Bilirubin is an endogenous substance derived from heme catabolism. In this study, we aimed to assess the anti-inflammatory activity of bilirubin, and to determine the mechanism thereof. The ...anti-inflammatory activity of bilirubin was evaluated using lipopolysaccharide (LPS)-treated peritoneal macrophages (PMs) and Raw264.7 cells, and mice with alum-induced peritonitis. The mRNA and proteins of NOD-like receptor family pyrin domain containing 3 (Nlrp3) and inflammatory cytokines were determined using qPCR and Western blotting, respectively. Distribution of phosphorylated (p) p65 a NF-κB (nuclear factor-κB) subunit in the cytoplasm and nucleus were evaluated by immunofluorescence analysis and electrophoretic mobility shift assay. Bilirubin prior to LPS treatment decreased protein expressions of Nlrp3, pro-interleukin (IL)-1β and mature IL-1β in PMs, whereas bilirubin post LPS treatment showed no effects. Bilirubin prior to LPS treatment dose-dependently repressed expressions of Nlrp3 and IL-1β, and inhibited translocation of p-p65 to nucleus in Raw264.7 cells. Bilirubin treatment decreased myeloperoxidase activity and reduced the levels of inflammatory cytokines (i.e., IL-1β, TNFα and IL-6) in lavage fluid in mice with alum-induced peritonitis. This was accompanied by a lower mortality rate. In addition, the mRNAs of Nlrp3 and IL-1β in peritoneal exudates cells were decreased, and the levels of p-p65 and mature IL-1β proteins were reduced. In conclusion, bilirubin acted on inflammation and alleviated alum–induced peritonitis through inactivation of Nlrp3 inflammasome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Compared with the original backprojection (BP) algorithm, the fast factorized BP algorithm accelerates enormously. As it is known to all, 2-D image interpolations are always utilized to raise the ...accuracy, yet leadings to the tradeoff with the efficiency. In this paper, a novel factorized BP algorithm based on Cartesian coordinate without interpolation, is proposed for high-resolution spotlight SAR with much better efficiency and accuracy. The innovative idea is achieved by establishing two spectrum compressing filters to decrease the cross-range Nyquist sampling rate enormously, thus avoid spectrum aliasing. The proposed algorithm, termed as the Cartesian factorized BP (CFBP) algorithm, can produce images with the similar quality as the BP does, but is better than FFBP, where the interpolations accumulate errors to some extent. The CFBP is designed for spotlight mode working in both the linear and curved trajectories. Simulation results and real-data processing validate the superiorities of CFBP by the comparisons with FFBP and the original BP individually.
Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of ...metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1−/− (a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration.
•Hypaconitine exhibits dosing time-dependent toxicity with a more severe toxicity in the light phase than in the dark phase.•Hepatic Cyp3a11 expression is diurnal, accounting for circadian metabolism and chronotoxicity of hypaconitine.•Bmal1 regulates diurnal rhythm of Cyp3a11 expression and chronotoxicity of hypaconitine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
, a renowned medicinal plant with a rich history in traditional medicine, has gained attention for its potential therapeutic applications. However, the leaves of this plant have been largely ...overlooked and discarded due to limited knowledge of their biological activity and chemical composition. To bridge this gap, a comprehensive study was conducted to explore the therapeutic potential of the 70% ethanol extract derived from
leaves (LAE) for the treatment of cardiovascular disease (CVD). Initially, the cytotoxic effects of LAE on human umbilical vein endothelial cells (HUVECs) were assessed, revealing no toxicity within concentrations up to 5 μg/mL. This suggests that LAE could serve as a safe raw material for the development of health supplements and drugs aimed at promoting cardiovascular well-being. Furthermore, the study found that LAE extract demonstrated anti-inflammatory properties in HUVECs by modulating the PI3K/Akt and MAPK signaling pathways. These findings are particularly significant as inflammation plays a crucial role in the progression of CVD. Moreover, LAE extract exhibited the ability to suppress the expression of adhesion molecules VCAM-1 and ICAM-1, which are pivotal in leukocyte migration to inflamed blood vessels observed in various pathological conditions. In conjunction with the investigation on therapeutic potential, the study also established an optimal HPLC-PDA-ESI-MS/MS method to identify and confirm the chemical constituents present in 24 samples collected from distinct regions in South Korea. Tentative identification revealed the presence of 14 saponins and nine phenolic compounds, while further analysis using PCA and PLS-DA allowed for the differentiation of samples based on their geographical origins. Notably, specific compounds such as chlorogenic acid, isochlorogenic acid A, and quercitrin emerged as marker compounds responsible for distinguishing samples from different regions. Overall, by unraveling its endothelial protective activity and identifying key chemical constituents, this research not only offers valuable insights for the development of novel treatments but also underscores the importance of utilizing and preserving natural resources efficiently.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Controlling bilirubin to a low level is necessary in physiology because of its severe neurotoxicity. Therefore, it is of great interest to understand the regulatory mechanisms for bilirubin ...homeostasis. In this study, we uncover a critical role for circadian clock in regulation of bilirubin detoxification and homeostasis.
: The mRNA and protein levels of Bmal1 (a core clock gene), metabolic enzymes and transporters were measured by qPCR and Western blotting, respectively. Luciferase reporter, mobility shift and chromatin immunoprecipitation were used to investigate transcriptional gene regulation. Experimental hyperbilirubinemia was induced by injection of bilirubin or phenylhydrazine. Unconjugated bilirubin (UCB) and conjugated bilirubin were assessed by ELISA.
: We first demonstrated diurnal variations in plasma UCB levels and in main bilirubin-detoxifying genes
and
. Of note, the circadian UCB levels were antiphase to the circadian expressions of Ugt1a1 and Mrp2. Bmal1 ablation abrogated the circadian rhythms of UCB and bilirubin-induced hepatotoxicity in mice. Bmal1 ablation also decreased mRNA and protein expressions of both Ugt1a1 and Mrp2 in mouse livers, and blunted their circadian rhythms. A combination of luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Bmal1 trans-activated
and
through specific binding to the E-boxes in the promoter region. Further, Bmal1 ablation caused a loss of circadian time-dependency in bilirubin clearance and sensitized mice to chemical induced-hyperbilirubinemia. Moreover, bilirubin stimulated Bmal1 expression through antagonism of Rev-erbα, constituting a feedback mechanism in bilirubin detoxification.
: These data supported a dual role for circadian clock in regulation of bilirubin detoxification, generating circadian variations in bilirubin level via direct transactivation of detoxifying genes Ugt1a1 and Mrp2, and defending the body against hyperbilirubinemia via Rev-erbα antagonism. Thereby, our study provided a potential mechanism for management of bilirubin related diseases.
The study of position control for variable stiffness actuators is important for improving their energy efficiency and robustness. In this paper, for the previously proposed nonlinear variable ...stiffness actuator, firstly, a dynamic model of the variable stiffness actuator system is established based on a two-inertia-system theory. Secondly, the effects of friction and gravity factors on the dynamic performance of the system are analyzed. The results of the study show that friction and gravity have obvious effects on the dynamic characteristics of the system in the constant stiffness state, and that these effects are more complex and obvious in the variable stiffness state, which proves the reasonableness and necessity of considering friction and gravity in the dynamics modeling process. Then, in order to improve the dynamic performance of the system and make its positioning performance meet the requirements, the control strategy of the variable stiffness actuator system is studied. The results show that the sliding mode control strategy based on nonlinear disturbance observer and dynamics model is a good solution to the effect of friction and gravity on the system, and can make its position-tracking performance meet the requirements. Finally, the correctness and effectiveness of the control strategy are verified experimentally.
Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the ...mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of
semen strychni
(SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. SS extract and TGT suspension were prepared with ultrasonication. Effects of SS and TGT on collagen-induced arthritis (CIA) were evaluated by measuring TNF-α and IL-6 levels. SS dosed at ZT18 was more effective in protecting against CIA than drug dosed at ZT6 (i.e., lower levels of key inflammatory factors at ZT18 than at ZT6). This was accompanied by higher systemic exposure levels of strychnine and brucine (two main putative active ingredients of SS) in ZT18-treated than in ZT6-treated CIA mice. TGT dosing at ZT2 showed a better efficacy against CIA as compared to herb doing at ZT14. Consistently, ZT2 dosing generated a higher exposure of triptolide (a main putative active ingredient of TGT) as compared to ZT14 dosing in CIA mice. Moreover, strychnine, brucine, and triptolide significantly inhibited the proliferation of fibroblast-like synoviocytes, and reduced the production of TNF-α and IL-6 and the mRNAs of TNF-α, IL-6, COX-2, and iNOS, suggesting that they possessed an anti-arthritis activity. In conclusion, SS and TGT display chronoefficacy against rheumatoid arthritis in mice, that is attributed to circadian pharmacokinetics of main active ingredients. Our findings have implications for improving treatment outcomes of SS and TGT
via
timed delivery.
Cellulolytic bacteria ferment dietary fiber into short-chain fatty acids, which play an important role in improving fiber utilization and maintaining intestinal health. Safe and effective ...cellulolytic bacteria are highly promising probiotic candidates. In this study, we isolated three strains of
which exhibited cellulolytic properties, from Kele pig feces. To assess the genetic basis of cellulose degradation by the isolates, whole-genome sequencing was used to detect functional genes associated with cellulose metabolism. Subsequently, we identified that the
CL2 strain was safe in mice by monitoring body weight changes, performing histopathologic evaluations, and determining routine blood indices. We next evaluated the biological characteristics of the CL2 strain in terms of its growth, tolerance, and antibiotic susceptibility, with a focus on its ability to produce short-chain fatty acids. Finally, the intestinal flora structure of the experimental animals was analyzed to assess the intestinal environment compatibility of the CL2 strain. In this study, we isolated a cellulolytic
CL2, which has multiple cellulolytic functional genes and favorable biological characteristics, from the feces of Kele pigs. Moreover, CL2 could produce a variety of short-chain fatty acids and does not significantly affect the diversity of the intestinal flora. In summary, the cellulolytic bacterium
CL2 is a promising strain for use as a commercial probiotic or in feed supplement.
Short-chain fatty acids are crucial constituents of the intestinal tract, playing an important and beneficial role in preserving the functional integrity of the intestinal barrier and modulating both immune responses and the structure of the intestinal flora. In the intestine, short-chain fatty acids are mainly produced by bacterial fermentation of cellulose. Therefore, we believe that safe and efficient cellulolytic bacteria have the potential to be novel probiotics. In this study, we systematically evaluated the safety and biological characteristics of the cellulolytic bacterium
CL2 and provide evidence for its use as a probiotic.
Rodents (order Rodentia), followed by bats (order Chiroptera), comprise the largest percentage of living mammals on earth. Thus, it is not surprising that these two orders account for many of the ...reservoirs of the zoonotic RNA viruses discovered to date. The spillover of these viruses from wildlife to human do not typically result in pandemics but rather geographically confined outbreaks of human infection and disease. While limited geographically, these viruses cause thousands of cases of human disease each year. In this review, we focus on three questions regarding zoonotic viruses that originate in bats and rodents. First, what biological strategies have evolved that allow RNA viruses to reside in bats and rodents? Second, what are the environmental and ecological causes that drive viral spillover? Third, how does virus spillover occur from bats and rodents to humans?
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The pollutant transport equilibrium in a watershed can be analyzed on a large time scale, and land‐use export coefficients can be calculated directly under certain hydrologic and transport ...conditions, by ignoring hydrologic and transport processes at small space and time scales on hydrologic response units. In this study, the water environment system of a watershed was deconstructed into three parts (source, source‐sink, and runoff transport) to construct a pollutant transportation equilibrium model on a large time scale. A watershed with an annual source‐sink accumulation of zero was defined as a completely transported watershed; therefore, we derived a completely transported equilibrium equation. The problem of seeking the land export coefficient was converted into a problem of seeking the optimal solution of linear programming, which can be estimated according to the variation in pollutant output processes. The feasibility of the solution can be analyzed using multi‐year stochastic rainfall processes. The model was used to analyze the transport equilibrium of chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) upstream of the monitored cross‐sections in a watershed, which covered 3145.66 km2. The land export coefficients were calculated according to the model. The model calculations indicated that the watershed was completely transported during perennial years. The calculated export coefficients of COD, TN, and TP for farmland, primary vegetation, and urban land were within the range of general empirical values. The calculated maximum accumulations of COD, TN, and TP were 0.19 × 107, 0.063 × 107, and 0.049 × 106 kg, respectively, for perennial rainfall.
Practitioner Points
A completely transported watershed was defined, and a model of pollutant transportation equilibrium with large time‐scale was constructed.
A problem of seeking the optimal solution of a linear programming was designed to estimate the land export coefficient of COD, TN, and TP.
The runoff transport and accumulation processes of COD, TN, and TP in a watershed was analyzed.
(1)A pollutant transportation equilibrium model with large time‐scale for a watershed was constructed. (2)The model was used for analyzing the transport and accumulation of pollutants in watersheds, and calculating the land export coefficients of COD, TN, and TP.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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