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ABSTRACTInflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.

IntroductionParasites can facilitate their own spread and reproduction by manipulating insect hosts behavior, as seen in the interaction between Thitarodes xiaojinensis and Ophiocordyceps sinensis. Infection by O. sinensis leads to the mummification of T. xiaojinensis larvae, but the underlying mechanisms remain mysterious.MethodsThe morphology of O. sinensis infected larvae and fungal growth were first observed. Subsequently, the metabolite changes in the larvae before and after infection with the fungus were analyzed by LC/MS and targeted metabolomics. The expression of mannitol-related genes was detected using RT-qPCR, and morphological changes in larvae were observed after injection of different concentrations of mannitol into the O. sinensis-infected larvae.ResultsSignificant changes were found in phenotype, fungal morphology in hemocoel, larval hardness, and mannitol metabolites in infected, mummified 0 h larvae and larvae 5 days after mummification behavior. Surprisingly, the occurrence of mummification behavior was accompanied by fungal dimorphism, as well as the absence of mannitol in both infected and non-infected larvae, until the initial accumulation of mannitol and the expression of mannitol-associated genes occurred at the time of mummification behavior. The presence of mannitol may promote fungal dimorphism to mediate changes in fungal toxicity or resistance, leading to the end of the fungus-insect coexistence period and the incidence of mummification behavior. Furthermore, mannitol injections increase the mummification rate of the infected larvae without significant difference from the normal mummification phenotype.DiscussionThis finding suggests the importance of mannitol in the mummification of host larvae infected with O. sinensis.

Abstract Background Researches and practice of traditional Chinese medicine indicated that Agrimonia pilosa Ledeb could improve insulin resistance (IR) and treat type 2 diabetes (T2DM). To reveal its underling mechanisms, we isolated Flavonoid component (FC) from Agrimonia pilosa Ledeb and elucidated its effects on glucose metabolism to improve IR by suppressing oxidative stress and inflammation. Methods Adipocytes or mice IR model was established with overdosed glucose and insulin or high-fat diet. The uptake of 2-NBDG and glucose consumption were measured to verify insulin sensitivity in vitro and vivo. Reactive oxidative species (ROS) were detected by flow cytometry, and superoxide dismutase (SOD) activity as well as the malondialdehyde (MDA) content were also measured. Meanwhile, factors associated with insulin signal pathway including PPARγ, insulin receptor substrate-1 (IRS-1), GLUT4, and oxidative stress including NF-E2-related factor 2 (Nrf2), as well as the related inflammatory cytokines such as NF-κB, IL-1β, IL-6 and TNF-α were tested. Furthermore, the JNK/PI3K/Akt signal pathway was also explored. Results FC extracted from Agrimonia pilosa Ledeb ameliorated the impaired glucose metabolism significantly. Further study indicated that FC could regulate the insulin signal pathway to improve insulin resistance. Moreover, it could upregulate PPARγ with the similar efficacy as pioglitazone (Piog) straightway. FC also decreased the endogenous ROS and MDA content, increased SOD activity and Nrf2 expression to facilitate oxidative homeostasis. It attenuated expression and secretion of inflammatory cytokines obviously. At last, our results indicated JNK/PI3K/Akt pathway was regulated by FC in adipocytes and adipose tissue. Conclusion FC could ameliorate glucose metabolism and improve IR. It exerted these effects by suppressing oxidative stress and inflammation. FC from Agrimonia pilosa Ledeb has a good prospect to be drugs or functional foods for IR and T2DM.

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Mechanisms underlying the pathogenesis of nonalcoholic steatohepatitis are unclear. Here, the authors show that ROS-mediated DUSP22 degradation participates in the progression of fatty liver, contributing to the development of NASH and associated HCC via regulating FAK and its downstream ERK1/2 and NF-κB signaling cascade.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with complex disease mechanisms. Here the authors report that the E3 ubiquitin-protein ligase Trim31 mitigates development of NASH via inhibition of rhomboid 5 homolog 2 (Rhbdf2) in mice.

Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl4)-induced liver injury and dysfunction in mice. Furthermore, CCl4-triggerd collagen deposition and liver fibrosis were remarkably attenuated in mice with Mul supplementation through suppressing transforming growth factor β1 (TGF-β1)/SMAD2/3 signaling pathway. Additionally, Mul treatments strongly restrained the hepatic inflammation in CCl4-challenged mice via blocking nuclear factor-κB (NF-κB) signaling. Importantly, we found that Mul markedly increased liver TRIM31 expression in CCl4-treated mice, accompanied with the inactivation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCl4-triggered hepatic oxidative stress was also efficiently mitigated by Mul consumption via improving nuclear factor E2-related factor 2 (Nrf2) activation. Our in vitro studies confirmed that Mul reduced the activation of human and mouse primary hepatic stellate cells (HSCs) stimulated by TGF-β1. Consistently, Mul remarkably retarded the inflammatory response and reactive oxygen species (ROS) accumulation both in human and murine hepatocytes. More importantly, by using hepatocyte-specific TRIM31 knockout mice (TRIM31Hep-cKO) and mouse primary hepatocytes with Nrf2-knockout (Nrf2KO), we identified that the anti-fibrotic and hepatic protective effects of Mul were TRIM31/Nrf2 signaling-dependent, relieving HSCs activation and liver fibrosis. Therefore, Mul-ameliorated hepatocyte injury contributed to the suppression of HSCs activation by improving TRIM31/Nrf2 axis, thus providing a novel therapeutic strategy for hepatic fibrosis treatment.

Fisetin (FisT) is a bioactive flavonoid polyphenol with antioxidant, anti-inflammatory and anti-tumor activities. Although the effects of FisT to meliorate non-alcoholic fatty liver disease (NAFLD) have been investigated, the underlying mechanisms are not fully understood. In the present study, we found that FisT remarkably suppressed cellular and mitochondrial reactive oxygen species (ROS) generation in human and murine hepatocytes with palmitate (PA) stimulation. Additionally, mitochondrial impairment and dysfunction induced by PA were considerably abrogated in hepatocytes with FisT co-incubation. Furthermore, Cyto-c releases and mitochondrial apoptosis were detected in PA-treated hepatocytes, while being greatly repressed by FisT. PA-induced inflammation and lipid deposition were also strongly reduced by FisT in hepatocytes. Importantly, our in vitro experiments showed that promoting ROS by nuclear factor erythroid 2-related factor 2 (Nrf2) deletion significantly abolished the function of FisT to meliorate apoptosis, inflammation and lipid accumulation in PA-incubated hepatocytes. What’s more, ER stress was strongly induced by PA via increasing 78-kDa glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP), which were, however, dramatically repressed after FisT co-exposure. Intriguingly, we found that strengthening ER stress by GRP78 over-expression considerably abolished the capacity of FisT to retard ROS generation and mitochondrial impairment in PA-stimulated hepatocytes, but GRP78 knockdown exhibited totally opposite effects. Thus, ER stress blockage was required for FisT to ameliorate NAFLD development in vitro. Consistently, our in vivo studies using high fat diet (HFD)-fed mice confirmed that FisT administration exerted inhibitory and therapeutic potential on fatty liver progression via the same mechanisms monitored in vitro. Collectively, all our findings disclosed that FisT can efficiently attenuate NAFLD through restraining ROS generation and mitochondrial impairment mediated by ER stress.

In this paper, the decision-making model of discretionary lane-changing is established using cumulative prospect theory (CPT). Through analyzing the vehicles’ dynamic running states, safety spacing calculating approaches for discretionary lane-changing and lane-keeping have been put forward firstly. Then, based on CPT, a lane-changing decision model with accelerating space as its utility is proposed by estimating the difference between actual spacings and the safety spacings for discretionary lane-changing as well as lane-keeping. In order to calculate the utility of discretionary lane-changing, dynamic reference points and a parameter representing driver’s risk preference are introduced into the model. With the real data collected from an urban expressway, the distribution of discretionary lane-changing duration is analyzed, and the model parameters are also calibrated. Furthermore, the applicability of the model is evaluated by comparing with the actual observation and random unity model. Finally, the sensitivity analysis of the model is carried out, that is, assessing the influence degree of each variable on the decision result. The study reveals that the CPT-based model can describe discretionary lane-changing behavior more accurately, which consider drivers’ risk-aversion during decision-making.

Travelers’ route choice shows bounded-rationality because of different perceptions of route attributes. Based on the bounded-rationality, the paper proposes the dynamic evolution rules and route choice model, and simulation method is applied to study the evolution process and results. The model includes three parameters reflecting the bounded-rationality of travelers. First, simulation results show that the bounded-rationality affects the evolution process. The switching threshold or the perception deviance is larger, convergence rate is faster, and shorter time is needed to reach equilibrium state. Also, fewer perfect rational travelers will lead to similar results. Second, the system can reach equilibrium and the final equilibrium volume of every route is almost unaffected by bounded-rationality. The equilibrium volume of every route is an approximately fixed value under all simulation scenes. At last, it is found that equilibrium volume of every route obeys normal distribution. That is, bounded-rationality affects the equilibrium convergence rate, but volume equilibrium results will not be influenced.

To clarify the substantial basis of the excellent antioxidant capacity of Agrimonia pilosa Ledeb. Fourteen flavonoids were isolated and identified from Agrimonia pilosa Ledeb, seven of which have notable DPPH radical scavenging activities, i.e., catechin, luteolin, quercetin, quercitrin, hyperoside, rutin, luteolin-7-O-β-glucoside with IC50 values of 5.06, 7.29, 4.36, 7.12, 6.34, 6.36 and 8.12 µM, respectively. The DNA nicking assay showed that five flavonoids from Agrimonia pilosa Ledeb—taxifolin, catechin, hyperoside, quercitrin and rutin—have good protective activity against DNA oxidative damage. Further, we analyzed the bioactivity-structure relationship of these 14 flavonoids by applying quantum theory. According to their O-H bond dissociation enthalpy (BDE), C ring’s spin density and stable molecular structure, the relationship between their structures and radical scavenging capacities was evaluated and clarified. We found that among flavonoid aglycones from Agrimonia pilosa Ledeb, the O-H BDE of quercetin is lowest with the values of 69.02 and the O-H BDE of apigenin is highest with the values of 79.77. It is interesting that the O-H BDE value of isovitexin (78.55) with glycoside at C-6 position is lower than that of its aglycone (79.77) and vitexin (99.20) with glycoside at C-8 position. Further analysis indicated that the glycosidation of flavonoids at C-6 in the A-ring makes a more uniform distribution of spin density and improves the stability of free radicals leading to the increase in antioxidant capacity. Flavonoids with good antioxidant capacity might contribute to the pharmacological effects of Agrimonia pilosa Ledeb.

Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors have read and agreed to the published version of the manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In this paper, we studied the naphthalene degradation by using Pseudomonas aeruginosa under low-intensity ultrasonic stimulation. In our experiment, the degradation rate of naphthalene was the main parameter. We found that low-intensity ultrasonic could not only promote the growth of immobilized P. aeruginosa, but also could improve the degradation of naphthalene. In this article, 1% naphthalene was added into MM culture medium as imitation wastewater. The effect of low-intensity ultrasonic parameter and gel-globes size were considered. We found the influence was obvious, and the optimum degradation rate was acquired when the parameters of ultrasonic are: frequency, 24 kHz; power, 8 W; ultrasonic time, interval time, 10 s; total time, 10 m and the gel-globes were made by using injector no. 14. The naphthalene degradation rate of immobilized cells with ultrasonic stimulation is 82%, which is 12.9 and 42.2% higher than that of immobilized cells and suspended cells without ultrasonic stimulation, respectively.

Quercetin manganese(II) complexes were investigated focusing on its DNA hydrolytic activity. The complexes successfully promote the cleavage of plasmid DNA, producing single and double DNA strand breaks. The amount of conversion of supercoiled form (SC) of plasmid DNA to the nicked circular form (NC) depends on the concentration of the complex as well as the duration of incubation of the complexes with DNA. The maximum rate of conversion of the supercoiled form to the nicked circular form at pH 7.2 in the presence of 100 microM of the complexes is found to be 1.32 x 10(-4) s(-1). The hydrolytic cleavage of DNA by the complexes was supported by the evidence from free radical quenching, thiobarbituric acid-reactive substances (TBARS) assay and T4 ligase ligation.

Quercetin zinc(II) complex was investigated focusing on its hydrolytic activity toward DNA. The complex successfully promotes the cleavage of plasmid DNA, producing single and double DNA strand breaks. The amount of conversion of supercoiled form (SC) of plasmid to the nicked circular form (NC) depends on the concentration of the complex as well as the duration of incubation of the complex with DNA. The rate of conversion of SC to NC is 1.68x10(-4) s(-1) at pH 7.2 in the presence of 100 microM of the complex. The hydrolytic cleavage of DNA by the complex is supported by the evidence from free radical quenching, thiobarbituric acid-reactive substances (TBARS) assay, and T4 ligase ligation.

In the paper, two main methods, which are Serum Pharmacology and Traditional Pharmacology, were adopted to study Chinese traditional medicine, such as Ginkgo biloba extract (GBE), ginsenosides (GS) and compound GG (GBE+GS), pharmacology in vitro. The results showed that there were evident difference between the results of Serum Pharmacology and that of Traditional Pharmacology. There was no significant difference between the drug effect of crude GS on nitric oxide (NO) production in ECV304 and that of crude GBE, and the drug effect of GG was superior to that of GS and GBE, respectively. But, compared with GBE serum, the GS serum up-regulation of NO production in ECV304 increased significantly, and the GG serum up-regulation of the NO production in ECV304 was inferior to that of GS serum and GBE serum significantly. The results suggested that Serum Pharmacological study should be adopted in the pharmacological investigation on the Chinese traditional medicine and the drug screening of the Chinese traditional medicine.

Pharmacokinetic research, which is one of the most important parts of preclinic research, plays an important role in guiding medicine compatibility and preparation improvement. In this paper, the influence of the compatibility of GGV on pharmacokinetics of ginsenosides (GS) was studied, which consisted of ginsenosides, ginkgo biloba extract (GBE) and a chemical monomer V. The result indicated that the addition of either GBE or V could influence the pharmacokinetic parameters of ginsenosides and the influence was different when different administering routes were adopted. Therefore, it could be concluded that there are interactions among GS, GBE and V, and the synergetic and inhibitory effects of the three ingredients contribute to the pharmacological effect of GGV.

Nitric oxide (NO) controls several physiological functions of the cardiovascular system. The study on the effect of diamide (N(2)H(4).H(2)O) on NO production in vascular endothelial cells (VEC) may provide significant reference for VEC's modeling in studying cardiovascular diseases. The objective of this study was to elucidate how high concentration diamide (V(diamide)/V(culture miedium) = 5 ml/l) and low concentration diamide (V(diamide)/V(culture miedium) = 0.5 ml/l) affect NO production in a human endothelial cell line (ECV304). After cells were incubated with diamide (5 or 0.5 ml/l) for 4, 6, 8 or 10h, respectively, the amounts of NO metabolites released by the cells were quantitated and the degree of damage of VEC was observed using microscope. The results showed that NO production in VEC tended to decrease with the lapse of time in the 0.5 ml/l diamide group. In the 5 ml/l diamide group, on the contrary, NO production in VEC tended to increase with the lapse of time. At the same time, from the morphologic observation, the VEC were damaged severely after treated with 5 ml/l diamide. So it could be concluded that the severe damage induced by high concentration diamide would have triggered the express of inducible nitric oxide synthases (iNOS). Just for the expresssion of iNOS, NO production in VEC treated with high concentration diamide occurred abnormally in contrast to the 0.5 ml/l group.