Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.
Cellular and molecular life sciences : CMLS
Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.
10.1007/s00018-023-04971-w
Botanical immunodrugs: scope and opportunities.
Drug discovery today
Modulation of the immune system can be addressed through a variety of specific and non-specific approaches. Many agents of synthetic and natural origin have stimulatory, suppressive or regulatory activity. There is growing evidence that drugs or biological agents capable of modulating single pathways or targets are of limited value as immune-related therapies. Systems biology approaches are now gaining more interest compared with monovalent approaches, which can be of limited benefits with complications. This has stimulated interest in the use of 'cocktails' of immunodrugs to restore immunostasis. Botanicals are chemically complex and diverse and could therefore provide appropriate combinations of synergistic moieties useful in drug discovery. Here, the importance of traditional medicine in natural product drug discovery related to immunodrugs is reviewed.
10.1016/S1359-6446(04)03357-4
Drug Development from Natural Products Based on the Pathogenic Mechanism of Asthma.
International journal of molecular sciences
Asthma is a chronic inflammatory disease of the pulmonary system associated with many wheeze-to-sleep apnea complications that may lead to death. In 2019, approximately 262 million patients suffered from asthma, and 455 thousand died from the disease worldwide. It is a more severe health problem in children and older adults, and as the aging of society intensifies, the problem will continue to worsen. Asthma inducers can be classified as indoor and outdoor allergens and can cause asthma due to their repeated invasion. There are several theories about asthma occurrence, such as the imbalance between Th1 and Th2, inflammation in the pulmonary system, and the abnormal apoptosis/cell proliferation of cells related to asthma. Although there are many medications for asthma, as it is an incurable disease, the purpose of the drugs is only to suppress the symptoms. The current drugs can be divided into relievers and controllers; however, as they have many adverse effects, such as immune suppression, growth retardation, promotion of cataracts, hyperactivity, and convulsions, developing new asthma drugs is necessary. Although natural products can have adverse effects, the development of asthma drugs from natural products may be beneficial, as some have anti-asthmatic effects such as immune modulation, anti-inflammation, and/or apoptosis modulation.
10.3390/ijms241512469
Natural polysaccharides protect against diet-induced obesity by improving lipid metabolism and regulating the immune system.
Food research international (Ottawa, Ont.)
Unhealthy dietary patterns-induced obesity and obesity-related complications pose a great threat to human health all over the world. Accumulating evidence suggests that the pathophysiology of obesity and obesity-associated metabolic disorders is closely associated with dysregulation of lipid and energy metabolism, and metabolic inflammation. In this review, three potential anti-obesity mechanisms of natural polysaccharides are introduced. Firstly, natural polysaccharides protect against diet-induced obesity directly by improving lipid and cholesterol metabolism. Since the immunity also affects lipid and energy metabolism, natural polysaccharides improve lipid and energy metabolism by regulating host immunity. Moreover, diet-induced mitochondrial dysfunction, prolonged endoplasmic reticulum stress, defective autophagy and microbial dysbiosis can disrupt lipid and/or energy metabolism in a direct and/or inflammation-induced manner. Therefore, natural polysaccharides also improve lipid and energy metabolism and suppress inflammation by alleviating mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagy and regulating gut microbiota composition. Specifically, this review comprehensively summarizes underlying anti-obesity mechanisms of natural polysaccharides and provides a theoretical basis for the development of functional foods. For the first time, this review elucidates anti-obesity mechanisms of natural polysaccharides from the perspectives of their hypolipidemic, energy-regulating and immune-regulating mechanisms.
10.1016/j.foodres.2023.113192
Bryodulcosigenin attenuates bleomycin-induced pulmonary fibrosis via inhibiting AMPK-mediated mesenchymal epithelial transition and oxidative stress.
Phytotherapy research : PTR
Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in several organs, including the lungs. Bryodulcosigenin (BDG) is a cucurbitane-type triterpene isolated from Siratia grosvenori and has clear-cut anti-inflammatory effects, yet its benefit of pulmonary fibrosis (PF) remains unclear. In this study, we investigated the protective effects of BDG (10 mg/kg/day, for 14 days) against TGF-β1-stimulated mouse alveolar epithelial MLE-12 cells and bleomycin (BLM)-induced PF mice. In vitro experiments showed that BDG could inhibit epithelial-mesenchymal transition (EMT) and oxidative stress. In vivo experiments indicated that BDG could ameliorate BLM-induced PF in mice as evidenced by characteristic structural changes in histopathology, increased collagen deposition and reduced survival and weight of mice. The abnormal increased expressions of TGF-β1, p-Smad2/3, α-SMA, COL-I, and NOX4 and decreased expressions for Sirt1 and p-AMPK were improved in BDG treatment. But these beneficial effects could be eliminated by co-treatment with Compound C (CC, a selective AMPK inhibitor). Molecular docking technology also revealed the potential of BDG to activate AMPK. In summary, AMPK activation modulated by BDG not only ameliorated TGF-β1/Smad2/3 signaling pathways but also partially mediated the suppression effects on EMT and oxidative stress, thus mediating the anti-fibrotic effects.
10.1002/ptr.7535
Bryodulcosigenin a natural cucurbitane-type triterpenoid attenuates dextran sulfate sodium (DSS)-induced colitis in mice.
Li Renshi,Chen Ce,Liu Bei,Shi Wen,Shimizu Kuniyoshi,Zhang Chaofeng
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Bryodulcosigenin (BDG) a cucurbitane-type triterpenoid has been isolated from the roots of Bryonia dioca and possesses marked anti-inflammatory effects, although its beneficial effect against intestinal disorders remains unclear. PURPOSE:To explore the underlying mechanism of BDG on the dysbiosis of chronic ulcerative colitis (UC) and its associated side-effects on lung tissues. METHODS:A chronic UC model was established using 2.5% dextran sulfate sodium (DSS) in mice treated for 64 days and diagnostic assessments, western blot analysis and quantitative real time-PCR were employed to determine the protective mechanism of BDG. RESULTS:Oral administration of BDG (10 mg/kg/day) significantly improved colon length, disease activity index, and alleviated colonic histopathological damage in the DSS-induced colitis mice. BDG not only reversed the TNF-α-induced degradation of tight junction proteins (occludin and ZO-1) but also suppressed the elevated apoptosis seen in intestinal epithelial cells (NCM460). In addition, BDG significantly attenuated damage in alveolar epithelial cells (MLE-12) co-cultured with NCM460 cells under inflammatory conditions. Furthermore, BDG in vivo significantly prevented the symptoms of respiratory disorders and repressed alveolar inflammation by regulating DSS-induced chronic colitis in mice. CONCLUSION:BDG effectively inhibited the apoptosis of intestinal epithelial cells and suppressed the activation of the NLRP3 inflammasome which resulted in the restoration of the intestinal barrier. Therefore, the enhanced integrity of intestinal epithelial cells produced by BDG intervention contributed to its anti-colitis effects, indicating its great potential as an inhibitor of UC and lung injury. Therefore, restoring intestinal integrity may represent a promising strategy in the prevention of pulmonary disease.
10.1016/j.phymed.2021.153814
Congenital malformations and other reproductive hazards from environmental chemicals.
Sullivan F M,Barlow S M
Proceedings of the Royal Society of London. Series B, Biological sciences
From a number of disasters which have already occurred throughout the world, it is known that the reproductive process in both animals and man may be severely affected by chemicals. The range of effects that might occur include not only foetal death or malformation, but also effects on the subsequent development, behaviour, intelligence and reproductive capacity of offspring which appear otherwise normal at birth. The special sensitivity of the foetus to some environmental carcinogens is also discussed. Some of the problems in screening for such effects in animals are mentioned along with the need for adequate monitoring programmes to detect reproductive toxicity both from industrial exposure to chemicals and from more general environmental exposure.
10.1098/rspb.1979.0051
A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquilisers and of stimulants.
File S E,Hyde J R
Pharmacology, biochemistry, and behavior
The effects of minor tranquilisers and of stimulant drugs were studied in the Social Interaction test of anxiety in which the illuminance and unfamiliarity of the test arena are manipulated. Acute administration of sodium phenobarbitone (25 mg/kg) was without effect. Acute administration of sodium phenobarbitone (35 mg/kg) and of meprobamate (60 mg/kg) produced sedation: both locomotor activity and social interaction were reduced. On the other hand, amphetamine sulphate (2 mg/kg) and caffeine citrate (20 mg/kg) reduced social interaction, but increased locomotor activity. Chronic administration dissociated the pattern of results produced by sodium phenobarbitone (35 mg/kg) from that produced by flurazepam (0.5 mg/kg). With chronic treatment (5 days) neither drug reduced motor activity, but whereas phenobarbitone increased social interaction regardless of the test illuminance and unfamiliarity, the increase produced by flurazepam was limited to the more stressful test conditions, i.e., when the arena was unfamiliar or brightly lit.
10.1016/0091-3057(79)90298-3
The assessment of sublethal effects of pollutants in the sea. Review of the problems.
Waldichuk M
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Sublethal effects of pollution may be significant to survival of a stock of marine fish or even a species. Such effects sometimes lead to reproductive failure and have been identified so far only in freshwater systems. Atlantic salmon have disappeared from many streams in Europe and eastern North America, partly as a result of pollution in their freshwater spawning areas and in their estuarine nursing grounds. Reductions in populations of marine fishes due to pollution solely have not yet been demonstrated. However, Baltic Sea seals, where reproductive failure is apparently associated with high concentrations of DDT and polychlorinated biphenyl in the blubber, may have suffered a decline owing to the presence of these organochlorines. Sublethal effects of pollutants have been studied in the laboratory, essentially under four categories: (1) physiology (growth, swimming performance, respiration, circulation); (2) biochemistry/cell structure (blood chemistry, enzyme activity, endocrinology, histochemistry); (3) behaviour/neurophysiology; and (4) reproduction. Not all pollutants elicit meaningful responses in all categories, and a response is not always linear with pollutant concentration. For application to survival of populations the response has to be ultimately related to a healthy progression through a full life cycle, including successful reproduction. In recent time, physiological studies have moved into polluted marine environments with mobile laboratories having continuous sampling capability, to observe effects of pollutants in situ on marine organisms. The Controlled Ecosystem Pollution Experiment (Cepex) in Saanich Inlet, British Columbia, endeavours to investigate the effects of low concentrations of pollutants on marine organisms in large plastic silos having a slow replacement of water.
10.1098/rstb.1979.0037
Some characteristics of 17 beta-estradiol dehydrogenase from bovine placenta.
Bitar K G,Cochran M,Warren J C
Steroids
The activity of 17 beta-estradiol dehydrogenase (E.C. 1.1.1.62) was measured, and its distribution in the subcellular fractions of bovine placenta was compared. Assay of activity was based on the formation of radioactive estrone from 17 beta[4(-14)C]-estradiol. Either NAD+ or NADP+ can serve as cofactor for the enzyme. The nuclear and microsomal fractions of the placental homogenate exhibited the highest specific enzymatic activities before and after treatment with Triton X-100. Electron micrographs of these two fractions prior to treatment with Triton X-100 showed satisfactory purity. 17 beta-estradiol dehydrogenase from bovine placenta exhibits a pH optimum of about 9.5-10.5, and is activated by 5 x 10(-6)M ZnCl2; comparable concentrations of CaCl2 and MgCl2 inactivate the enzyme. The apparent Michaelis constants, Km, for 17 beta-estradiol and NAD+ are 1.4 x 10(-6)M and 5.5 x 10(-5)M respectively. No 17 alpha-estradiol dehydrogenase activity was demonstrable when using 17 alpha-estradiol as substrate.
Renal excretion of hydrogen ions in stone formers.
Marya R K,Dadoo R C,Khurana S,Keshwani R K,Chhabra H L
Urologia internationalis
Urinary hydrogen ion excretion has been studied in 68 adult stone formers and in 50 controls. Under basal state, the stone formers showed statistically significant higher urinary pH, and lower 24-hour urinary titrable acid, ammonium and total hydrogen. On the 3rd day of ammonium chloride loading test, the stone formers showed statistically significant higher urinary pH and lower 24-hour urinary titrable acid, ammonium, total hydrogen and plasma bicarbonate. 'Clearance' indices of hydrogen ion excretion were also depressed in a great majority of the stone formers. The results indicate the frequent co-existence of defective urinary acidification with nephrolithiasis.
10.1159/000280282
Cross-neutralization between vesicular stomatitis virus type Indiana and Chandipura virus.
Dragúnová J,Závada J
Acta virologica
Using highly potent immune sheep sera, it was possible to demonstrate that: (1) Two rhabdoviruses, classified in the Vesiculovirus genus on morphological grounds but previously considered unrelated, viz., the vesicular stomatitis virus type Indiana (VSV), and Chandipura virus (ChV), show a low-level, but distinct cross-neutralization. This was, in most combinations, considerably increased by complement. (2) The species of cells used for growing the viruses for immunization and for neutralization tests, influenced the level of cross-neutralization. (3) No cross-reaction between VSV and ChV could be detected in the immunodiffusion reaction. (4) Immune sera, raised in sheep by immunization with the two purified rhabdoviruses contained complement-dependent cytotoxic antibodies specifically reacting with the cell species used for growing the viruses.
[The Cerebral Function Monitor in intensive care].
Romano P,Margenet A,Gaben M C,Hrouda P
Annales de l'anesthesiologie francaise
The Monitor of Cerebral Function, the first apparatus designed for continual cerebral monitoring for prolonged periods, is used frequently as an aid during revival. Due to its ease of operation and its straight-forward displaying of the data, it can supply continual information on the state of cerebral activity. Wem used it in various situations where there was a risk of cerebral circulatory insufficiency. Besides this role in the prevention of emergency, we used the M.C.F. as a diagnostic tool in the assessment of brain death. An early confirmation of the presence of stage IV allows of a more efficient removal and grafting of the kidneys. Finally, we also use the M.C.F. in the study of abnormalities of behaviour in patients whose revival to consciousness is slow.
10.1097/00003246-198103000-00388
Role of immune complexes in rheumatoid polyarteritis.
Farrell J B,Person D A,Rossen R D,Lidsky M D
Annals of the rheumatic diseases
Serial clinical and serological observations were made on a patient with necrotising polyarteritis associated with rheumatoid arthritis. Significant levels of circulating immune complexes, as determined by a C1q binding assay, were observed up to 2 years before the clinical manifestations of polyarteritis but rose abrumptly immediately before and concurrently with the onset of polyarteritis. Concomitant serial determinations of C3, latex fixation titres for anti-immunoglobulin, and patterns of fluorescence of antinuclear antibody afforded insight into the nature of these somplexes, as did clinical and serological response to glucocorticoid and cytotoxic therapy. Our data suggest that the antibody involved in the complex was of the IgG class and capable of complement fixation.
10.1136/ard.38.4.390