Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Beyond Traditional Medicine: EVs-Loaded Hydrogels as a Game Changer in Disease Therapeutics.

Extracellular vesicles (EVs), especially exosomes, have shown great therapeutic potential in the treatment of diseases, as they can target cells or tissues. However, the therapeutic effect of EVs is limited due to the susceptibility of EVs to immune system clearance during transport in vivo. Hydrogels have become an ideal delivery platform for EVs due to their good biocompatibility and porous structure. This article reviews the preparation and application of EVs-loaded hydrogels as a cell-free therapy strategy in the treatment of diseases. The article also discusses the challenges and future outlook of EVs-loaded hydrogels.

Uptake and accumulation of di(2-ethylhexyl) phthalate (DEHP) in a soil-ginseng system and toxicological mechanisms on ginseng (Panax ginseng C.A. Meyer).

Di(2-ethylhexyl) phthalate (DEHP) is regarded as a priority environmental pollutant. This study explored the adsorption and accumulation of DEHP within the ginseng-soil system and the mechanism of DEHP toxicity to ginseng (Panax ginseng C.A. Meyer). Under exposure to 22.10 mg/kg DEHP in soil, DEHP mainly accumulated in ginseng leaves (20.28 mg/kg), stems (4.84 mg/kg) and roots (2.00 mg/kg) after 42 days. The oxidative damage, metabolism, protein express of ginseng were comprehensively measured and analyzed. The results revealed that MDA presented an activation trend in ginseng stems and leaves after 42 days of DEHP exposure, while the opposite trend was observed for POD. Levels of ginsenoside metabolites Rg2, Rg3, Rg5, Rd, Rf and CK decreased in the ginseng rhizosphere exudates under DEHP stress. Further investigations revealed that DEHP disrupts ginsenoside synthesis by inducing glycosyltransferase (GS) and squalene synthase (SS) protein interactions. Molecular docking indicated that DEHP could stably bind to GS and SS by intermolecular forces. These findings provide new information on the ecotoxicological effect of DEHP on ginseng root.

Loss of SHROOM3 affects neuroepithelial cell shape through regulating cytoskeleton proteins in cynomolgus monkey organoids.

Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.

[Characteristics of Bacterial Community Structure in the Sediment of Rural Black and Odorous Water Bodies].

Sediment microorganisms are the main drivers of the material circulation and organic matter degradation processes in rural black and odorous water bodies(RBOWB), and the community structure of sediment microorganisms follows the changes in the external environment. Here, the pollutant indicators, including nitrogen, phosphorus, and heavy metals in the overlying water and sediment of 29 RBOWB in Dongming County of Heze City were measured, respectively. Combined with Illumina sequencing results, the composition and diversity characteristics of sediment bacterial communities in RBOWB and their correlation with environmental factors were further analyzed. The experimental results showed a wide distribution of pollutants in both of the overlying water and sediment in the RBOWB of this region. Compared with agricultural non-point source pollution, the concentrations of nitrogen and phosphorus pollutants in the overlying water with domestic sewage as the main source of pollution were 3.1 and 1.5 times higher than those of agricultural non-point source pollution, respectively. In addition, the contents of heavy metals in the sediments of RBOWB were generally lower than the soil element background value in Heze City. The dominant bacteria phyla in the sediments of the RBOWB were Proteobacteria, Actinobacteria, Chloroflexi, Firmicutes, and Acidobacteria, and the total abundance of these five dominant phyla accounted for 70.3%-83.6% of all sequences. The dominant classes were γ-Proteobacteria, α-Proteobacteria, Anaerolineae, and Actinobacteria. The dominant genera were Thiobacillus and Pseudarthrobacter. Moreover, Spearman correlation analysis showed that the environmental factors of DO, COD, TN, TP, and organic matter exerted significant effects(P<0.05) on sediment bacterial genera in RBOWB, and sediment bacterial community richness was significantly influenced by TN(P<0.05). The above results provided the microbiological knowledge for treating RBOWB.

The Mechanical Properties and Fracture Characteristics of Shale Layered Samples from the Lucaogou Formation Considering Natural Crack and Mineral Distribution.

Shale oil is one of the most promising alternative unconventional energies in the world, and recently the Lucaogou Formation showed significant exploration potential, becoming the primary target in northwestern China. This paper focuses on the mechanical properties and fracture characteristics of shale layered samples from the Lucaogou Formation, conducting uniaxial compressive tests with real-time micro-CT scanning, as well as mineral analysis after failure. It has been found that the mechanical and fracture features are both related to the composition, distribution, content and particle size of minerals, as well as natural fractures. The main crack tends to form in the weak mineral band, for example, calcite or clay band. Since the discontinuous stress usually forms at the interfaces of different minerals, the sample with several major minerals of close content is easier to break into a fractured zone, causing lower uniaxial compressive strength and elastic modulus, compared with the composition of only one dominant mineral. Also, the region will be more fractured after failure if the mineral particles there become smaller. Additionally, although natural cracks have a certain influence on the development of new fractures, not all of the natural ones will propagate into the final fracture network, some of them are just compacted and closed.

A Pectate Lyase Gene Plays a Critical Role in Xylem Vascular Development in Arabidopsis.

As a major component of the plant primary cell wall, structure changes in pectin may affect the formation of the secondary cell wall and lead to serious consequences on plant growth and development. Pectin-modifying enzymes including pectate lyase-like proteins (PLLs) participate in the remodeling of pectin during organogenesis, especially during fruit ripening. In this study, we used Arabidopsis as a model system to identify critical PLL genes that are of particular importance for vascular development. Four PLL genes, named AtPLL15, AtPLL16, AtPLL19, and AtPLL26, were identified for xylem-specific expression. A knock-out T-DNA mutant of AtPLL16 displayed an increased amount of pectin, soluble sugar, and acid-soluble lignin (ASL). Interestingly, the atpll16 mutant exhibited an irregular xylem phenotype, accompanied by disordered xylem ray cells and an absence of interfascicular phloem fibers. The xylem fiber cell walls in the atpll16 mutant were thicker than those of the wild type. On the contrary, AtPLL16 overexpression resulted in expansion of the phloem and a dramatic change in the xylem-to-phloem ratios. Altogether, our data suggest that AtPLL16 as a pectate lyase plays an important role during vascular development in Arabidopsis.

Anthracnose of Tribulus terrestris Caused by Colletotrichum truncatum in Northeast China.

Tribulus terrestris L. is an annual herbaceous medicinal plant of Zygophyllaceae, which is cultivated commercially in China. Subrotund or irregular gray, sunken, necrotic spots ranging from 2 to 9 mm were observed on diseased leaves of T. terrestris landrace in Fushun County, Liaoning Province of northeast China in July 2021, with more than 32% of the plants being infected in a 18-ha field. The symptoms first appeared on older leaves and gradually spread to younger leaves. The lesions developed a white center gradually and became perforated; multiple lesions could coalesce (Fig. 1). Ten symptomatic leaves were collected and the diseased tissues were cut into small pieces, immersed in 1% NaOCl for 2 min, rinsed three times with sterile water, and placed on acidified potato dextrose agar (PDA) in Petri dishes at 25°C in darkness. Fifteen suspected Colletotrichum single-spore fungal isolates (JL1 to JL15) with consistent morphological characteristics were obtained, and isolate JL6 was selected for identification and pathogenicity testing. Colonies on PDA were flat with an entire margin, dense and white at first, then became dark gray with numerous black microsclerotia and formed a concentric circular pattern with aging. Conidia were single-celled, sickle-curved with a tapered tip and truncate base, ranging from 16.46 to 20.26 µm in length and 2.81 to 3.96 µm in width (n=100). Setae were dark brown, septate, straight with a slightly acute tip, 75.45 to 135.63×3.19 to 4.95 µm in size. Appressoria were dark brown, round or irregular, mostly in groups. All characteristics were consistent with the descriptions of C. truncatum (Damm et al. 2009). Further confirmation of the identification was determined according to methods described previously (Damm et al. 2009). The rDNA internal transcribed spacer region (OP364400, 585 bp), and actin (OP380867, 290 bp), beta-tubulin (OP380868, 498 bp), chitin synthase 1 (OP380869, 277 bp), glyceraldehyde-3-phosphate dehydrogenase (OP380870, 280 bp), and histone (OP380871, 411 bp) genes were amplified by PCR and sequenced (Carbone and Kohn 1999; Glass and& Donaldson 1995; Guerber et al. 2003; O'Donnell and Cigelnik 1997). BLAST results showed 98-100% similarity at 85-97% coverage compared to the corresponding sequences of the type strain CBS 151.35 (GU227862, GU227960, GU228156, GU228352, GU228254, and GU228058). Phylogenetic analysis combining all loci revealed that the isolate JL6 and the type strains of C. truncatum clustered in one group (Fig. 2). One-year-old healthy seedlings of T. terrestris (cultivar: landrace) were used for pathogenicity test. Suspension (1×105 conidia/mL) of isolate JL6 was sprayed on ten seedlings, and ten seedlings sprayed with sterilized distilled water were used as the control. Three replicates were performed on each treatment. All plants were kept at 28±1°C (12 h photoperiod), and were evaluated after 7 days. The inoculated plants showed lesions on the leaf surface, similar to those in the field, and the control remained symptomless. The pathogen was successfully reisolated and identified using the methods mentioned above. To our knowledge, this is the first report of C. truncatum causing anthracnose on T. terrestris, which will provide valuable information for designing strategies to manage anthracnose on T. terrestris.

CSL112 (Apolipoprotein A-I [Human]) Strongly Enhances Plasma Apoa-I and Cholesterol Efflux Capacity in Post-Acute Myocardial Infarction Patients: A PK/PD Substudy of the AEGIS-I Trial.

INTRODUCTION: Cholesterol efflux capacity (CEC) is impaired following acute myocardial infarction (AMI). CSL112 is an intravenous preparation of human plasma-derived apoA-I formulated with phosphatidylcholine (PC). CSL112 is intended to improve CEC and thereby prevent early recurrent cardiovascular events following AMI. AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b study, designed to evaluate the hepatic and renal safety of CSL112. Here, we report an analysis of a pharmacokinetic (PK) and pharmacodynamic (PD) substudy of AEGIS-I. METHODS: AMI patients were stratified by renal function and randomized 3:3:2 to 4, weekly, 2-hour infusions of low- and high-dose (2 g and 6 g) CSL112, or placebo. PK/PD assessments included plasma concentrations of apoA-I and PC, and measures of total and ABCA1-dependent CEC, as well as lipids/lipoproteins including high density lipoprotein cholesterol (HDL-C), non-HDL-C, low density lipoprotein cholesterol (LDL-C), ApoB, and triglycerides. Inflammatory and cardio-metabolic biomarkers were also evaluated. RESULTS: The substudy included 63 subjects from AEGIS-I. CSL112 infusions resulted in rapid, dose-dependent increases in baseline corrected apoA-I and PC, which peaked at the end of the infusion (Tmax ≈ 2 hours). Similarly, there was a dose-dependent elevation in both total CEC and ABCA1-mediated CEC. Mild renal impairment did not affect the PK or PD of CSL112. CSL112 administration was also associated with an increase in plasma levels of HDL-C but not non-HDL-C, LDL-C, apoB, or triglycerides. No dose-effects on inflammatory or cardio-metabolic biomarkers were observed. CONCLUSION: Among patients with AMI, impaired CEC was rapidly elevated by CSL112 infusions in a dose-dependent fashion, along with an increase in apoA-I plasma concentrations. Findings from the current sub-study of the AEGIS-I support a potential atheroprotective benefit of CSL112 for AMI patients.

Network Pharmacology and Molecular Docking Validation to Reveal the Pharmacological Mechanisms of Kangai Injection against Colorectal Cancer.

Background: Kangai injection is a traditional Chinese medicine (TCM) mixed by extracts from astragalus, ginseng, and kurorinone with modern technology. It is a commonly used antitumor injection in China, but the mechanism of Kangai injection in the treatment of colorectal cancer (CRC) is still unclear. The purpose of this study is to explore the mechanism of Kangai injection against CRC using network pharmacology and molecular docking technology. Methods: Targets of Kangai injection in CRC were predicted by SwissTargetPrediction and DisGeNET databases. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by using the DAVID database. A component-disease-target gene-pathway network was constructed by Cytoscape 3.8.0 software. Results: 114 overlapping targets of Kangai injection and CRC were used to construct a PPI network, and the top 10 hub targets of Kangai injection were rated from high to low as TP53, VEGFA, EGFR, TNF, ESR1, STAT3, HSP90AA1, HDAC1, AR, and MMP9. The ingredient-target-disease interactive network was constructed, which included 22 compounds and 114 overlapping targets with 161 nodes and 707 edges. Entries of enrichment analysis were obtained based on P value (<0.05), which included 19 of GO-MF, 217 of GO-BP, 8 of GO-CC, and 13 KEGG. Molecular docking analysis showed that Kangai injection strongly interacted with top 10 hub target proteins. Conclusion: Network pharmacology intuitively showed the multicomponent, multiple targets, and multiple pathways of Kangai injection in the treatment of CRC. The molecular docking experiment verified that compounds of Kangai injection had good binding ability with top 10 hub target proteins as well.

Cardiotonic Pills® protects from myocardial fibrosis caused by in stent restenosis in miniature pigs.

BACKGROUND: Stent implantation has been increasingly applied for the treatment of obstructive coronary artery disease, which, albeit effective, often harasses patients by in-stent restenosis (ISR). PURPOSE: The present study was to explore the role of compound Chinese medicine Cardiotonic Pills® (CP) in attenuating ISR-evoked myocardial injury and fibrosis. STUDY DESIGN: Chinese miniature pigs were used to establish ISR model by implanting obsolete degradable stents into coronary arteries. Quantitative coronary angiography (QCA) was performed to confirm the success of the model. METHODS: CP was given at 0.2 g/kg daily for 30 days after ISR. On day 30 and 60 after stent implantation, the myocardial infarct and myocardial blood flow (MBF) were assessed. Myocardial histology was evaluated by hematoxylin-eosin and Masson's trichrome staining. The content of ATP, MPO, and the activity of mitochondrial respiratory chain complex Ⅳ were determined by ELISA. Western blot was performed to assess the expression of ATP5D and related signaling proteins, and the mediators of myocardial fibrosis. RESULTS: Treatment with CP diminished myocardial infarct size, retained myocardium structure, attenuated myocardial fibrosis, and restored MBF. CP ameliorated energy metabolism disorder, attenuated TGFß1 up-regulation and reversed its downstream gene expression, such as Smad6 and Smad7, and inhibited the increased expression of MCP-1, PR S19, MMP-2 and MMP-9. CONCLUSION: CP effectively protects myocardial structure and function from ISR challenge, possibly by regulating energy metabolism via inactivation of RhoA/ROCK signaling pathway and inhibition of monocyte chemotaxis and TGF ß1/Smads signaling pathway.

Effects of non-covalent binding of lignans with rice starch driven by high-pressure homogenization on the starch structure and in vitro nutritional characteristics.

As a type of phytoestrogen, lignans have attracted attention in recent years for their nutritional functions. To investigate the effects of lignans on the structural and nutritional functions of starch, honokiol (HK) and arctiin (AC) were complexed with rice starch respectively under high-pressure homogenization (UHPH) (UHPHRS/HK and UHPHRS/AC). The results showed that both HK and AC could form inclusive complexes with rice starch via non-covalent bonding (hydrophobic interaction and hydrogen bonds), and these complexes could further form V-type crystals and aggregates, which reduced the starch digestibility as well as endowing them with the ability to retard glucose release and bind sodium cholate. Interestingly, due to its smaller molecular size, HK could induce starch to form a more compact structure than AC, leading to better nutritional functions. When the addition of HK/AC reached 8%, the resistant starch content could reach 26% and 19.8%, respectively. Meanwhile, the glucose dialysis retardation index could increase to 17.2% and 14.8%, respectively, and the sodium cholate-binding capacity could increase to 33.1 mg g-1 and 21.8 mg g-1, respectively. These results demonstrated that UHPH with lignans' molecular interaction could be beneficial for controlling the nutritional functions of starch products with the desired digestibility.

Effect of Paclitaxel Combined with Doxorubicin Hydrochloride Liposome Injection in the Treatment of Osteosarcoma and MRI Changes before and after Treatment.

Objective: The aim of this study is to investigate the effect of paclitaxel combined with doxorubicin hydrochloride liposome injection (DHLI) in the treatment of osteosarcoma and the MRI changes before and after treatment. Methods: A total of 108 osteosarcoma patients treated in our hospital (January 2020-April 2022) were selected to carry out a single-center retrospective study. Among them, 54 patients receiving the combination chemotherapy (MDT) with high-dose methotrexate, ifosfamide, cisplatin, and ADM were selected as the control group (COG), while 54 patients receiving MDT with high-dose methotrexate, ifosfamide, cisplatin, paclitaxel, and DHLI were chosen as the study group (STG). The COG and STG had the same dose intensity and chemotherapy cycles, and clinical and MRI evaluations were performed after treatment. Results: The evaluation of postoperative clinical efficacy showed that the disease control rate (DCR) of the STG was markedly higher than that of the COG (P < 0.05). The incidence of cardiac toxicity was remarkably lower in the STG than that in the COG (P < 0.05), with no between-group differences in the incidence of fever, abnormal liver function, myelosuppression, stomatitis, and alopecia (P > 0.05). Obvious differences were found in the semiquantitative parameters of MRI in the STG before and after chemotherapy (P < 0.05) and were also found in the SImax, TTP, SEE, PPE, WOR, and R values in the COG before and after chemotherapy (P < 0.05). After chemotherapy, statistical differences were observed in the semiquantitative parameters of MRI between the two groups, with lower parameters such as Slope, SImax, SEE, and R values and higher parameters such as TTP, PPE, and WOR values in the STG than those in the COG (P < 0.05). Conclusion: Paclitaxel combined with DHLI has definite efficacy in osteosarcoma chemotherapy, which is conducive to narrowing the lesion, controlling the disease, and reducing the occurrence of cardiac-related risk events. In addition, the semiquantitative parameters of dynamic contrast-enhanced MRI (DCE-MRI) have a high predictive value for the efficacy of chemotherapy, which can reflect the degree of tumor necrosis and contribute to a timely and objective assessment of the efficacy of osteosarcoma chemotherapy.

[Research progress on role of traditional Chinese medicine in hepatic fibrosis based on miRNA-mediated activation of NLRP3 inflammasome].

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1ß and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

Efficacy and Mechanism of Active Fractions in Fruit of Amomum villosum Lour. for Gastric Cancer.

Amomi Fructus is the dried ripe fruit of Amomum villosum Lour. (A. villosum). It is a well-known traditional Chinese medicine widely used to treat gastrointestinal diseases, while the efficacy or mechanism of main components in Amomi Fructus on cancer treatment remains unknown. In this study, volatile oil of A. villosum (VOAV), total flavonoids of A. villosum (FNAV) and the other residue of A. villosum (RFAV) were distilled, extracted and separated as different active fractions of A. villosum. The cell toxicity test results indicated that VOAV and FNAV can effectively inhibit the cell growth of MFC cells. Flow cytometry test results confirmed that MFC cells were caused apoptosis after being treated with VOAV, FNAV or RFAV. VOAV, FNAV or RFAV induced MFC cells apoptosis through reactive oxygen species (ROS)-mediated mitochondrial pathway, evident by the increase of endogenous ROS and mitochondrial membrane potential collapse. In addition, FNAV exhibited robust inhibitory effects on MFC tumor growth, and could improve the health status of mice compared to that of mice in 5-FU treated group. To sum up, all the above results suggest that FNAV may be a good candidate for the development of new drugs for the treatment of gastric cancer.

Discovery of a Carbamoyl Phosphate Synthetase 1-Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis.

BACKGROUND AND AIMS: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS: A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.

[Research advance in multi-component pharmacokinetics of Chinese herbal extracts in recent five years].

The multi-component pharmacokinetic study of Chinese herbal extracts elaborates the in vivo processes,including absorption,distribution,metabolism,and excretion,of multiple bioactive components,which is of significance in revealing pharmacodynamic material basis of Chinese herbal medicine. In recent years,with the innovation in ideas,and development of techniques and methods on traditional Chinese medicine( TCM) research,the pharmacokinetic studies of Chinese herbal extracts were extensively performed,and notable progress has been made. This paper reviewed the advancement of multi-component pharmacokinetics of Chinese herbal extracts in recent five years from analysis technology of biological sample,the pharmacokinetic characteristics of Chinese herbal medicine with complex system,and the impacts of processing and pathological state on pharmacokinetics of Chinese herbal extracts,aiming to provide a reference for quality control,product development and rational medication of Chinese herbal extracts.

Manipulation of the internal structure of starch by propionyl treatment and its diverse influence on digestion and in vitro fermentation characteristics.

High amylose maize starch (HAMS) and waxy maize starch (WMS) were modified by propionylation and their corresponding physicochemical characteristics, digestion and fermentation properties were studied. The results indicated that two new peaks related to methylene (2.20 ppm) and methyl (0.97 ppm) in the NMR spectrum were formed, indicating the occurrence of propionylation, and this was further confirmed by the formation of a characteristic absorption at 1747 cm-1 in the FTIR spectrum. The propionylation led the modified starch having a lower electron density contrast between the crystalline and amorphous flakes, resulting in the formation of a more compact structure following the increased degrees of substitution (DS). The propionylated starch also had a higher thermal stability and hydrophobicity. These structural changes increased the content of resistant starch (RS) and reduced the predicted glycemic index. More importantly, the gut microbiota fermentation properties indicated that the propionylation of the starch can not only increase the yield of propionate, but also increase the concentration of total short-chain fatty acids (SCFAs). This study highlights a new approach to significantly enhance the RS content in starch, together with an increased SCFA generation capacity.

The efficacy and safety of silver needle in the treatment of rheumatoid arthritis: A protocol of randomized controlled trial.

BACKGROUND: Rheumatoid arthritis is a kind of chronic crippling disease, the condition is complex, the course of the disease is repeated, seriously affecting the quality of life of patients. Adverse reactions and drug resistance associated with conventional treatment can no longer meet the clinical need. Therefore, complementary and alternative therapies need to be explored. The evidence shows that silver needle therapy has advantages in the treatment of rheumatoid arthritis, but there is a lack of standard clinical studies to verify this conclusion. METHODS: This is a prospective randomized controlled trial to study the efficacy and safety of silver needles in the treatment of rheumatoid arthritis. Approved by the Clinical Research Ethics Committee of our hospital. The patients are randomly divided into a treatment group (silver needle treatment group) or control group (routine western medicine treatment group). The patients are followed up for 2 months after 4 weeks of treatment. Observation indicators include: TCM symptom score, HAQDI score, DAS-28 score, laboratory indicators, adverse reactions and so on. Data will be analyzed using the statistical software package SPSS version 18.0 (Chicago, IL). DISCUSSION: This study will evaluate the clinical efficacy of a silver needle in the treatment of rheumatoid arthritis. The results of this study will provide a reliable reference for the clinical use of a silver needle in the treatment of rheumatoid arthritis. TRIAL REGISTRATION: OSF Registration number: DOI 10.17605/OSF.IO/4X5QB.