabolism, cysteine and methionine metabolism in the rats with chronic glomerulonephritis intervened by tannins from Pericarpium Granati participate the pathological process.
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Objective:To study the preventive effect of Sanguisorba officinalis on renal fibrosis by observing the influence of San-guisorba officinalis tannins extract (STE) on the proliferation of human renal epithelia (HK-2) induced by transforming growth factor-β1 ( TGF-β1 ) . Methods:HK-2 cells were cultured in DMEM medium with high glucose containing 10% fetal bovine serum. The cul-tured cells were divided into 5 groups, including the blank control group, TGF-β1 group (5 ng· ml-1 TGF-β1), intervention group 1 (5 ng·ml-1 TGF-β1 +12. 5μg·ml-1 STE), intervention group 2 (5 ng·ml-1 TGF-β1 +25μg·ml-1 STE) and intervention group 3(5 ng·ml-1 TGF-β1 +50 μg·ml-1 STE). The changes of cell morphology were observed under an inverted microscope and the in-fluence of SET on the cell proliferation was detected by CCK8 assay. Results: TGF-β1 could significantly induce the proliferation of HK-2 and promote the cell fibrosis with significant difference when compared with the control group (P<0. 05). However, after trea-ted with STE, the cell proliferation was inhibited obviously (P<0. 05) and the cells morphology tended to be normal in a dose-depend-ent manner. Conclusion:STE can inhibit the proliferation of HK-2 and prevent renal fibrosis to some extent.
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Objective:To study the influence of pomegranate tannins on the endogenous metabolites in the urine of normal rats by metabonomics method. Methods:The rats were divided into two groups, the blank control group and tannins group. The rats in tan-nins group were orally administered 78. 5 mg·ml-1 pomegranate tannins for 4 weeks. The urine samples were collected and used in the metabonomics study. The urine data were collected by HPLC-MS and comparatively analyzed using PCA and PLS-DA method in SIM-CA-P software. Results:The score points of tannins group displayed obvious distance compared with those of the blank control group, and the changes were the most obvious on the 22nd administration day. Conclusion:Endogenous metabolites in rat urine are obviously influenced by pomegranate tannins, and the research provides the basis for the further study of pomegranate tannins.
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<p><b>OBJECTIVE</b>To investigate the effects of benzo[a]pyrene (B[a]P) exposure on the behaviors and hippocampal oxidative stress and ATPase in rats and the molecular mechanism of neurobehavioral toxicity of B[a]P.</p><p><b>METHODS</b>A total of 120 male SD rats (21 days old) were randomly and equally assigned to five groups: blank control group, vegetable oil (solvent control) group, and 2.5, 5, and 10 mg/kg B[a]P exposure groups. The rats in B[a]P exposure groups were injected intraperitoneally with B[a]P once a day for 4 consecutive weeks. Then, Morris water maze and shuttle box were used to evaluate the learning and memory abilities of rats; colorimetric assay was used to measure the activities of superoxide dismutase (SOD), Na(+)/K(+)-ATPase, and Ca(2+)/Mg(2+)-ATPase and the content of malonaldehyde (MDA) in the hippocampus; the concentration of Ca(2+) in the hippocampus was measured by fluorescent labeling.</p><p><b>RESULTS</b>Compared with the blank control group and solvent control group, the B[a]P exposure groups exhibited significant increases in escape latency, active avoidance response latency, and passive avoidance response latency and significant decreases in number of platform crossings and active avoidance response frequency in the last test (P < 0.05 for all comparisons), with a dose-effect relationship. In addition, the B[a]P exposure groups had significantly lower activities of SOD, Na(+)/K(+)-AT-Pase, and Ca(2+)/Mg(2+)-ATPase and significantly higher MDA level and Ca(2+) concentration than the blank control group and solvent control group (P < 0.05 for all comparisons), with a dose-effect relationship.</p><p><b>CONCLUSION</b>The neurobehavioral toxicity of B[a]P may be related to increased oxidative stress and decreased activities of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase in the hippocampus of rats.</p>
Subject(s)
Animals , Male , Rats , Benzo(a)pyrene , Toxicity , Ca(2+) Mg(2+)-ATPase , Metabolism , Hippocampus , Metabolism , Oxidative Stress , Rats, Sprague-Dawley , Sodium-Potassium-Exchanging ATPase , Metabolism , Superoxide Dismutase , MetabolismABSTRACT
Objective To evaluate the protective effects and mechanism of levocarnitine preconditioning (LCN) on myocardial is-chemia-reperfusion injury in patients undergoing cardiopulmonary bypass .Methods 60 cases of ASA Ⅱ or Ⅲ degree and NYHAⅡ or Ⅲ degree patients who aged 25 ~ 57 years old ,undergoing cardiopulmonary bypass with elective cardiac valve replacement were randomly divided into 2 groups (n = 30 each) :group C (treated with 0 .9% sodium chloride) and group L (treated with LCN) .Group L was infused levocarnitine 50 mg/kg per 1 day at the beginning of 7 days before operation ,group C was given the same amount of 0 .9% sodium chloride .Blood samples were taken from central vein at 5 min after the induction the level of anesthe-sia (T0 ,baseline) ,5 min before aortic cross-clamping (T1) ,30 min after release of the aortic cross-clamp (T2) and at 6 (T3) ,12 (T4) and 24 h (T5) after operation for determination .The level of plasma cardiac troponin I (cTnI) ,creatine kinase-MB (CK-MB) and tumor necrosis factor-α (TNF-α) .Myocardial specimens were obtained from right auricle before aortic cross-clamping and after release of aortic cross-clamp to observe the pathologic changes ,the protein expression of p38 MAPK and phosphorylational-p38 MAPK that analyzed by western blotting .Cardiac index (CI) and left ventricular ejection fraction (LVEF) were measured at 1st day before operation and 7th day after operation by using heart color ultrasonography .Results The levels of cTnI ,CK-MB and TNF-α were significantly lower at all time points in group L than in group C (P< 0 .05) .Myocardial mitochondrion impairment was lighter ,the expression of p38 MAPK and phosphorylational-p38 MAPK were significantly attenuated in group L than in group C (P< 0 .05) .CI and LVEF were significantly higher at 7th day after operation in group L than in group C(P< 0 .05) .Conclusion Le-vocarnitine preconditioning can attenuate myocardial ischemia-reperfusion injury and recover cardiac function in patients undergoing cardiopulmonary bypass ,the mechanism may be related to keep the integrity of the mitochondrial membrane and space structures , inhibit the expression of p38 MAPK and phosphorylational-p38 MAPK and decrease the inflammatory response .
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Objective To establish a capture enzyme-linked immunosorbent assay (ELISA) for detection of plague IgM antibody in herding dogs.Methods ELISA plates were coated with serum IgM antibody against dogs and F1 antibody to plague in the serum of herding dogs was detected by a sandwich ELISA.Results A total of 216 serum samples of herding dogs were tested,26 were positive for plague F1 antibody and the positive rate was 12.03％ (26/216); 14 were positive for plague IgM antibody and the positive rate was 6.48％ (14/216); IgM positive accounted for 53.8％(14/26) of all positive samples.Conclusions Serum plague IgM antibody of herding dogs can be used to predict the prevalent time and distribution of recent animal plague in plague foci indirectly,and to provide reference information for timely implementation of control measures.
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Extracellular adenosine 5 inch-triphosphate (ATP) is a key signaling molecule present in the central nervous system (CNS), and now is receiving greater attention due to its role as a messenger in the CNS during different physiological and pathological events. ATP is released into the extracellular space through vesicular exocytosis or from damaged and dying cells. Once in the extracellular environment, ATP binds to the specific receptors termed P2, which mediate ATP effects and are present broadly in both neurons and glial cells. There are P2X, the ligand-gated ionotropic receptors, possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, the metabotropic G-protein-coupled receptors, possessing high affinity for ATP. Since massive extracellular release of ATP often occurs after stress, brain ischemia and trauma, the extracellular ATP is considered relating to or involving in the pathological processes of many nervous system diseases. Conversely, the trophic functions have also been extensively described for the extracellular ATP. Therefore, extracellular ATP plays a very complex role in the CNS and its binding to P2 receptors can be related to toxic and/or beneficial effects. In this review, we described the extracellular ATP acting via P2 receptors as a potent therapeutic target for treatment of nervous system diseases.
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Animals , Humans , Adenosine Triphosphate , Metabolism , Therapeutic Uses , Extracellular Fluid , Metabolism , Nervous System Diseases , Drug Therapy , Metabolism , Receptors, Purinergic P2 , PhysiologyABSTRACT
<p><b>AIM</b>To investigate the effects of endothelin-1 (ET-1) and nitric oxide (NO) on lipopolysaccharide(LPS)-induced myocardial dysfunction, and explore the related underlying mechanisms.</p><p><b>METHODS</b>Experimental septic model was established by intraperitoneal injection of LPS (10 mg x kg(-1)). The study was carried out on the isolated rat hearts to determine the roles of ET-1 and NO in the effect of LPS on the cardiac contractility and on the isolated rat ventricular myocytes model to observe the [Ca2+]i homeostasis in cardiac myocytes.</p><p><b>RESULTS</b>(1) The levels of serum NO2-/NO3- and plasma ET-1 were markedly increased by LPS treatment for 4 hours. (2) LPS induced the decrease in rate-pressure product (RPP), and increase in left ventricular end-diastolic pressure (LVEDP) in the isolated perfused rat hearts. Pretreatment with either aminoguanidine (AMG) (100 mg x kg(-1), i.p.) or BQ-123 (1 mg x kg(-1), i.p.) partially attenuated LPS-induced myocardial depression. When these two drugs were simultaneously given, myocardial depression elicited by LPS was almost abolished. (3) LPS significantly decreased the amplitude of caffeine induced [Ca2+]i transients compared to the control cells. The activity of SR Ca22+ -ATPase was significantly decreased in the cardiac myocytes from LPS-treated rats. Single pretreatment with either AMG or BQ-123 did not attenuate the impairment of SR Ca2+ -ATPase induced by LPS.</p><p><b>CONCLUSION</b>ET-1 and NO mediate myocardial dysfunction in hearts isolated and decrease [Ca2+]i transients in cardiac myocytes from LPS-treated rats. But neither ET-1 nor NO participates in the impairment of SR Ca2+ -ATPase induced by LPS.</p>
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Animals , Male , Rats , Depression, Chemical , Endothelin-1 , Physiology , Lipopolysaccharides , Toxicity , Myocardial Contraction , Physiology , Nitric Oxide , Physiology , Rats, Sprague-Dawley , Shock, SepticABSTRACT
<p><b>OBJECTIVE</b>To investigate the cardiac effect of interleukin-2 (IL-2) and to explore the underlying mechanism.</p><p><b>METHODS</b>The video tracking system and spectrofluorometric method were used to measure the cell contraction and intracellular calcium. Fura-2/AM was used as a calcium fluorescence probe. Langendorff perfusion technique was used to determine the effect of IL-2 on the intact heart.</p><p><b>RESULTS</b>Compared with the control group, IL-2 5 U/ml, 50 U/ml significantly decreased cell contraction amplitude [(74.95+/-4.79) vs (98.09+/-5.02)%, (64.30+/-5.24) vs (97.38+/-4.05)%], peak velocity of cell shortening [(70.23+/-4.85)% vs (98.09+/-5.46)%, (61.15+/-5.20)% vs (97.38+/-6.85)%], peak velocity of cell relengthening [(71.22+/-4.79)% vs (98.32+/-6.08)%, (68.16+/-5.24)% vs (97.55+/-5.00)%] and end- diastolic cell length [(88.28+/-5.84)% vs (97.95+/-5.52)%, (84.18+/-6.52)% vs (98.94+/-6.76)%]. IL-2 (5 U/ml, 50 U/ml) also markedly inhibited intracellular calcium transient [(74.94+/-4.90)% vs (98.09+/-3.74)%,(71.00+/-5.28)% vs (97.38+/-5.52)%], and elevated end-diastolic calcium level of ventricular myocytes [(113.91+/-5.93)% vs (100.10+/-3.02)%, (119.09+/-7.12)% vs (100.52+/-6.00)%], which were attenuated by the opioid receptor antagonist naloxone (Nal,10 nmol/L). In the isolated perfused rat heart,when compared with the control group, IL-2 50 U/ml markedly decreased left ventricular developed pressure [(79.91+/-2.18) vs (93.84+/-2.94)mmHg], maximal rate of rise of left ventricular pressure [(2370.7358.29) vs (2591.50+/-62.81)mmHg] maximal rate of fall of left ventricular [-(1460.95+/-38.6) vs -(1634.24+/-54.05) mmHg/s] and heart rate [(217.35+/-10.56) vs (244.52+/-11.23) beats/min], but increased left ventricular end-diastolic pressure (11.44+/-1.02 vs 9.23+/-0.46). Pretreatment with Nal (10 nmol/L) antagonized the cardiac depression and left ventricular end-diastolic pressure elevation induced by IL-2.</p><p><b>CONCLUSION</b>The cardiac effect of IL-2 is mediated by opioid receptors on the membrane of cardiomyocytes.</p>
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Animals , Male , Rats , Calcium , Metabolism , Depression, Chemical , In Vitro Techniques , Interleukin-2 , Pharmacology , Myocardial Contraction , Naloxone , Pharmacology , Rats, Sprague-Dawley , Receptors, Opioid, kappa , PhysiologyABSTRACT
AIM: To evaluate the alterations in calcium metabolism of the vascular smooth muscle in the late phase of septic shock and test the hypothesis that nitric oxide might be involved in sepsis-induced vascular hyporeactivity. METHODS: Male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). 18 hours post CLP,rat aortic rings were employed for measurement of contractile responses by using organ bath technique. RESULTS: In endothelium-denuded aortic rings from CLP rats,concentration-contraction curves to phenylephrine (PE) and KCl were significantly decreased when compared to that from sham control rats. The transient contraction induced by PE in calcium-free Krebs solution and the concentration-dependent contraction to CaCl_2 in KCl-depolarized medium were also markedly reduced. The hyporeactivity was partially reversed by treatment with aminoguanidine,a selective inducible nitric oxide synthase inhibitor. CONCLUSION: An impairment in calcium handling in vascular smooth muscle is involved in the vascular hyporeactivity during the late phase of septic shock,in which an excessive nitric oxide production might be the major mechanism.