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The Chinese lizard gudgeon,Saurogobio dabryiBleeker, belongs to the subfamily Gobioninea, which is an economic fish widely distributed in East Asia. In this study, we sequenced the complete mitochondrial genome of theS. dabryi. The complete mitogenome was 16,601 bp in size, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 1 control region. It has the typical circular molecule structure of vertebrate’s mitochondrial genome. The whole base composition was estimated to be 29.64%A, 26.47%T, 27.06%C and 16.83%G with AT bias of 56.11%. This study is a first report the complete mitogenome ofS. dabryiand provides the basis for preservation of genetic resources and phylogenetic analyses on this species. [ABSTRACT FROM PUBLISHER]

• Zn 0.5 Cd 0.5 S@MoS 2 core@shell heterostructures were synthesized. • The Zn 0.5 Cd 0.5 S@MoS 2 exhibits outstanding H 2 evolution performance. • The Zn 0.5 Cd 0.5 S@MoS 2 retains long-term stability in catalytic reaction. • The formation and catalytic mechanisms of Zn 0.5 Cd 0.5 S@MoS 2 were investigated. Photocatalytic H 2 evolution from water splitting offers an attractive scientific and technological method to address the energy and environmental crisis. In this study, noble-metal-free Zn 0.5 Cd 0.5 S@MoS 2 core@shell nanoheterostructures were elaborately designed and successfully synthesized. The visible-light-driven photocatalytic performance investigation shows that the Zn 0.5 Cd 0.5 S@MoS 2 exhibits a state-of-the-art H 2 evolution rate of 40.2 mmol g−1 h−1 far exceeding that of pristine Zn 0.5 Cd 0.5 S by more than 57 times. Moreover, thanks to the protection of MoS 2 shells, the Zn 0.5 Cd 0.5 S@MoS 2 can retain long-term stability in four-cycles of 24 h reactions. Furthermore, a tentative mechanism on H 2 generation was systematically investigated and proposed, which contributes to understand the enhanced photocatalytic activity of the Zn 0.5 Cd 0.5 S@MoS 2 heterostructures and may inspire the synthesis of other desirable catalytic systems. [ABSTRACT FROM AUTHOR]

Background: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood., Methods: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differences in the lower esophageal sphincter (LES) using enzyme-linked immunosorbent assay and single-cell RNA sequencing (scRNA-seq) profiling, respectively. We further employed bioinformatics approaches to investigate underlying mechanisms., Results: We revealed positive associations of circulating Eotaxin, macrophage inflammatory protein-1b (MIP1b), soluble E-selectin (SeSelectin) and TNF-related apoptosis-inducing ligand (TRAIL) with achalasia. When combining MR findings with scRNA-seq data, we observed upregulation of TRAIL (OR = 2.70, 95% CI, 1.20-6.07), encoded by TNFSF10, in monocytes and downregulation of interleukin-1 receptor antagonist (IL-1ra) (OR = 0.70, 95% CI 0.59-0.84), encoded by IL1RN, in FOS_macrophages in achalasia. TNFSF10 high monocytes in achalasia displayed activated type I interferon signaling, and IL1RN low FOS_macrophages exhibited increased intercellular communications with various lymphocytes, together shaping the proinflammatory microenvironment of achalasia., Conclusions: We identified circulating Eotaxin, MIP1b, SeSelectin and TRAIL as potential drug targets for achalasia. TNFSF10 high monocytes and IL1RN low macrophages may play a role in the pathogenesis of achalasia., (© 2024. Japanese Society of Gastroenterology.)

Three new cyclopentanoid monoterpenes, neopiscrocins A-C ( 1 - 3 ), together with 14 known compounds ( 4 - 17 ), were isolated from the roots of Picrorhiza scrophulariiflora . The structres of these compounds were elucidated on the basis of their spectroscopic data. All compounds were evaluated for cytotoxicity against six human tumor cell lines (PC9, PANC1, HCT-116, Hep-G2, BGC-823, and MCF-7), hepatoprotective activity and anti-inflammatory activity.

Gastrodiae Rhizoma is a valuable traditional Chinese medicine(TCM) and was newly approved as a catalogue species of medicinal and food homologous substances in 2023. The consumption of Gastrodiae Rhizoma as a food has been increasing year by year, and its nutrients content has become a public concern. However, there is a lack of systematic research on its nutrients content. Gastrodiae Rhizoma is widely distributed and exhibits various specifications. The quality of Gastrodiae Rhizoma varies among different varieties, origins, and grades. In this paper, 76 batches of samples were selected, involving 2 varieties(G. elata f. elata and G. elata f. qlauca), 6 origins(Anhui, Shaanxi, Hubei, Yunnan, Henan and Northeast China) and 5 grades(special grade, first grade, second grade, third grade, and fourth grade). The content of main nutrients of the above samples was determined and analyzed to explore the differences in the content of different specifications of Gastrodiae Rhizoma. The results show that Gastrodiae Rhizoma is rich in a variety of nutrients, including protein, fat, starch, crude fiber, total saponins, moisture, polysaccharides, mineral elements, amino acids, and volatile oils. The total mass of volatile oils reached about 96.00%. The percentages of starch, moisture and polysaccharides werethe highest, accounting for 64.52%, 10.45%, and 8.32%, respectively. There were also differences in nutrient content among different specifications, especially the polysaccharide content of different varieties. Therefore, the research direction of Gastrodiae Rhizoma medicinal and food homologous products can be inclined to the development of meal replacement staple food or polysaccharide functional food. This study provides a reference for the research of Gastrodiae Rhizoma in the field of medicinal and food homologous products.

This study aims to investigate the therapeutic effect and mechanism of Panax notoginseng saponins(PNS) on diabetic kidney disease(DKD) based on network pharmacology, molecular docking, animal experiments. Network pharmacology was employed to screen the potential targets, and STRING was employed to build the protein-protein interaction network. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were carried out for the core targets screened out, and a ″components-targets-pathways″ visualization network was constructed to predict the potential mechanism of PNS in treating DKD. Five active ingredients were screened from PNS, the core targets of which for treating DKD were AKT1, STAT3, ESR1, HSP90AA1, MTOR, et al. The KEGG enrichment analysis showed that the pathways related to PNS for treating DKD included the pathway in cancer, chemical carcinogenesis-receptor activation, and PI3K-AKT signaling pathway. GO analysis revealed that protein binding, homologous protein binding, enzyme binding, and ATP binding were the main biological processes involved in the treatment of DKD with PNS. Male 6-week-old db/db mice were randomized into model, dapagliflozin, and low-dose and high-dose PNS groups, with 10 mice in each group. Ten 6-week-old db/m mice were used as the control group. Mice were administrated with corresponding drugs or distilled water(control and model groups) by gavage once a day for 8 weeks. The body weight, fasting blood glucose, kidney index, microalbuminuria, creatinine, microalbuminuria/creatinine ratio, and urea nitrogen content in the urine of mice were determined. Hematoxylin-eosin(HE) staining, periodic acid-Schiff(PAS) staining, and Masson staining were performed to observe the protective effect of PNS on the renal tissues in db/db mice. The results showed that PNS could significantly reduce the fasting blood glucose level and improve the renal damage in db/db mice. Western blot results showed that PNS down-regulated the protein levels of p-AKT1 and p-STAT3 and decreased the p-AKT1/AKT1 and p-STAT3/STAT3 ratios. In addition, high-dose PNS down-regulated the protein level of PIK3CA. In conclusion, PNS may exert the kidney-protecting effects in DKD by inhibiting STAT3 via the PI3K-AKT signaling pathway.

As people's living standards and awareness of health care are increasing in recent years, the demand for the medicinal and food homologous substances is rising. Promoting the healthy development of this industry to meet people's growing demand and popularizing the TCM concept of preventive treatment of diseases are essential for building a healthy China. The abuse of pesticides by some growers in the one-sided pursuit of economic benefits causes serious pesticide residue, which affects the safety and effectiveness of the medicinal and food homologous substances. Since pesticide residues has received increasing attention, the reasonable control of pesticide residues becomes an important part of the research on these herbs, which, however, is rarely studied. This paper reviewed the publications involving pesticide residues in the cultivation of medicinal and food homologous substances that were published in the last two decades, and put forward the problems faced by the cultivation. According to the current situation of this industry, this paper proposed the management suggestions for the control of pesticide residues in the cultivation. This review will provide the government with data and references for formulating relevant policies and standards to promote the high-quality development of the industry of medicinal and food homologous substances and guarantee the development of TCM and the building of a healthy China.

Herein we present an efficient chiral phosphoric-acid-catalyzed atropoenantioselective asymmetric reductive amination of biaryl dialdehydes. The process involves desymmetrization and the following kinetic resolution, with a wide range of axially chiral aryl aldehydes obtained with high optical purities.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC 50 values were 24.53 ± 0.32 μM in rat liver microsomes and 18.24 ± 0.12 μM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC (0-t) , C max of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest need to be stated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Post-stroke infection is the most common complication of stroke and poses a huge threat to patients. In addition to prolonging the hospitalization time and increasing the medical burden, post-stroke infection also significantly increases the risk of disease and death. Clarifying the risk factors for post-stroke infection in patients with acute ischemic stroke (AIS) is of great significance. It can guide clinical practice to perform corresponding prevention and control work early, minimizing the risk of stroke-related infections and ensuring favorable disease outcomes., Aim: To explore the risk factors for post-stroke infection in patients with AIS and to construct a nomogram predictive model., Methods: The clinical data of 206 patients with AIS admitted to our hospital between April 2020 and April 2023 were retrospectively collected. Baseline data and post-stroke infection status of all study subjects were assessed, and the risk factors for post-stroke infection in patients with AIS were analyzed., Results: Totally, 48 patients with AIS developed stroke, with an infection rate of 23.3%. Age, diabetes, disturbance of consciousness, high National Institutes of Health Stroke Scale (NIHSS) score at admission, invasive operation, and chronic obstructive pulmonary disease (COPD) were risk factors for post-stroke infection in patients with AIS ( P < 0.05). A nomogram prediction model was constructed with a C-index of 0.891, reflecting the good potential clinical efficacy of the nomogram prediction model. The calibration curve also showed good consistency between the actual observations and nomogram predictions. The area under the receiver operating characteristic curve was 0.891 (95% confidence interval: 0.839-0.942), showing predictive value for post-stroke infection. When the optimal cutoff value was selected, the sensitivity and specificity were 87.5% and 79.7%, respectively., Conclusion: Age, diabetes, disturbance of consciousness, NIHSS score at admission, invasive surgery, and COPD are risk factors for post-stroke infection following AIS. The nomogram prediction model established based on these factors exhibits high discrimination and accuracy., Competing Interests: Conflict-of-interest statement: All the authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Competing Interests: None declared.

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction., Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed., Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo , when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group., Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions., Competing Interests: The authors declare there are no competing interests., (©2024 Gao et al.)

Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway is an important mechanism underlying myocardial pyroptosis and plays an important role in inflammatory damage to myocardial tissue in patients with cardiovascular diseases (CVDs), such as diabetic cardiomyopathy, ischemia/reperfusion injury, myocardial infarction, heart failure and hypertension. Noncoding RNAs (ncRNAs) are important regulatory factors. Many Chinese medicine (CM) compounds, including their effective components, can regulate pyroptosis and exert myocardium-protecting effects. The mechanisms underlying this protection include inhibition of inflammasome protein expression, Toll-like receptor 4-NF-κB signal pathway activation, oxidative stress, endoplasmic reticulum stress (ERS), and mixed lineage kinase 3 expression and the regulation of silent information regulator 1. The NLRP3 protein is an important regulatory target for CVD prevention and treatment with CM. Exploring the effects of the interventions mediated by CM and the related mechanisms provides new ideas and perspectives for CVD prevention and treatment., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity of CYP2B6 gene in a Chinese Han population for potential use in precision medicine. All exons in CYP2B6 gene from 1483 Chinese Han adults (Zhejiang province) were sequenced using Sanger sequencing. The effects of nonsynonymous variants on recombinant protein catalytic activity were investigated in vitro with Sf12 system. The haplotype of novel nonsynonymous variants with other single nucleotide variants in the same allele was determined using Nanopore sequencing. Of 38 alleles listed on the Pharmacogene Variation Consortium, we detected 7 previously reported alleles and 18 novel variants, of which 11 nonsynonymous variants showed lower catalytic activity (0.00-0.60) on bupropion compared to CYP2B6*1 . Further, these 11 novel star-alleles ( CYP2B6*39-49 ) were assigned by the Pharmacogene Variation Consortium, which may be valuable for pharmacogenetic research and personalized medicine., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Da-peng Dai reports financial support was provided by 10.13039/100007225Ministry of Science and Technology of the People's Republic of China. Da-Peng Dai reports a relationship with 10.13039/100007225Ministry of Science and Technology of the People's Republic of China that includes: funding grants., (© 2024 Published by Elsevier Ltd.)

Cold exposure exerts negative effects on hippocampal nerve development in adolescent mice, but the underlying mechanisms are not fully understood. Given that ubiquitination is essential for neurodevelopmental processes, we attempted to investigate the effects of cold exposure on the hippocampus from the perspective of ubiquitination. By conducting a ubiquitinome analysis, we found that cold exposure caused changes in the ubiquitination levels of a variety of synaptic-associated proteins. We validated changes in postsynaptic density-95 (PSD-95) ubiquitination levels by immunoprecipitation, revealing reductions in both the K48 and K63 polyubiquitination levels of PSD-95. Golgi staining further demonstrated that cold exposure decreased the dendritic-spine density in the CA1 and CA3 regions of the hippocampus. Additionally, bioinformatics analysis revealed that differentially ubiquitinated proteins were enriched in the glycolytic, hypoxia-inducible factor-1 (HIF-1), and 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathways. Protein expression analysis confirmed that cold exposure activated the mammalian target of rapamycin (mTOR)/HIF-1α pathway. We also observed suppression of pyruvate kinase M2 (PKM2) protein levels and the pyruvate kinase (PK) activity induced by cold exposure. Regarding oxidative phosphorylation, a dramatic decrease in mitochondrial respiratory-complex I activity was observed, along with reduced gene expression of the key subunits NADH: ubiquinone oxidoreductase core subunit V1 ( Ndufv1 ) and Ndufv2 . In summary, cold exposure negatively affects hippocampal neurodevelopment and causes abnormalities in energy homeostasis within the hippocampus.

Competing Interests: There are no conflicts of interest.

Four new iridoid glycosides ( 1 - 4 ), rehmaglutosides L-O, were isolated from the air-dried roots of Rehmannia glutinosa . Their structures were established from the spectroscopic data obtained and by chemical evidence. The known mellittoside ( 5 ) and ajugol ( 6 ) were also obtained in the current investigation, and the structure of mellittoside was unequivocally defined using X-ray diffraction data. Compounds 1 - 6 were tested for their cytotoxicity against five human tumor cell lines and proliferation effects on Lactobacillus Reuteri .

Aim: To quantitatively measure ocular morphological parameters of guinea pig with Python technology., Methods: Thirty-six eyeballs of eighteen 3-week-old guinea pigs were measured with keratometer and photographed to obtain the horizontal, coronal, and sagittal planes respectively. The corresponding photo pixels-actual length ratio was acquired by a proportional scale. The edge coordinates were identified artificially by ginput function. Circle and conic curve fitting were applied to fit the contour of the eyeball in the sagittal, coronal and horizontal view. The curvature, curvature radius, eccentricity, tilt angle, corneal diameter, and binocular separation angle were calculated according to the geometric principles. Next, the eyeballs were removed, canny edge detection was applied to identify the contour of eyeball in vitro . The results were compared between in vivo and in vitro ., Results: Regarding the corneal curvature and curvature radius on the horizontal and sagittal planes, no significant differences were observed among results in vivo , in vitro , and the keratometer. The horizontal and vertical binocular separation angles were 130.6°±6.39° and 129.8°±9.58° respectively. For the corneal curvature radius and eccentricity in vivo , significant differences were observed between horizontal and vertical planes., Conclusion: The Graphical interface window of Python makes up the deficiency of edge detection, which requires too much definition in Matlab. There are significant differences between guinea pig and human beings, such as exotropic eye position, oblique oval eyeball, and obvious discrepancy of binoculus. This study helps evaluate objectively the ocular morphological parameters of small experimental animals in emmetropization research., Competing Interests: Conflicts of Interest: Di Y, None; Qiao ZB, None; Ye HY, None; Li XY, None; Luo WT, None; Fang WY, None; Qiao T, None., (International Journal of Ophthalmology Press.)

Cladophora rupestris is ubiquitous in many kinds of waterbodies, and C. rupestris biomass can serve as a carrier for adsorbing and transferring heavy metals. Batch experiments and characterization were performed. Results showed that the organic frameworks of C. rupestris (CROF) had a specific surface area of 2.58 m 2 /g and an external surface area of 2.06 m 2 /g. Many mesopores were present in CROF, mainly distributed in 2.5-7.5 nm. The zeta potentials were within the range of - 4.46 to - 13.98 mV in the tested pH of 2.0-9.0. CROF could effectively adsorb Pb 2+ in large pH range. The maximum adsorption capacity (q max ) of Pb 2+ on CROF was 15.02 mg/g, and 97% of Pb 2+ was adsorbed onto CROF after 25 min. CROF had a preferential adsorption of Pb 2+ . The protein secondary structures and carbon skeletons of CROF all worked in adsorption. The main Pb 2+ adsorption mechanisms were pore filling, electrostatic attraction, Pb-π interaction, and surface complexation. Therefore, it is valuable as a biosorbent for the removal of Pb 2+ from waterbodies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Seven new pentasaccharides ( 1 - 7 ), rehmaglupentasaccharides A-G, were isolated from the air-dried roots of Rehmannia glutinosa . Their structures were established from the spectroscopic data obtained and by chemical evidence. The known verbascose ( 8 ) and stachyose ( 9 ) were also obtained in the current investigation, and the structure of stachyose was unequivocally defined using X-ray diffraction data. Compounds 1 - 9 were tested for their cytotoxicity against five human tumor cell lines, influence on dopamine receptor activation, and proliferation effects against Lactobacillus reuteri .

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca 2+ release from the ER and promoting the re-absorption of Ca 2+ into the ER, thus relieving Ca 2+ -dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/β5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated βOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or βOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated βOHB metabolism activates NRF2 by enhancing the metabolic flux of βOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either βOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.

Background and Objective: Ibuprofen, a common non-steroidal anti-inflammatory drug, is used clinically for pain relief and antipyretic treatment worldwide. However, regular or long-term use of ibuprofen may lead to a series of adverse reactions, including gastrointestinal bleeding, hypertension and kidney injury. Previous studies have shown that CYP2C9 gene polymorphism plays an important role in the elimination of various drugs, which leads to the variation in drug efficacy. This study aimed to evaluate the effect of 38 CYP2C9 genotypes on ibuprofen metabolism., Methods: Thirty-eight recombinant human CYP2C9 microsomal enzymes were obtained using a frugiperda 21 insect expression system according to a previously described method. Assessment of the catalytic function of these variants was completed via a mature incubation system: 5 pmol CYP2C9*1 and 38 CYP2C9 variants recombinant human microsomes, 5 μL cytochrome B5, ibuprofen (5-1000 μM), and Tris-HCl buffer (pH 7.4). The ibuprofen metabolite contents were determined using HPLC analysis. HPLC analysis included a UV detector, Plus-C18 column, and mobile phase [50% acetonitrile and 50% water (containing 0.05% trifluoroacetic acid)]. The kinetic parameters of the CYP2C9 genotypes were obtained by Michaelis-Menten curve fitting., Results: The intrinsic clearance (CL int ) of eight variants was not significantly different from CYP2C9*1; four CYP2C9 variants (CYP2C9*38, *44, *53 and *59) showed significantly higher CL int (increase by 35%-230%) than that of the wild-type; the remaining twenty-six variants exhibited significantly reduced CL int (reduced by 30%-99%) compared to that of the wild-type., Conclusion: This is the first systematic evaluation of the catalytic characteristics of 38 CYP2C9 genotypes involved ibuprofen metabolism. Our results provide a corresponding supplement to studies on CYP2C9 gene polymorphisms and kinetic characteristics of different variants. We need to focus on poor metabolizers (PMs) with severely abnormal metabolic functions, because they are more susceptible to drug exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The objective of this study was to determine the effect of flavonoids on midostaurin disposition considering co-administration and metabolic enzyme gene polymorphism. Enzymatic incubation assays were performed in vitro, while in vivo experiments were conducted in Sprague-Dawley rats. The analytes were determined via UPLC-MS/MS. We found that myricetin was the most potent among the investigated 10 flavonoids in suppressing the metabolism of midostaurin, with an IC 50 at a low μM level. After co-administration of midostaurin and myricetin, the plasma concentration of midostaurin's primary metabolite CGP62221 was reduced corresponding to myricetin exposure. Furthermore, CYP3A4 homologous rat protein CYP3A2 was reduced significantly in the co-administration group. Thereafter, the kinetic parameters of 23 recombinant human CYP3A4 variants were determined using midostaurin. The relative intrinsic clearance varied from 269.63% in CYP3A4.29-8.95% in CYP3A4.17. In addition, the inhibitory potency of myricetin was substantially different for CYP3A4.29 and CYP3A4.17 compared with wild type, with IC 50 values of 9.85 ± 0.27 μM and 90.99 ± 16.13 μM, respectively. Collectively, our data demonstrated that flavonoids, particularly myricetin, can inhibit the metabolism of midostaurin. Additionally, CYP3A4 genetic polymorphism may contribute to stratification of midostaurin blood exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To cope with fluctuating light conditions, terrestrial plants have evolved precise regulation mechanisms to help optimize light capture and increase photosynthetic efficiency. Upon blue light-triggered autophosphorylation, activated phototropin (PHOT1 and PHOT2) photoreceptors function solely or redundantly to regulate diverse responses, including phototropism, chloroplast movement, stomatal opening, and leaf positioning and flattening in plants. These responses enhance light capture under low-light conditions and avoid photodamage under high-light conditions. NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) and ROOT PHOTOTROPISM 2 (RPT2) are signal transducers that function in the PHOT1- and PHOT2-mediated response. NPH3 is required for phototropism, leaf expansion and positioning. RPT2 regulates chloroplast accumulation as well as NPH3-mediated responses. NRL PROTEIN FOR CHLOROPLAST MOVEMENT 1 (NCH1) was recently identified as a PHOT1-interacting protein that functions redundantly with RPT2 to mediate chloroplast accumulation. The PHYTOCHROME KINASE SUBSTRATE (PKS) proteins (PKS1, PKS2, and PKS4) interact with PHOT1 and NPH3 and mediate hypocotyl phototropic bending. This review summarizes advances in phototropic growth and chloroplast movement induced by light. We also focus on how crosstalk in signaling between phototropism and chloroplast movement enhances weak light capture, providing a basis for future studies aiming to delineate the mechanism of light-trapping plants to improve light-use efficiency., (© 2022. The Author(s).)

Various kinds of bioactive compounds contribute to versatile health-promoting properties of Eucommia ulmoides Oliver (E. ulmoides). In present study, we developed a UPLC-QqQ-MS/MS method for simultaneous quantification of fourteen characteristic active compounds, including 3 lignans, 4 iridoids, 3 flavonoids and 4 phenolics in E. ulmoides and its tea product for the first time. The running time of the method is 6.5 min. It has good linearity, sensitivity, precision, accuracy, and stability. Using this high-throughput method, the distributions of fourteen characteristic active compounds in E. ulmoides and its tea product were clarified. Also, it was found that E. ulmoides tea exhibited superiority in contents of chlorogenic acid as compared with natural resources. Overall, the study provided a rapid, reliable, and efficient analysis method, which could be applied for the quality evaluation of E. ulmoides natural resources and their relative products in the field of food and medicine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Animal medicine is an important part of traditional Chinese medicine(TCM). Bear bile is one of the rare animal-derived medicinal materials with the functions of clearing the liver, promoting bile secretion, calming the liver, relieving convulsions, clearing heat, and removing toxins. From the Jin Dynasty to the Tang Dynasty, bear bile was mainly used to treat internal diseases, surgical diseases, and pediatric diseases with limitations. At present, bear bile has been used to treat various diseases in pediatrics, gynecology, internal medicine, and surgery. Studies on the chemical constituents and pharmacological effects of bear bile mostly focused on bile acids. Although the non-bile acids also showed certain pharmacological effects, their mechanism of action was less investigated. At present, the source animals of bear bile are national second-class protected animals. Obtaining transformed bear bile powder through biotransformation is expected to alleviate the shortage of bear bile resources to a certain extent. Although related research on bear bile substitutes has protected bear bile resources, there are problems in functional quantification and modern interpretation. It is necessary to sort out the functions and indications of bear bile recorded in ancient books according to related modern research. This study firstly reviewed the evolution of bear bile functions and indications, analyzed the chemical components of bear bile, sorted out the relevant records of the efficacy and clinical application of bear bile in ancient books, and summarized the research progress in the safety of bear bile based on the modern pharmacological effects and clinical applications of bear bile, which is conducive to the clarification of modern efficacy and functional quantification of bear bile and the tentative exploration of the modern interpretation of bear bile.

Fel Ursi(bear bile) has been used as medicine for a long history, with wide clinical applications and definite curative efficacy. Fel Ursi has good pharmacodynamic activities in the treatment of liver and gallbladder diseases, and cardiovascular and cerebrovascular diseases. According to the places of origin, traditional Fel Ursi is divided into &quot;Dongdan&quot; and &quot;Nandan&quot;. According to the gallbladder properties, it is divided into &quot;Jindan&quot; &quot;Tiedan&quot; &quot;Caihuadan&quot;, and &quot;Youdan&quot;. With the development of bear bile drainage technology, Pulvis Fellis Ursi has entered the market and been used clinically instead of Fel Ursi. At present, obtaining artificial Pulvis Fellis Ursi by chemical compounding and biotransformation is the hotspot in medical research, which can solve the shortage problem of bear bile resources, and also protect endangered animals. The quality problem of Fel Ursi in the market is prominent, with counterfeit products prepared from sheep bile, cow bile, pig bile, and chicken bile. Due to the scarcity of bear bile resources, the related research contents are scattered, and there is a lack of systematic analysis and summary. This paper focused on the development of Fel Ursi to clarify the source and classification of traditional Fel Ursi, and summarized the harvesting, processing, identification, and use of Fel Ursi. Additionally, the paper also compared the quality standards of Fel Ursi, summarized the technological development process of Pulvis Fellis Ursi, and prospected the modern research and clinical application of Pulvis Fellis Ursi, which is expected to provided references for the collation of bear bile resources, the clinical application of Fel Ursi, the development of Fel Ursi drugs, and related research on artificial Pulvis Fellis Ursi.

Unsatisfied clinical outcome drives to better understand hepatic carcinogenesis, microenvironment and escape of immune surveillance in hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-Seq) has generated enormous data to pinpoint pathophysiologic alterations in tumor microenvironment (TME) or trace lineage development in cancer stem cells (CSCs), circulating tumor cells (CTCs), and subsets of immune cells, such as exhausting T cells, tumor-associated macrophages (TAMs), dendritic cells or other lineages. New insights have significantly advanced current understanding in progression, poor responses to molecular-targeted therapeutics or immune checkpoint inhibitors, metastasis in both basic research and clinical practice. The present review intends to cover a basic workflow of the scRNA-seq technology, existing limitations and improvement areas. Moreover, in-depth understanding in TME, exhausting T cells, CSCs, CTCs, tumor-associated macrophages, dendritic cells in HCC facilitates implementation of personalized and precise therapy in an era of availability with an array of systemic regimens., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: To compare the assessment outcomes of the characteristics of mild to moderate non-proliferative diabetic retinopathy (NPDR) established by fundus photography and fundus fluorescein angiography (FFA)., Methods: The fundus photos and FFA results of 260 patients with diabetes mellitus were reviewed. Diabetic retinopathy (DR) severity was graded based on the international classification standard. The microaneurysms, hemorrhages, and intraretinal microvascular abnormalities (IRMA) in FFA images of patients with mild to moderate NPDR were observed. The differences between the fundus photos and the FFA results were summarized, analyzed, and compared., Results: The counting of intraretinal hemorrhages identified by FFA revealed that only 9 eyes (1.9%) had more than 20 intraretinal hemorrhages in all four quadrants; 15 eyes (3.1%) had more than 20 intraretinal hemorrhages in three quadrants; 26 eyes (5.4%) had over 20 intraretinal hemorrhages in two quadrants; and 37 eyes (7.7%) had more than 20 intraretinal hemorrhages in only one quadrant. Furthermore, the number of IRMAs appeared ≥4 in 17 eyes, 3 in 35 eyes, 2 in 69 eyes, and 1 in 93 eyes., Conclusion: FFA has higher detection accuracy of retinal angiopathy than fundus photography. FFA grading results are helpful for timely detection and proper treatment of lesions easily missed by fundus photography., (International Journal of Ophthalmology Press.)

In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease "MAFLD" as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD., (© 2022. The Author(s).)

Reasonable nutrient and water management is effective ways to improve productivity and biodiversity of degraded grasslands. However, little is known about the effects of nutrient and water addition on soil inorganic phosphorus (P) fractions in old-field grasslands. Based on a field experiment with nutrient addition (N: 10 g·m -2 ·a -1 , P: 10 g·m -2 ·a -1 ) and water addition (180 mm water irrigated during plant growing season) in Duolun County, Inner Mongolia in 2005, we examined the changes of inorganic P fractions and Olsen-P contents in the topsoil (0-10 cm). Results showed that 11-year P addition significantly increased total inorganic P (TIP) content, and that exogenous P was mostly transformed into calcium phosphate (Ca-P: 62.6%-69.2%), and then into aluminium phosphate (Al-P: 19.9%-25.1%), ferric phosphate (Fe-P) and occluded P (O-P). Phosphorus incorporated with nitrogen (N) addition significantly increased Fe-P and Al-P contents by declining soil pH and activating Fe 3+ and Al 3+ in soil. Water addition alone significantly increased Fe-P, Al-P, and decalcium phosphate (Ca 10 -P) fractions, and the contents of Fe-P, Al-P, octacalcium phosphate (Ca 8 -P), and Ca 10 -P were greater in P incorporated with water treatment than in P addition alone. There was no difference of each inorganic P fraction between P incorporated with N and water treatment and P incorporated with N treatment. Phosphorus and P incorporated with N additions significantly increased soil Olsen-P content, while water addition significantly decreased soil Olsen-P content under P addition alone and P incorporated with N treatment. In the calcareous soils, calcium superphosphate addition could enhance soil inorganic P pool through increasing Ca-P fraction.

In order to understand the composition and stability of soil aggregate in paddy filed, as well as the changes of soil aggregate-associated nitrogen (N), phosphorus (P) and potassium (K) after straw addition combined with chemical fertilization, soil samples were collected from a 34-year positioning experiment with three treatments, including no chemical fertilizer (CK), chemical fertilizer only (NPK), and straw addition plus chemical fertilizer (NPKS). The composition of water-stable aggregates at the soil layers of 0-20 cm and 20-40 cm were analyzed with the wet sieving method, as well as the distribution characteristics, contribution rate and activation rate of soil aggregate-associated N, P, and K. Results showed that the fractions of >2 mm and 0.25-1 mm aggregates dominated the soil water-stable aggregates in paddy field, while the contribution of <0.053 mm aggregates was lowest. Compared with CK, NPKS treatment increased the contents of >2 mm and 1-2 mm aggregates at the layers of 0-20 and 20-40 cm, and reduced the contents of 0.053-0.25 mm and <0.053 mm. Similar result in NPK treatment was observed at the layer of 0-20 cm. Compared with tat under the NPK treatment, mean weight diameter (MWD) and geometric mean diameter (GMD) increased by 3.9%-15.5% and 6.3%-41.7% in NPKS treatment, respectively. However, the unstable aggregate index ( E LT ) reduced by 5.7%-28.7% in the NPKS treatment. NPKS significantly increased the contents of total N (TN), available P (AP), and available K (AK) in soil aggregates, especially in the >0.25 mm aggregates. There were no significant diffe-rences about alkali-hydrolysable N (AN) and total K (TK) between NPK and NPKS treatments. The nutrient contribution of soil aggregates in paddy field was affected by aggregate composition. NPKS significantly increased the contribution of AN, AP, and AK within >1 mm aggregates. In all, straw addition combined with chemical fertilizer could increase the stability of soil aggregates at the layers of 0-20 cm and 20-40 cm, and increase the contents of soil aggregate-associated N, P and K, especially for the >1 mm aggregates. Our results provided insights into ensuring soil quality and sustainable development of resources in paddy field by adjusting the ratio of soil C to N.

Arecae Semen, as the first place among &quot;Four South Medicines&quot; in China, has great dual-use value of medicine and food. The research of Arecae Semen was mainly focused on the active ingredients and efficacy value, and its potential safety hazards were also concerned. Until now, there is still a lack of clear boundaries between medicine and food, resulting in its safety cannot be guaranteed. Therefore, it is of great significance to establish clear boundaries of medicine and food use and health risk assessment. In this paper, the differences of pretreatment and application methods of Arecae Semen were analyzed, and the research progress of Arecae Semen in chemical composition identification and toxicology research and safety evaluation were reviewed emphatically. Finally, the differences of quality control and safety evaluation of Arecae Semen in pharmacopoeias or standards were analyzed at home and abroad. It was expected to provide reference value for quality control, safety evaluation and international standardization research of Arecae Semen.

As important components of PM 2.5 , metal elements are extremely harmful to people and also have source specificity. Understanding the characteristics of PM 2.5 metal pollution in the two different types of cities can help adjust the layout of regional industrial structure and improve the environment. PM 2.5 samples during haze/non-haze periods were collected in Chengdu City and Renshou County. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used to determine the mass concentrations of eighteen metal elements in collected PM 2.5 samples. The positive matrix factorization (PMF) model was used for source apportionment analysis for metal elements in PM 2.5 . The analysis showed that the ratio of trace elements from fugitive dust, motor vehicle emissions, and coal burning to the total elements is greater in Chengdu City than that in Renshou County. The proportion of trace elements from biomass combustion, industrial, and fuel sources in Renshou County is higher than that in Chengdu City. In addition, concentrations of Cd, As, and Cr in both areas exceeded the standards, indicating the occurrences of heavy metal pollution. During the haze period, the total concentrations of compositional metal elements in PM 2.5 increased, although the rate was much lower than that for PM 2.5 . The ratios of elements between haze and non-haze periods ranged from 0.7 (Al) to 2.8 (Ba) in Chengdu City, and from 0.8 (Al) to 3.1 (Mn) in Renshou County. Among all metal elements, the increase rate for trace elements from coal burning and industrial activities was relatively large but small for those from fugitive dust, with the growth in trace elements from motor vehicles being modest. The results of this study indicated that the characteristics of pollution and source of metal elements in PM 2.5 varied by economic scale, development mode, and industrial layout. In large cities such as Chengdu City, where economic development is mainly focused on tertiary industry, air pollution is mainly caused by transportation and urban construction, while in suburban area such as Renshou County, where secondary or heavy industry are the focus for economic development, the pollution is mainly affected by energy consumption and industrial production.

To compare the pollution characteristics of carbonaceous aerosol components in the atmosphere between urban and suburban areas, Chengdu City and Renshou County were selected as study areas from which 88 samples of PM 2.5 during haze and non-haze periods were collected and analyzed. Quantification of mass concentrations of PM 2.5 , carbonaceous aerosol components[organic carbon (OC), elemental carbon (EC), and secondary organic carbon (SOC)], along with correlation analysis of OC and EC, and principal component analysis (PCA) of carbon components were carried out. The results show that pollutant concentrations during the haze period were higher than those during the non-haze period. The OC and EC for Chengdu City and Renshou County were positively correlated, with their correlation coefficients during the non-haze period higher than those during the haze period. The ratios of SOC/PM 2.5 in Renshou County were higher than those in Chengdu City during the haze period. This indicates that secondary aerosols play a more important role in haze formation in Renshou than in Chengdu City. In contrast, the proportion of secondary aerosols during the non-haze period in Chengdu City was significantly higher, indicating that direct emissions are still the main cause of air pollution in Chengdu City. PCA results showed that PM 2.5 formation in both Chengdu City and Renshou County was mainly due to coal burning, vehicle operation, and biomass burning.

In order to further improve the quality and safety evaluation standards of traditional Chinese medicine compound preparation,Xiaochaihu Tang compound preparations were selected to analyze the pollution level of heavy metals deeply,and the potential health risks were evaluated under taking such kind of compound preparations. In this study,the contents of copper( Cu),arsenic( As),cadmium( Cd),mercury( Hg),and lead( Pb) in different Xiaochaihu Tang compound preparations were determinated by the method of inductively coupled plasma mass spectrometry( ICP-MS). Moreover,combined with target hazard coefficient method and in vitro artificial system,the bioaccessibility and health risk level was investigated in three main consumption ways including powder,decoction and granule. The result was showed that,under the maximum residual limit set by International Standard Organization,only one batch of raw herb was eight times exceeded the Hg MRL,however,in water decoctions and granules,the heavy metal residue rate was reduced to 2. 02%( Hg in granules)-42. 85%( Cd in granules). So,the heavy metal pollutions and health risks can be reduced to safe region in spite of the serious pollution in raw herbs. Besides,the THQ and CR values of the three consumption methods were lower than the standard values of non-carcinogenic and carcinogenic risks of each heavy metal. It can be seen that even if the heavy metals in the raw herbs exceed the standard,the use of Xiaochaihu Tang decoction and granules can reduce the harm of heavy metals to the human body. Above all,the establishment of this health risk assessment model can be provided experimental basis and reference value for improving the safety evaluation standard of other heavy metals contained traditional Chinese medicine( TCM) compound preparations,and further improving the quality control methods of other different toxic compounds in clinical use.

In order to comprehensively analyze the pollution level and bioaccessibility of different types of heavy metals and hazardous elements in animal medicine,this paper selected Bombyx Batryticatus as the research object,and used inductively coupled plasma mass spectrometry( ICP-MS) to detect As,Cu,Hg,Pb,Ni,Cr,Zn and Cd. Based on the artificial gastrointestinal digestion model and the health risk assessment model of Chinese medicinal materials,the pollution level,in vivo and in vitro transfer rate and health risk grade of eight harmful elements in the above-mentioned medicinal materials of Bombyx Batryticatus were obtained respectively. The test result was found that under the ISO international standard of Chinese medicine-Chinese herbal medicine heavy metals,the unqualified rate was 50% for Bombyx Batryticatus,which including 2 batches of As and 4 batches of Cr exceeded the MRL. In artificial gastrointestinal digestion solution,the transfer rates of heavy metals As,Cu,Hg,Pb,Ni,Cr,Zn and Cd were 36. 849%,72. 372%,41. 152%,75. 354%,46. 603%,27. 981%,19. 707% and 76. 282%,respectively. The data of risk assessment model showed that the total THQ values of the most polluted batches for adults and children was 0. 021 548 and 0. 018 418,respectively. After digestion,the THQ values decreased to 0. 012 599 for adults and 0. 010 769 for children,which were still higher than the THQ standard values of animal medicine Bombyx Batryticatus. However,the CR value of carcinogenic risk is less than 1×10-6,so the potential non-carcinogenic risk caused by taking this batch of Bombyx Batryticatus medicines is higher and the carcinogenic risk can be ignored. To sum up,heavy metals and hazardous elements in Bombyx Batryticatus still exceed the standard,but the health risk level caused by heavy metals still needs to be investigated according to different medicinal materials,in order to provide data support for further improving the quality and safety of animal medicine.

As an important branch of traditional medicines,medicinal marine organisms have many advantages,including biological diversity,remarkable biological activity,especial for the treatment of anti-cancer,anti-virus,anti-coagulation,analgesia,anti-bacterial,cardiovascular and cerebrovascular diseases. In recent years,with the continuous exploration of marine organisms by human beings,many marine organisms with specific biological activities and medicinal prospects have been found,which have attracted great attention around the world and thus called &quot; new hope&quot; to solve human health problems. However,due to the rapid development of modern industry,heavy metal pollution not only poses a great threat to medicinal marine living resources,but also hinders the development of marine biomedical industry and threatens human health. In view of this,this paper introduced the development trend of medicinal marine organisms and the current situation of heavy metal pollution and focusing on the analysis technology and chemical removal technology of heavy metals in medicinal marine organisms,which is to provide reference for the heavy metals control in marine medicines and the development and utilization of marine medicines.