Paeoniflorin Coordinates Macrophage Polarization and Mitigates Liver Inflammation and Fibrogenesis by Targeting the NF-[Formula: see text]B/HIF-1α Pathway in CCl4-Induced Liver Fibrosis.

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200[Formula: see text]mg/kg) or YC-1 (2[Formula: see text]mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF-[Formula: see text]B/HIF-1[Formula: see text] signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway.

Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

Inspiratory muscle training improves cardiopulmonary function in patients after transcatheter aortic valve replacement: a randomized clinical trial.

AIMS: Inspiratory muscle training (IMT) can increase the strength or endurance of the diaphragm and accessory muscles of inspiration, yet there is no evidence that endorses the role of IMT in patients of transcatheter aortic valve replacement (TAVR). This study for the first time tested the effects of IMT plus usual cardiac rehabilitation (CR) function in patients after TAVR. METHODS AND RESULTS: A double-blinded, randomized controlled, single-centre clinical trial was undertaken. Participants who had a confirmed diagnosis of valve heart disease and were clinically stable after TAVR were recruited and received a CR programme during the hospital stay. A total of 96 patients were recruited and randomly assigned to the IMT + CR group (n = 48) or the CR group (n = 48) in a 1:1 ratio. The group difference in the primary outcome, the 6-min walk distance at the discharge of the hospital, significantly favoured the IMT + CR group (mean difference -33.52, 95% CI: -64.42 to -2.62, P = 0.034). The significant difference was maintained at the 1-month and 3-month follow-ups (mean difference: 41.51, 95% CI: 1.82-81.21, P = 0.041). In addition, the mean hospital stays of subjects in the IMT + CR group was 11 days, which was significantly shorter than the 12.5 days in the CR group (P = 0.016). Sensitivity analysis using per-protocol analysis supported these findings. No adverse treatment-related events were reported. CONCLUSION: Compared with usual CR, IMT plus CR can effectively improve exercise endurance, pulmonary ventilation function, and inspiratory muscle strength in patients after TAVR and shorten the length of hospital stay.

Biejiajian pill inhibits progression of hepatocellular carcinoma by downregulating PDGFRß signaling in cancer-associated fibroblasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Biejiajian pill (BJJP) is a canonical formula that is clinically used to treat chronic liver disease, especially to decrease the incidence of hepatocellular carcinoma (HCC). However, the mechanisms underlying the prevention of HCC progression by BJJP remain unclear. AIM OF THE STUDY: This study aimed to determine whether BJJP inhibits HCC progression by downregulating platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer-associated fibroblasts (CAFs) in a mouse model of diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC. MATERIALS AND METHODS: C57BL/6 male mice were intraperitoneally injected with DEN 2 weeks after birth, followed by repeated injections of CCl4 weekly from 6 weeks of age onwards, to recapitulate features of HCC. At week 14, BJJP was orally administered to mice. The effects of BJJP on HCC progression were evaluated using histology, immunohistochemistry, and serum biochemical marker levels. Transcriptome analysis, molecular docking, quantitative real-time PCR, and Western blot were used to study the genes targeted by BJJP and the associated signaling pathway. The effects of BJJP on PDGFRß signaling in CAFs and the underlying mechanism were demonstrated. RESULTS: BJJP treatment significantly suppressed carcinogenesis and cancer progression, and it ameliorated liver inflammation in mice with HCC. A total of 176 genes, including PDGFRß, were significantly downregulated after BJJP treatment and five components of BJJP with high binding affinity to PDGFRß were identified. BJJP inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3ß) by suppressing PDGFRß expression in CAFs, and it also downregulated the expression of the downstream proteins hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A). Furthermore, BJJP-containing serum consistently reduced PDGFRß, HGF, and VEGF-A expression levels in HSC-derived CAFs in vitro. Importantly, PDGF-BB induced PDGFRß activation in CAFs and both BJJP and sunitinib (a kinase inhibitor) inhibited PDGF-BB/PDGFRß signaling. CONCLUSION: BJJP inhibits the progression of HCC through suppressing VEGF-A and HGF expression in CAFs by downregulating PDGFRß signaling.

A Study of Heat Shock Protein 90 and Serum CCL21 Expression in Pregnant Women with Preeclampsia.

Objective: The purpose of the study was to determine the significance of heat shock protein 90 (HSP 90) and serum chemokine ligand 21 (CCL-21) in pregnant women with preeclampsia (PE). Methods: From June 2021 to June 2022, the study enrolled 100 women undergoing obstetric examinations and delivering in our hospital; 50 PE patients undergoing routine obstetric examinations and delivering during the same period were enrolled in the research group; according to the severity, they were divided into mild PE and severe PE groups, while 50 healthy pregnant women undergoing obstetric examinations and delivering in our hospital during the same period were enrolled in the control group. In a subsequent analysis, serum levels of CCL-21 and HSP90 were compared between the two groups, and the correlation among CCL-21, HSP 90, and PE severity was analyzed. Results: An overall total of 50 patients with PE were enrolled in the study, which included 32 patients with mild PE and 18 patients with severe PE. Patients with severe PE had lower mean arterial pressure (MAP), HSP 90, and CCL21 index levels than those with mild PE; MAP, HSP 90, and CCL21 in the severe PE group were higher than those in the mild PE group, but the difference was not statistically significant; In the research group, MAP was weakly correlated with HSP90 concentration and CCL21 concentration, with correlation coefficients of 0.33 and 0.30, respectively, and the correlation analysis was significant. Conclusion: Patients with PE showed significantly increased serum concentrations of HSP90 and CCL-21, but a significant difference did not exist between mild and severe PE. In addition, there was a weak relationship between HSP90 and CCL-21 concentrations in PE patients and MAP, suggesting that HSP90 and CCL-21 play an instrumental role in the pathogenesis of PE, although more studies are needed to clarify the exact mechanisms.

Correlation of Serum Chemokine (C-C Motif) Ligand 21 and Heat Shock Protein 90 with Preeclampsia.

Objective: The study aimed to explore the correlation of serum chemokine (C-C motif) ligand 21 (CCL21) and heat shock protein 90 (Hsp90) with preeclampsia (PE). Methods: Between June 2021 and June 2022, 50 pregnant women with PE were included in the PE group, and 50 healthy pregnant women were included in the control group. The serum levels of CCL21 and Hsp90 were compared between the two groups. Results: PE patients showed significantly higher levels of CCL21 and Hsp90 than healthy pregnant women (P < 0.05). Correlation analysis showed a positive correlation between CCL21 and Hsp90 levels (r > 0, (P < 0.05)). Binary logistic regression analysis suggested that high expression of CCL21 and Hsp90 were influencing factors for PE (OR >1, (P < 0.05)). The area under the receiver operating characteristic (AUC) curves of Hsp90 and CCL21 levels for predicting PE were 0.895 and 0.864, respectively, suggesting a good predictive value. Conclusion: Serum CCL21 and Hsp90 show great potential as disease markers for PE prediction. Further trials are, however, required prior to clinical promotion.

[Bioinformatics and expression analysis on MYB-related family in Angelica dahurica var. formosana].

In recent years, the MYB-related gene family has been found pivotal in plant growth and development. MYB-related gene family in Angelica dahurica var. formosana was systematically investigated based on "Chuanzhi No. 2" through transcriptome database search and bioinformatics and the temporal and spatial expression patterns were analyzed through real-time fluorescence-based quantitative polymerase chain reaction(PCR). The results showed that 122 MYB-related proteins family were identified, mainly including the unstable hydrophilic proteins with good thermal stability. Most of the proteins were located in nuclei. The majority of the proteins had the structures of random coil and α-helix. Five MYB-related proteins family of A. dahurica var. formosana had membrane-binding domains. The conserved domain analysis of MYB-related proteins family of A. dahurica var. formosana showed that the MYB domains of genes in five subgroups, similar to 2 R-, 3 R-, and 4 R-MYB proteins, contained three evenly distributed Trp(W) residues in the MYB repeat sequence. The phylogenetic analysis of MYB-related proteins family in A. dahurica var. formosana and Arabidopsis thaliana showed that the MYB-related members were unevenly distributed in five subgroups, and A. thaliana and A. dahurica var. formosana had almost the same number of genes in the CCA1-like subgroup. There were differences in the number, type, and distribution of motifs contained in 122 encoded proteins. Transcription factors with similar branches had similar domains and motifs. The expression pattern analysis showed that the transcription factors AdMYB53, AdMYB83, and AdMYB89 responded to hormones to varying degrees, and they were highly expressed in leaves and responded quickly in roots. This study lays a foundation for further investigating the function of MYB-related transcription factors of A. dahurica var. formosana and solving the corresponding biological problems such as bolting early.

Biejiajian Pill Promotes the Infiltration of CD8+ T Cells in Hepatocellular Carcinoma by Regulating the Expression of CCL5.

Tumor-infiltrating CD8+T lymphocytes are mostly associated with a favorable prognosis in numerous cancers, including hepatocellular carcinoma (HCC). Biejiajian Pill (BJJP) is a common type of traditional Chinese medicine that is widely used in the treatment of HCC in China. Previous studies showed that BJJP suppressed the growth of HCC cells both in vivo and in vitro, by exerting direct cytotoxic effects on tumor cells. The present study demonstrated that in addition to direct cytotoxicity, BJJP inhibits the growth of tumor cells by promoting the infiltration of CD8+T cells into the tumor in H22-bearing mice. Mechanistically, chemokine ligand 5 (CCL5) was identified as one of the most highly expressed chemokines by tumor cells in vivo after treatment with BJJP. Additionally, CCL5 was knocked down in H22 cells and the results showed that knockdown of the gene significantly impaired the infiltration of CD8+T cells in vivo. Furthermore, the effects of BJJP on human HCC cell lines were assessed in vitro. Similarly, cells treated with BJJP had higher expression of CCL5 mRNA, which was consistent with increased levels of CCL5 protein in human tumor cells. These findings provide new insights into the anticancer effects of BJJP, which regulated the expression of CCL5 and the infiltration of CD8+T cells. The results, therefore, suggest that BJJP has great potential application in clinical practice.

The Role of TGF-ß Signaling Pathways in Cancer and Its Potential as a Therapeutic Target.

The transforming growth factor-ß (TGF-ß) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-ß signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-ß signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-ß signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-ß signaling. Specifically, this review evaluates TGF-ß's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-ß signaling pathway.

Sinisan Protects Primary Hippocampal Neurons Against Corticosterone by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway.

Objective: Corticosterone causes significant neurotoxicity in primary hippocampal neurons which is associated with depression. Dysfunctional autophagy is implicated in cognitive impairment and depressive-like behavior. The traditional Chinese medicine Sinisan (SNS) is highly effective in clinical treatment of depression. However, the molecular mechanisms underlying therapeutic effects of SNS are unknown. Purpose: The aim of this study was to elucidate the protective effect of SNS and the underlying mechanisms against corticosterone-induced neuronal damage. Study Design: The effects of serum derived from rats containing SNS (or untreated controls) on the expression of autophagy-related molecules in primary rat hippocampal neurons exposed to different concentrations of corticosterone for different intervals were explored. Methods: CCK-8 assay, LDH assay were used to analyze cell viability and LDH activity. Western blot, qRT-PCR, and immunofluorescence assays were used to determine protein and mRNA expression levels of molecules such as LC3, p62, Beclin1, ULK1, PI3K, p-PI3K, Akt p-Akt, mTOR, p-mTOR, p70S6, p-p70S6, 4ebp1 and p-4ebp1. Results: Corticosterone induced a dose- and time-dependent reduction in cellular viability. Moreover, corticosterone (100-400 µM) treatment for 24 h increased LC3-II/LC3-I protein ratio, increased Beclin1 and ULK1 protein expression levels, and decreased p62, PI3K, p-PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein expression levels. Notably, SNS-containing serum reversed corticosterone-induced reduction of neuronal viability, and increased p62, PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein and mRNA expression levels. In addition, SNS-containing serum decreased LC3-II/LC3-I protein ratio, and downregulated Beclin1, and ULK1 protein and mRNA expression in primary hippocampal neurons. Conclusion: SNS protects primary hippocampal neurons against corticosterone-induced neurotoxicity by preventing excessive autophagy through activation of PI3K/AKT/mTOR pathway.

Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3ß/Snail Signaling Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most usual cancers globally. In China, Biejiajian pill (BJJP), Traditional Chinese Medicine clinical prescription, is broadly utilized for the prevention and therapy of HCC. However, the mechanisms by which BJJP exerts its effects on the prevention of tumor invasion and metastasis are still largely unknown. In this study, in vitro multiple hepatic cancer cell lines and an in vivo xenograft mice model were used to validate the preventive effects and molecular mechanisms of BJJP in HCC. We established that BJJP significantly repressed the proliferation, metastasis and infiltration of HCC cells. Furthermore, BJJP remarkably suppressed HCC cell migration, as well as invasion via epithelial-mesenchymal transition (EMT) by modulating Snail expression, which was associated with the repression of Akt/GSK-3ß/Snail signaling axis activation. In vivo HCC xenograft results indicated that BJJP delayed HCC development and efficiently inhibited lung metastasis. Taken together, BJJP was shown to be an effective therapeutic agent against HCC through repression of the Akt/GSK-3ß/Snail signaling cascade and EMT.

New C21-steroidal aglycones from the roots of Cynanchum otophyllum and their anticancer activity.

Naturally occurring C21-steroidal aglycones from Cynanchum exhibit significant antitumor effects. To expand the chemical diversity and get large scale C21-steroidal aglycones, the extracts of the roots of Cynanchum otophyllum were treated with 5% HCl in aqueous and the resulting hydrolysate was investigated. Nine new C21-steroidal aglycones (1-9) namely cynotogenins A-I, along with seventeen known analogous (10-26), were isolated from the hydrolysate. The structures of compounds 1-9 were elucidated by spectroscopic analysis (IR, HR-ESI-MS, 1D and 2D NMR) and comparison of observed spectroscopic data with those of reported in the literature. Aglycones 2-5 with rare cis-cinnamoyl group as well as 8 and 9 with 5ß,6ß-epoxy group were found from the genus of Cynanchum for the first time. The cytotoxicities of compounds 1-26 toward human cancer HeLa, H1299, HepG2, and MCF-7 cells were evaluated and preliminary structure-activity relationship (SAR) was discussed. Moreover, compound 20 inhibits HepG2 cell apoptosis and induces of G0/G1 phase arrest in a dose dependent manner.

Parasitic Infection Misdiagnosed As Bacterial Pneumonia: A Case Report.

Bacterial pneumonia is a common lung disorder, and the pathogenesis remain elusive. Parasitic infections of the lung are able to affect the respiratory system, and the clinical features could mimic tuberculosis and malignancy. Therefore, it is essential to identify parasitic pneumonia at early stage, and most cases are curable with medical intervention. In this study, one case of parasitic pneumonia was misdiagnosed as bacterial infection, revealing the importance of pathological biopsy and MDT, especially when clinical features are not typical and routine tests are not specific. Therefore, more paragonimiasis cases can be diagnosed more effectively by the clinicians and misdiagnose should be avoided in future clinical practice.

The first complete chloroplast genome of Hovenia acerba Lindl.

Hovenia acerba Lindl. is an important medicinal plant, for which complete chloroplast genome (Accession: MN782301) was sequenced, assembled and annotated. The genome size is 161,668 bp and the overall GC content is 36.69%, with large single-copy (LSC, 89,451bp) regions, small single-copy (SSC, 18,979 bp) regions, and two inverted repeat regions (IRs, 26,619 bp each). A total of 130 genes are successfully annotated, including 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenetic relationships showed that H. acerba is closely related to the species of Ziziphus genus.

Comparison and Risk Assessment for Trace Heavy Metals in Raw Pu-erh Tea with Different Storage Years.

This research conducted an exploration of the content of microelements (As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg) in raw Pu-erh tea with different storage years. The contents of As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg were 0.14, 0.82, 0.02, 0.52, 14.59, 33.51, 564.02, and 0.01 µg/g, respectively, and were all less than the national standard limit values in China. The target hazard quotients (THQs) of each heavy metal were all lower than 1, and the value of combined risk hazard index (HI) of all to adults was 0.221, which presents no health risk when consumed properly by adults of the raw Pu-erh tea infusions. Interestingly, there was no significant correlation between the heavy metal element (As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg) contents and the THQ values of raw Pu-erh tea samples and storage years; the correlation coefficients (R2) range from 0.01 to 0.33 and from 0.01 to 0.57, respectively. The result showed that the storage years showed no effect on the exposure risk of heavy metals; the heavy metal elements in tea samples come from the atmosphere and soil.

Identfication of Potent LXRß-Selective Agonists without LXRα Activation by In Silico Approaches.

Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause undesired lipogenic effects. Discovery of highly LXRß-selective agonists without LXRα activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXRß-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXRα/ß dual agonists. Initially, Kohonen and stepwise multiple linear regression SW-MLR were performed to construct models for LXRß agonists and LXRα agonists based on the structural characteristics of LXRα/ß dual agonists, respectively. The obtained LXRß agonist model gave a good predictive ability (R²train = 0.837, R²test = 0.843, Q²LOO = 0.715), and the LXRα agonist model produced even better predictive ability (R²train = 0.968, R²test = 0.914, Q²LOO = 0.895). Also, the two QSAR models were independent and can well distinguish LXRß and LXRα activity. Then, compounds in the ZINC database met the lower limit of structural similarity of 0.7, compared to the 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione scaffold subjected to our QSAR models, which resulted in the discovery of ZINC55084484 with an LXRß prediction value of pEC50 equal to 7.343 and LXRα prediction value of pEC50 equal to -1.901. Consequently, nine newly designed compounds were proposed as highly LXRß-selective agonists based on ZINC55084484 and molecular docking, of which LXRß prediction values almost exceeded 8 and LXRα prediction values were below 0.

[Chemical constituents from lipophilic parts of stems of Celastrus monospermus].

The chemical constituents from lipophilic parts of the stems of Celastrus monospermus were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods including silica gel, ODS and Sephadex LH-20, and the structures of compounds were determined by spectral data analyses. Twenty six compounds were obtained and identified as 3-oxofriedelane(1), 3-oxofriedelan-28-al(2), 3,12-dioxofriedelane(3), 3ß-hydroxyolean-12-en(4), 3-oxo-28-hydroxyfriedelane(5), 3-oxo-29-hydroxyfriedelane(6), 3-oxo-11ß-hydroxyfriedel-ane(7), 3-oxo-16α-hydroxyfriedelane(8), 3,12-dioxo-28-hydroxyfriedelane(9), 1,3-dioxo-15α-hydroxyfriedelane(10), 3ß,6α-dihydroxyolean-12-en(11), 3-oxo-7α,26-dihydroxyfriedel-ane(12), oleanolic acid(13), 3,15-dioxofriedelane(14), 3α-friedelinol(15), 3,12-dioxofriedelan-28-al(16), 3-oxo-12α-hydroxyfriedelane(17), 3,15-dioxo-12α-hydroxyfriedelane(18), 3ß,11ß-dihydroxyolean-12-en(19), 1ß,3ß-dihydroxylupan-20(29)-en(20), 3-oxo-12α,28-dihydroxyfriedelane(21), 3ß,23-epoxyfriedelan-28-oic acid(22), salaquinone A(23), 2α,3ß-dihydroxyfriedelan-28-oic acid(24), 23-nor-6-oxodemethylpristimerol(25) and 3-oxo-friedelan-27,28-dioic acid(26). Among them, compounds 8, 10-15, 18-20, 22-26 were obtained from this plant for the first time, and compounds 8, 10, 12, 14-15, 18, 22-24, 26 were separated from the genus Celastrus for the first time.

An intelligent NIR-responsive chelate copper-based anticancer nanoplatform for synergistic tumor targeted chemo-phototherapy.

The chelate copper-based anticancer drug bleomycin (BLM) is usually believed to bind metal ions especially Cu(ii) to generate the "activated BLM" for DNA cleavage. Herein, BLM and L-menthol (LM) co-loaded hollow mesoporous Cu2-xS nanoparticles (HMCu2-xS NPs) with surface folic acid (FA) modification were formulated to construct an intelligent NIR-responsive nanoplatform for synergistic tumor targeted chemo-phototherapy. With the tumor targeting ability of the folate receptor (FR)-positive, FA-HMCu2-xS/BLM/LM could pinpoint tumor cells efficiently. Under NIR irradiation, the versatile HMCu2-xS would be bound to exploit the merits of phototherapy (including PTT and PDT-like effects) for cancer treatment. Meanwhile, benefiting from the controllable "solid-liquid" (S-L) phase transition feature of LM as a gatekeeper, FA-HMCu2-xS/BLM/LM offered a platform for simultaneous NIR-mediated temperature-responsive BLM and copper ion release, which further initiated the generation of the "activated BLM". As a matter of course, the remarkable synergistic combination of Cu-dependent chemo-phototherapy in vitro and in vivo by such a smart all-in-one drug delivery nanoplatform developed here provided information for advancing nanotherapy in biomedical fields.

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach.

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)-a famous traditional Chinese medicine formula-has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS.