Inhibition of Human UDP-Glucuronosyltransferases1A1-Mediated Bilirubin Glucuronidation by the Popular Flavonoids Baicalein, Baicalin, and Hyperoside Is Responsible for Herb (Shuang-Huang-Lian)-Induced Jaundice.

Bilirubin-related adverse drug reactions (ADRs) or malady (e.g., jaundice) induced by some herbs rich in certain flavonoids have been widely reported. However, the causes and mechanisms of the ADRs are not well understood. The aim of this paper was to explore the mechanism of Shuang-huang-lian (SHL) injections and its major constituents-induced jaundice via inhibiting human UDP-glucuronosyltransferases1A1 (hUGT1A1)-mediated bilirubin glucuronidation. The inhibitory effects of SHL and its major constituents in the herbal medicine, including baicalein (BAI), baicalin (BA), and hyperoside (HYP), on bilirubin glucuroBBREVInidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides [i.e., mono-glucuronide 1 (BMG1), BMG2, and bilirubin diglucuronide] displayed significant differences (P < 0.05). Specifically, the formation of BMGs was favored regardless of whether an inhibitor was absent or present. SHL, BAI, BA, and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC50 values against total bilirubin glucuronidation were in the range of (7.69 ± 0.94)-(37.09 ± 2.03) µg/ml, (4.51 ± 0.27)-(20.84 ± 1.99) µM, (22.36 ± 5.74)-(41.35 ± 2.40) µM, and (15.16 ± 1.12)-(42.80 ± 2.63) µM for SHL, BAI, BA, and HYP, respectively. Both inhibition kinetics assays and molecular docking simulations suggested that SHL, BAI, BA, and HYP significantly inhibited hUGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibition. Collectively, some naturally occurring flavonoids (BAI, BA, and HYP) in SHL have been identified as the inhibitors against hUGT1A1-mediated bilirubin glucuronidation, which well explains the bilirubin-related ADRs or malady triggered by SHL in clinical settings. SIGNIFICANCE STATEMENT: Herbal products and their components (e.g., flavonoids), which been widely used across the entire world, may cause liver injury. As a commonly used herbal products rich in flavonoids, SHL injections easily lead to symptoms of liver injury (e.g., jaundice) owing to significant inhibition of hUGT1A1-mediated bilirubin glucuronidation by its flavonoid components (i.e., baicalein, baicalin, and hyperoside). Herb-induced bilirubin-related ADRs and the associated clinical significance should be seriously considered.

Toxic effect of nickel on microalgae Phaeodactylum tricornutum (Bacillariophyceae).

Nickel acts as an essential trace nutrient or toxicant for organisms, depending on its concentration. The increased concentrations of nickel, due to anthropogenic activity, in the aquatic environment are potential threats to aquatic organisms. However, the knowledge on toxic mechanisms of nickel to microalgae remains incompletely understood. In the present study, we investigated the toxic effects of nickel in the cosmopolitan diatom Phaeodactylum tricornutum via evaluation of physiological and transcriptome responses. The results showed that the median effective concentration-72 h (EC50-72 h) and EC50-96 h of nickel was 2.48 ± 0.33 and 1.85 ± 0.17 mg/L, respectively. The P. tricornutum cell abundance and photosynthesis significantly decreased by 1 mg/L of nickel. Results from photosynthetic parameters including efficiency of the oxygen evolving complex (OEC) of photosystem II (PSII) (Fv/F0), maximum photosynthetic efficiency of PS II (Fv/Fm), electron transport rate (ETR), actual photosynthetic efficiency of PS II (Y(II)), non-photochemical quenching (NPQ), and photochemical quenching (qP) indicated that OEC of PS II might be impaired by nickel. The transcriptome data also reveal that OEC apparatus coding gene PS II oxygen-evolving enhancer protein 2 (PsbP) was regulated by nickel. Moreover, induced reactive oxygen species (ROS) production and chlorophyll a content were also detected under nickel stress. Transcriptome analysis revealed that nickel affected a variety of differentially expressed genes (DEGs) that involved in redox homeostasis, nitrogen metabolisms, fatty acids, and DNA metabolism. However, thiol-disulfide redox system might play important roles in nickel-induced oxidative stress resistance. This study improved the understanding of the toxic effect of nickel on the diatom P. tricornutum.

Atherogenic index of plasma is a novel and better biomarker associated with obesity: a population-based cross-sectional study in China.

BACKGROUND: Atherogenic index of plasma (AIP) has been reported to be associated with cardiovascular diseases. However no study has yet systematically evaluated the association between AIP and obesity and its advantage in obesity prediction compared with conventional lipid components. METHODS: A total of 6465 participants aged over 30 years were included in this study. Blood lipid components including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured, and AIP was calculated as log10(TG/HDL-C). Pearson correlation analyses, multivariable logistic analyses and predictive analyses were used to evaluate the association and discrimination ability between AIP, four conventional lipid profiles and obesity. RESULTS: Subjects in the higher quartiles of AIP all had a significantly increased risk of obesity compared with those in the lowest quartile (P for trend< 0.01). AIP showed a stronger association with obesity than the conventional lipid components as the pearson coefficient reached up to 0.372 and the adjusted odds ratio was 5.55. Using AIP rather than HDL-C and TG significantly improved risk prediction for obesity (AUC improvement = 0.011, P = 0.011; Continuous net reclassification index = 29.55%, P < 0.01; Category net reclassification index = 6.06%; Integrated discrimination improvement = 0.68%, P < 0.01). CONCLUSIONS: Higher AIP level was positively and strongly associated with obesity. AIP is a novel and better biomarker associated with obesity. Controlling the AIP level would be more helpful for the prevention of obesity.

Associations of non-high density lipoprotein cholesterol and traditional blood lipid profiles with hyperuricemia among middle-aged and elderly Chinese people: a community-based cross-sectional study.

BACKGROUND: Increased serum uric acid (SUA) is associated with dyslipidemia. However, there are conflicting data about the role of single lipid species including non-high density lipoprotein cholesterol (non-HDL-C) in promoting SUA accumulation. Here, we aimed to compare non-HDL-C with other traditional blood lipid profiles in relation to hyperuricemia in a middle-aged and elderly Chinese population. METHODS: Data was collected from 9580 participants undergoing routine physical examinations in Xiangcheng district of Suzhou. SUA, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were examined for all participants. Non-HDL-C was calculated by subtracting HDL-C from TC. The associations of blood lipid profiles with hyperuricemia were examined in men and women, respectively. The areas under Receiver Operating Characteristic (ROC) curves (AUCs) were compared to assess the discriminatory value of blood lipid parameters for predicting hyperuricemia. RESULTS: All blood lipid parameters significantly correlated with SUA (all P values <0.001). The correlation coefficient between SUA and TG was the highest in both genders. The correlation coefficient of non-HDL-C was higher than HDL-C in males and was higher than TC and LDL-C but followed HDL-C in females. In male group, AUC of TG (0.659) was greater than that of non-HDL-C (0.595) (P values <0.001). The AUC values of HDL-C, TC and LDL-C were lower; respectively 0.581, 0.559 and 0.552. In female group, AUC was highest for TG (0.678) followed by HDL-C (0.616), non-HDL-C (0.610), LDL-C (0.559) and TC (0.557) (all P values<0.001). CONCLUSIONS: In both genders, serum TG has the strongest association with hyperuricemia among blood lipid parameters. Non-HDL-C is also significantly associated with hyperuricemia.

Mapping the main harmful algal species in the East China Sea (Yangtze River estuary) and their possible response to the main ecological status and global climate change via a global vision.

The Yangtze River Estuary (YRE) is one of the areas in China most severely affected by harmful algal blooms (HABs). This study explored the distributive patterns of HABs in the YRE and how they are influenced by the El Niño-Southern Oscillation (ENSO) and other environmental factors. Quantitative real-time PCR (qPCR) was employed to detect and quantify the four predominant HAB species in the YRE, Karenia mikimotoi, Margalefidinium polykrikoides, Prorocentrum donghaiense, and Heterosigma akashiwo. Additionally, the study analyzed how turbidity, pH, salinity, and temperature influence these algae. Distribution of the four HAB species in the YRE area shows clear geographical variations: K. mikimotoi is predominantly found in the northwest and central sea areas, M. polykrikoides (East Asian Ribotype, EAR) is mainly distributed in the southeastern part, P. donghaiense is abundant in the northern regions, and H. akashiwo is especially prevalent at stations S26 and S27 in the northeastern part of the study area. HABs dominated by H. akashiwo and P. donghaiense were observed in the northeastern sea area of the YRE on July 22, 2020. Our study reveals that K. mikimotoi, M. polykrikoides (EAR), and P. donghaiense are mainly affected by turbidity, pH, and salinity, while temperature predominantly influences the blooms of H. akashiwo. Moreover, runoff in the YRE has a certain correlation with ENSO events, which may also impact the nutrient content of the region. The findings of this study illustrate the distributive patterns of the four HAB species under various ecological conditions in the YRE and emphasize the importance of establishing practical cases for future warning systems. To better understand how climate change affects HABs, exploring the link between ENSO and HABs is essential.

Magnetic Soft Catheter Robot System for Minimally Invasive Treatments of Articular Cartilage Defects.

Articular cartilage defects are among the most common orthopedic diseases, which seriously affect patients' health and daily activities, without prompt treatment. The repair biocarrier-based treatment has shown great promise. Total joint injection and open surgery are two main methods to deliver functional repair biocarriers into the knee joint. However, the exhibited drawbacks of these methods hinder their utility. The repair effect of total joint injection is unstable due to the low targeting rate of the repair biocarriers, whereas open surgery causes serious trauma to patients, thereby prolonging the postoperative healing time. In this study, we develop a magnetic soft catheter robot (MSCR) system to perform precise in situ repair of articular cartilage defects with minimal incision. The MSCR processes a size of millimeters, allowing it to enter the joint cavity through a tiny skin incision to reduce postoperative trauma. Meanwhile, a hybrid control strategy combining neural network and visual servo is applied to sequentially complete the coarse and fine positioning of the MSCR on the cartilage defect sites. After reaching the target, the photosensitive hydrogel is injected and anchored into the defect sites through the MSCR, ultimately completing the in situ cartilage repair. The in vitro and ex vivo experiments were conducted on a 3D printed human femur model and an isolated porcine femur, respectively, to demonstrate the potential of our system for the articular cartilage repair.

Effect of Astragali radix extract on pharmacokinetic behavior of dapagliflozin in healthy and type 2 diabetic rats.

Objective: This study aimed to investigate effect of antidiabetic herb Astragali Radix (AR) on pharmacokinetic behavior of dapagliflozin (DAPA) in healthy rats and type 2 diabetes mellitus (T2DM) rats. Methods: The T2DM rats were induced by high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). Concentrations of DAPA in healthy and T2DM rat plasma were determined by UPLC-MS/MS method. Effect of AR extract (ARE) on pharmacokinetic behavior of DAPA in healthy and T2DM rats was evaluated, respectively. Results: The diabetes status and co-administrated with ARE significantly affected pharmacokinetic behaviors of DAPA in the rats. Compared to that in healthy rats, t max of DAPA significantly shortened, its C max significantly increased in T2DM rats, and its t 1/2, V, AUC, CL and MRT kept unchanged. When ARE was co-administrated with DAPA, C max of DAPA significantly increased, its t max and MRT significantly decreased, and its t 1/2, V, AUC and CL kept unchanged in healthy rats. t max and C max of DAPA significantly decreased, its t 1/2 and V significantly increased, and its AUC, CL and MRT were unchanged in T2DM rats when ARE was co-administrated with DAPA. Co-administration of DAPA and ARE promoted absorptive rate of DAPA, increased its extravascular tissue distribution, and prolonged its duration of action. ARE did not cause accumulation of DAPA in vivo. Conclusion: Both disease status of T2DM and co-administration of ARE affect pharmacokinetic behavior of DAPA in vivo. Potential pharmacokinetic interactions may occur in vivo when herbs and drugs are co-administrated, which may affect efficacy and safety of drugs.

Integration of pharmacodynamics, network pharmacology and metabolomics to elucidate effect and mechanism of Artemisia capillaris Thunb. in the treatment of jaundice.

ETHNOPHARMACOLOGICAL RELEVANCE: As one of the most commonly used herbs, Artemisia capillaris Thunb. (ACT) display favorable effect in the treatment of jaundice. However, mechanism of ACT in the treatment of jaundice remains unclear at present, which limits its development and application. AIM OF THE STUDY: To investigate effect and mechanism of Artemisia capillaris Thunb. (ACT) in the treatment of jaundice using pharmacodynamics, network pharmacology and metabolomics. METHODS: Effect of ACT in treating jaundice was evaluated by biochemical assays and pathological observation using the α-naphthyl isothiocyanate (ANIT)-induced mice. Jaundice-relieving mechanism of ACT was investigated by integration of network pharmacology and metabolomics. RESULTS: After the mice with jaundice were administrated ACT extract for 9 days, compared to that of the model group, serum D-BIL, T-BIL and ALP levels of the mice in the low, medium, high dose of ACT group decreased by 39.81%, 15.30% and 16.92%; 48.06%, 42.54% and 36.91%; 26.90%, 12.34% and 16.90%, respectively. The pathologic study indicated that ACT improved the symptoms of liver injury of the mice with jaundice. The network of herb (i.e., ACT)-components-targets-disease (i.e., jaundice) was established, which consisted of 17 components classified in flavonoids, chromones, organic acids, terpenoids, and 234 targets related to treatment of jaundice. Metabolomics analysis showed that, compared to that in the model group, level of 8 differential metabolites were upregulated and level of 29 differential metabolites were downregulated in the mice liver in the ACT group, respectively. The main metabolic pathways involved in treatment of jaundice by ACT were pantothenate and CoA biosynthesis, glutathione metabolism, biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis in the liver, respectively. The integrated analysis of network pharmacology and metabolomics showed that 3α,7α,12α a-Trihydroxy-5ß-cholanate, glycocholate, taurocholate, pantetheine 4'-phosphate, and d-4'-phosphopantothenate were the potential biomarkers for treatment of jaundice, and AKR1C4, ALDH2 and HSD11B were the potential drug targets in the treatment of jaundice by ACT. CONCLUSION: The study based on metabolomics and network pharmacology indicated that ACT can display favorable jaundice-relieving effect by its multiple components regulating multiple biomarkers, multiple targets and multiple pathways, and may be a rational therapy for the treatment of jaundice.

Late Oligocene fossil acorns and nuts of Quercus section Cyclobalanopsis from the Nanning Basin, Guangxi, South China.

Quercus is the largest genus within the Fagaceae and has a rich fossil record. Most of the fossil material is attributed to the subgenus Quercus based on leaves, pollen or rarely acorns and nuts. Fossil records of Q. section Cyclobalanopsis characterized by ring-cupped acorns are relatively few and especially those described based on nuts are scant. In this study, we described four new species of Quercus section Cyclobalanopsis based on mummified acorns and nuts: Q. paleodisciformis X.Y. Liu et J.H. Jin sp. nov., Q. paleohui X.Y. Liu et J.H. Jin sp. nov., Q. nanningensis X.Y. Liu et J.H. Jin sp. nov. and Q. yongningensis X.Y. Liu et J.H. Jin sp. nov. These species closely resemble the extant species Q. disciformis, Q. hui, Q. kerrii, and Q. dinghuensis. The occurrence of Q. section Cyclobalanopsis in the Oligocene stratum of Guangxi, South China, suggests that the section has diversified within its extant distribution center since the Oligocene. By combining records from other areas, we propose that the section first appeared in the middle Eocene of East Asia (Sino-Japan), has diversified in situ with a few elements scattering into West Asia and southern Europe since the Oligocene and Pliocene, respectively, and finally became restricted in East Asia since the Pleistocene. This indicates that the section originated and diversified in East Asia, before spreading into West Asia no later than the Oligocene and into southern Europe by the Pliocene. Subsequently it disappeared from South Europe and West Asia due to the appearance of the (summer dry) Mediterranean climate and widespread cooling during the Pleistocene.

Cardiovascular benefits and safety of sotagliflozin in type 2 diabetes mellitus patients with heart failure or cardiovascular risk factors: a bayesian network meta-analysis.

Background: As an antidiabetic agent, sotagliflozin was recently approved for heart failure (HF). However, its cardiovascular benefits in type 2 diabetic mellitus (T2DM) patients with HF or cardiovascular (CV) risk factors have not been systematically evaluated. The aim of this study is to evaluate the cardiovascular benefits and safety of sotagliflozin in T2DM patients with HF or CV risk factors using Bayesian network meta-analysis. Methods: Data were retrieved from PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library from their inception to 16 August 2023. Randomized controlled trials (RCTs) comparing sotagliflozin with a placebo, dapagliflozin, and empagliflozin in adult T2DM patients with HF or CV risks for at least 12 weeks were included in the study. Data analysis was conducted using R 4.2.3 and Stata 17.0. Cardiovascular efficacy outcomes included HF events (hospitalization or urgent visits for HF), MACE (deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and strokes), cardiovascular death, the decrease in SBP, and weight loss. Safety outcomes are urinary tract infection, diarrhea, and diabetic ketoacidosis. Results: Eleven studies with 30,952 patients were included. Compared to dapagliflozin and empagliflozin, 200 mg of sotagliflozin showed the best effect in reducing HF events [OR (95% CI), 0.79 (0.66, 0.94) and 0.90 (0.63, 1.27)]. Compared to dapagliflozin, 200 mg of sotagliflozin [OR (95% CI), 0.76 (0.66, 0.87)] was superior in preventing MACE. Compared to empagliflozin, 200 mg of sotagliflozin [OR (95% CI), 1.46 (1.04, 2.05)] was inferior in preventing CV death. Sotagliflozin showed a poorer SBP decreasing effect than empagliflozin and dapagliflozin [MD (95% CI), 1.30 (0.03, 2.56) and 2.25 (0.35, 4.14), respectively]. There was no significant difference between sotagliflozin and other interventions in weight loss. Sotagliflozin exhibited no increased risk for diabetic ketoacidosis or urinary tract infection among all interventions, however, it showed a mild risk for diarrhea than placebo [OR (95% CI), 1.47 (1.28, 1.69)]. Conclusion: Sotagliflozin displayed moderate CV benefits and acceptable safety. Sotagliflozin can be one of the recommended options for T2DM patients with HF or CV risk factors, which will be important for evidence-based use of sotagliflozin as well as decision-making of T2DM medication.

Detection and Quantification of the Harmful Dinoflagellate Margalefidinium polykrikoides (East Asian Ribotype) in the Coastal Waters of China.

As a marine ichthyotoxic dinoflagellate, Margalefidinium polykrikoides, previously named Cochlodinium polykrikoides, have caused mass mortalities of fish worldwide during blooms. Rapid detection of target species is a prerequisite for the timely monitoring and early warning of harmful algal blooms (HABs). However, it is difficult to achieve rapid identification with traditional methods. The technology of using quantitative real-time PCR (qPCR) to detect and quantify microalgae is relatively mature. Based on the accuracy, rapidity, and sensitivity of qPCR technology, it can be used in the monitoring and development of early warning systems for HABs. From 2017 to 2020, samples were collected from 15 locations off the Chinese coast or from local sea areas. Based on the qPCR detection and analysis, the target species, M. polykrikoides (East Asian ribotype, EAr), was found in samples from Tianjin, Yangtze River estuary, and offshore Fujian (East China Sea). This is the first time that M. polykrikoides (EAr) was detected in the coastal waters of Tianjin. The results reveal a distributive pattern of M. polykrikoides (EAr) along Chinese coastal waters. It is helpful to predict the future diffusion trend of M. polykrikoides (EAr) in the China Sea and provides a practical case for the future construction of monitoring and warning systems for M. polykrikoides and HABs.

Antidiabetic Effect of Rehmanniae Radix Based on Regulation of TRPV1 and SCD1.

Purpose: This study aimed to disclose the antidiabetic mechanisms of Rehmanniae Radix (RR). Methods: The antidiabetic effect of RR was studied in Streptozocin (STZ)-induced diabetes mellitus (DM) rats and HepG2 cells with insulin resistance (IR). Antidiabetic targets and signaling pathways of RR were confirmed by the network pharmacology and transcriptome analysis as well as HK2 cells induced by high glucose (HG). Results: After the DM rats were administrated RR extract (RRE) for 4 weeks, their body weight was 10.70 ± 2.00% higher than those in the model group, and the fasting blood glucose (FBG), AUC of the oral glucose tolerance test, and insulin sensitivity test values were 73.23 ± 3.33%, 12.31 ± 2.29%, and 13.61 ± 5.60% lower in the RRE group, respectively. When compared with the model group, an increase of 45.76 ± 3.03% in the glucose uptake of HepG2 cells with IR was seen in the RRE group. The drug (RR)-components-disease (DM)-targets network with 18 components and 58 targets was established. 331 differentially expressed genes (DEGs) were identified. TRPV1 and SCD1 were important DEGs by the intersectional analysis of network pharmacology and renal transcriptome. The TRPV1 overexpression significantly inhibited apoptosis and oxidative stress of the HK2 cells induced by HG, while SCD1 overexpression induced apoptosis and oxidative stress of the HK2 cells induced by low and high glucose. When compared to the HG group, the mRNA and protein expressions of TRPV1 in the presence of RRE (100 µg/ml) increased by 3.94 ± 0.08 and 2.83 ± 0.40 folds, respectively. Conclusion: In summary, RR displayed an inspiring antidiabetic effect by reducing FBG and IR, upregulating the mRNA and protein expressions of TRPV1, and downregulating mRNA expression of SCD1. Induction of TRPV1 and inhibition of SCD1 by RR was possibly one of its antidiabetic mechanisms.

Behavioral change in waste separation at source in an international community: An application of the theory of planned behavior.

Analysing and understanding the factors that influence the behavior of waste separation is critical to improved waste management. This study identified the factors behind behavioral change in waste separation at source in an international community. The theory of planned Behavior (TPB) was adopted to conduct a self-report questionnaire survey twice, in which 354 residents participated at Time1 and 331 at Time 2, with a retention rate of 93.5%. The questionnaires were designed based on TPB with additional questions regarding waste separation rules in the community, experience of waste separation, and environmental knowledge. With the questionnaire data and follow-up qualitative interviews, factors related to waste separation through factor analysis and structural equation modelling and text mining were specified. The panel data collected over three months demonstrated the changes in attitudes, subjective norms, and perceived behavioral control that affect behavioral intention in the process of behavior adaption. Combined with interview data, the reasons for these changes can be further attributed to individuals' environmental knowledge and community guidelines. The findings imply that policies targeting environmental education and rulemaking are effective to help residents form more positive intentions towards waste separation.