Achyranthes bidentata Blume (Amaranthaceae): a review of its botany, traditional uses, phytochemistry, pharmacology, and toxicology.

OBJECTIVES: Achyranthes bidentata Blume (A. bidentata) is a plant of Amaranthaceae family, and its root is the main medicinal part, named "Huai-Niu-Xi." It is used to expel blood stasis through menstruation, tonify liver and kidney, strengthen muscles and bones, and induce diuresis. This review aimed to provide a systematic summary of botany, traditional uses, phytochemistry, pharmacology, and toxicology of A. bidentata. METHODS: The present review covers the literature survey. The data have been collected from various journals, books, and some of the electronic search via Internet-based information such as Web of Science, PubMed, Google Scholar, Google patents, CNKI, SpringerLink, online electronic journals, and ScienceDirect. KEY FINDINGS: So far, more than 270 metabolites have been isolated from A. bidentata, including terpenoids, steroids, alkaloids, flavonoids, and so on. Among them, terpenoids and steroids are the main metabolites. The extract and metabolites exert multiple pharmacological activities such as alleviating osteoarthritis effect, antiosteoporosis activity, neuroprotective effect, antidiabetic activity-associated complications, immunoregulatory activity, and so on. SUMMARY: Some traditional uses of A. bidentata need further in-depth studies to confirm. Similarly, the separation and screening of active compounds, as well as the corresponding molecular mechanisms of action of compounds, are also needed to be studied.

A Combination of Deep-Sea Water and Fucoidan Alleviates T2DM through Modulation of Gut Microbiota and Metabolic Pathways.

Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and streptozocin (STZ) injection. Results demonstrate that, compared to those with DSW or FPS alone, the orally administered combination of DSW and FPS (CDF), especially the high dose (H-CDF), could preferably inhibit weight loss, decrease levels of fasting blood glucose (FBG) and lipids, and improve hepatopancreatic pathology and the abnormal Akt/GSK-3ß signaling pathway. The fecal metabolomics data show that H-CDF could regulate the abnormal levels of metabolites mainly through the regulation of linoleic acid (LA) metabolism, bile acid (BA) metabolism, and other related pathways. Moreover, H-CDF could adjust the diversity and richness of bacterial flora and enrich bacterial groups, such as Lactobacillaceae and Ruminococcaceae UCG-014. In addition, Spearman correlation analysis illustrated that the interaction between the gut microbiota and BAs plays an essential role in the action of H-CDF. In the ileum, H-CDF was verified to inhibit activation of the farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) pathway, which is regulated by the microbiota-BA-axis. In conclusion, H-CDF enriched Lactobacillaceae and Ruminococcaceae UCG-014, thereby changing BA metabolism, linoleic acid metabolism, and other related pathways, as well as enhancing insulin sensitivity and improving glucose and lipid metabolism.

CBX3 promotes breast cancer progression and high level of CBX3 predicts poor prognosis in patients.

Breast cancer is one of the leading cancer deaths around the world. Targeted drugs have greatly increased the survival rate of breast cancer patients in recent years. But in some patients, the current regimen is still ineffective. Therefore, more therapeutic targets for treating breast cancer are demanding. The core heterochromatin-related genes of breast cancer were identified by utilizing prognostic survival analysis and multivariate Cox hazard proportional regression analysis. Both breast cancer and adjacent normal tissue were collected and analyzed with western blot and immunohistochemistry. Colony formation assay, CCK-8 assay, and EdU assay were used to measure the effect of CBX3 on breast cancer cell growth, wound-healing assay and Transwell assay were used to analyze the effect of CBX3 on breast cancer cell migration and invasion. Flow cytometry assay and western blot were used to study the molecular mechanism of CBX3 in breast cancer. High expression of heterochromatin-related proteins CBX3, H2AFY, and SULF1 showed a poor prognosis in patients in both TCGA dataset and GEO datasets. Western blot demonstrated that the expression level of CBX3 was significantly higher in breast cancer than that in adjacent normal tissues. Colony formation assay, CCK-8 assay, and EdU assay showed that the knockdown of CBX3 could significantly inhibit breast cancer cell growth, and the overexpression of CBX3 could promote the growth of breast cancer cells. Transwell assay and wound healing assay showed that knockdown of CBX3 inhibited breast cancer cell migration and invasion, and the overexpression of CBX3 promoted breast cancer cell migration and invasion. Western blot showed that CBX3 might promote breast cancer cell proliferation, invasion, and migration in breast cancer by modulating the ERK1/2 signaling pathway and epithelial-mesenchymal transition (EMT)-related genes. CBX3 was a biomarker of poor prognosis in breast cancer patients. CBX3 promoted the proliferation of breast cancer cells through the ERK signaling pathway, and migration and invasion of breast cancer cells through EMT-related genes. The CBX3/p-ERK1/2 signaling axis might provide a new therapeutic method against breast cancer.

PUS1 is a novel biomarker for predicting poor outcomes and triple-negative status in breast cancer.

Breast cancer patients' outcomes have improved dramatically in recent years, but relapses and poor prognosis remain common due to its aggressiveness and heterogeneity. The development of reliable biomarkers is still needed for predicting prognosis and treatment effectiveness. Recently, a growing body of research suggests that pseudouridine synthases contribute to the development of many cancers, but their contribution to breast cancer remains largely unknown. Using an integrative analysis, we selected pseudouridine synthase1(PUS1) as the candidate biomarker. A tissue microarray of 131 breast cancer patients was then utilized to determine the clinical significance and prognostic value of PUS1. RNA sequencing analysis was conducted to identify downstream genes that differ between control and PUS1 knockdown cells. The effect of PUS1 on phenotypes of cells was assessed using cell proliferation, colony formation, and transwell invasion assays. We found that breast tumors overexpressed PUS1 compared with paired normal tissues. PUS1 expression was positively correlated with triple-negative breast cancer (TNBC) status (P= 0.020) and tumor grade (P <0.0001), but not with age (P= 0.736), tumor size (P= 0.608), lymph node (P= 0.742), oestrogen receptor (ER) (P= 0.162), progesterone receptor (PR) (P= 0.901), human epidermal growth factor receptor 2 (HER2) (P= 0.608) or tumor stage (P= 0.411). Comparatively, patients with high PUS1 levels had shorter overall survival time (P=0.0001) and relapse-free survival time (P = 0.0093). A univariate and multivariate survival analysis suggested that the overall survival of patients was independently influenced by the PUS1 score (Univariate Cox P <0.0001, HR=5.176, 95% CI =2.420-11.07; Multivariate Cox P = 0.001, HR = 5.291, 95% CI =1.893-14.78). RNA sequencing data revealed the PUS1 knockdown significantly affects a series of cancer related biological process such as regulation of cell proliferation and cell migration, as well as KEGG pathways including Mitophagy and PI3K-Akt signaling. In vitro, knockdown of PUS1 significantly suppressed the proliferation and colony formation abilities of MDA-MB-231 cells and BT-549 cells. Additionally, the ability of tumor cells to invade was remarkably attenuated in low PUS1 expression groups compared with the corresponding control groups. Our results suggested that PUS1 is a novel biomarker that predicts poor outcomes in patients with breast cancer and may prove to be a promising treatment target.

Deep Sea Water Alleviates Tau Phosphorylation and Cognitive Impairment via PI3K/Akt/GSK-3ß Pathway.

Deep sea water (DSW), as a noticeable natural resource, has been demonstrated to contain high levels of beneficial minerals and exert marked anti-diabetes effects. Epidemiological studies show that type 2 diabetes mellitus (T2DM) is closely related to high danger of Alzheimer's disease (AD); moreover, Akt/GSK-3ß signaling is the main underlying pathway that connects these two diseases. Besides, it has been demonstrated that minerals in DSW, such as Mg, Se, and Zn, could effectively treat cognitive deficits associated with AD. Herein, we first observed the protection of DSW against cognitive dysfunction in T2DM rats, then furtherly explored the neuroprotective mechanism in SH-SY5Y cell model. In T2DM rats, DSW obviously elevated the concentrations of elements Mg, V, Cr, Zn, and Se in brain and improved learning and memory dysfunction in behavior assays, including Morris water maze (MWM) and new object recognition (NOR). Western blot (WB) results demonstrated that DSW could stimulate PI3K/Akt/GSK-3ß signaling, arrest Tau hyperphosphorylation at serine (Ser) 396 and threonine (Thr)231, which was confirmed by immunohistochemistry (IHC). In order to further confirm the mechanism, we employed wortmannin to inhibit PI3K in SH-SY5Y cells; results showed that pretreatment with wortmannin almost abolished DSW-induced decreases in phosphorylated Tau. Taken together, these data elucidated that DSW could improve Tau hyperphosphorylation and cognitive impairment, which were closely related with the stimulation of Akt/GSK-3ß signaling, and the neuroprotective effects of DSW should be contributed to the synergistic effects of major and trace elements in it, such as Mg, V, Cr, Zn, and Se. These experimental evidence indicated that DSW may be explored as natural neuroprotective food for the prevention and treatment of AD.

A new dihydroflavone and a new polyacetylene glucoside from Bidens parviflora.

A new dihydroflavone, 2(S)-isookanin-4'-methoxy-8-O-ß-D-glucopyranoside (1), and a new polyacetylene glucoside, (10S)-tridecane-2E-ene-4,6,8-triyne-1-ol-10-O-ß-D-glucopyranoside (2), along with seven known compounds (3-9), were isolated from the herb of Bidens parviflora Willd. The structures of all the extracted compounds were elucidated by HR-ESI-MS, 1 D and 2 D NMR spectra, as well as circular dichroism (CD).

Screening of the novel immune-suppressive biomarkers of TMED family and whether knockdown of TMED2/3/4/9 inhibits cell migration and invasion in breast cancer.

Background: Transmembrane p24 trafficking protein (TMED) family members are implicated in several solid tumors, but their clinical relevance for breast cancer (BC) remains unclear. This study aimed to probe their prognostic values and relations with tumor immunity in BC. Methods: TMED family mRNA expression was assessed in five microarray datasets (GSE65212, GSE42568, GSE5364, GSE22820 and GSE45827) from Gene Expression Omnibus (GEO) database and invasive breast cancer (BRCA) cohort from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curve was performed to determine the predictive values of filtered members of the TMED family. The protein expressions of screen genes were validated by Clinical Proteomic Tumor Analysis Consortium (CPTAC) data from University of ALabama at Birmingham CANcer data analysis portal (UALCAN) and detected in the clinical specimens by western blot assay. Clinicopathologic variables were analyzed with bc-GenExMiner, and patient prognostic data were obtained with Kaplan-Meier Plotter. In vitro wound healing and invasion assays were performed on siRNA-transfected BC cell lines. TIMER 2.0, SangerBox, and ImmPort were used to evaluate tumor immune infiltration, immune checkpoints, and other immune-related genes. CbioPortal, Metascape, Expression2kinases, and LinkedOmics were used to explore gene regulatory network. Results: BC tissues expressed TMED2/3/4/9 at a higher level than normal tissues, providing diagnostic potential. All the areas under the ROC curve for TMED2/3/4/9 were more than 0.7. TMED2/3/4/9 correlated with numerous clinical variables, including lymph node status, Scarff-Bloom-Richardson score (SBR), Nottingham Prognostic Index (NPI), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and triple-negative breast cancer (TNBC) status, and their high expression predicted the poor prognosis of BC patients. TMED2/3/4/9 knockdown drastically inhibited the migratory and invasive capacities of MDA-MB-231 and HCC1937 cells. TMED2/3/4/9 expressions correlated negatively with the infiltration of tumor-suppressive immune cells such as CD8+ T cells, dendritic cells, and natural killer cells, and was inversely related to a variety of immune checkpoint genes, including programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). A set of kinases, transcription factors, and microRNAs (miRNAs) may regulate TMED2/3/4/9 abnormalities at the genome level. Conclusions: TMED2/3/4/9 may serve as diagnostic, prognostic, and immune-suppressive biomarkers in BC.

Study on the Intervention Effects of Pinggan Prescription () on Spontaneously Hypertensive Rats Based on Metabonomic and Pharmacodynamic Methods.

OBJECTIVE: To investigate the effects of Pinggan Prescription (, PGP) on hypertension by the associated methods of metabonomic and pharmacodynamic. METHODS: A total of 32 male spontaneously hypertensive rats (SHRs) were randomly divided into two groups by using the random number table method: a treatment group (n=18) and a model group (n=14). The Wistar rats (n=14) were used as the normal group. Different prescription were used to intervene three groups: the treatment group in which PGP extract was administered orally at a dose of 18.336 g/kg (PGP/body weight), and the model group in which physiological saline was administered at the equivalent dose. The same treatment was applied to the normal group as the model group. The blood pressure was measured by tail-cuff method, and pharmacodynamic indexes including cyclic adenosine monophosphate (cAMP) and angiotensin II (Ang II) were tested by enzyme-linked immunosorbent assay. The plasma samples from three groups were detected by gas chromatography-mass spectrometry (GC-MS). RESULTS: Compared with the model group, blood pressure of treatment group was obviously reduced after continuous curing with PGP (P<0.01). The pharmacodynamic results illustrated that the content of Ang II increased with the raised blood pressure and the cAMP expressed the converse trend. After curing with PGP, the content of Ang II decreased, the difference between model group and treatment group was significant (P<0.01), and the cAMP expressed the converse trend. Five potential biomarkers were identified, including arachidonic acid, hexadecanoic acid, elaidic acid, octadecanedioic acid and 9,12-octadecadienoic acid. These metabolites had shown significantly changes as followed: arachidonic acid, hexadecanoic acid and elaidic acid were significantly higher and octadecanedioic acid and 9,12-octadecadienoic acid were lowered in the model group than those in the normal group. After the treatment of PGP, the metabolites had the trends of returning to normal along with the reduced blood pressure. CONCLUSIONS: PGP intervention for hypertension played a major role in the metabolism of arachidonic acid and linoleic acid. Metabonomic with pharmacodynamic methods could be potentially powerful tools to investigate the mechanism of Chinese medicine.

Four new phenolic constituents from the rhizomes of Gastrodia elata Blume.

Four new gastrodin derivatives containing a trans-cinnamoyl unit (1-4) and nine known compounds (5-13) were isolated from the rhizomes of Gastrodia elata Blume. All these compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine-induced cell death, and compounds 7 and 12 showed potent activities with EC50 values of 10.5 and 10.2 µM, respectively.

Combination Treatment of Deep Sea Water and Fucoidan Attenuates High Glucose-Induced Insulin-Resistance in HepG2 Hepatocytes.

Insulin resistance (IR) plays a central role in the development of several metabolic diseases, which leads to increased morbidity and mortality rates, in addition to soaring health-care costs. Deep sea water (DSW) and fucoidans (FPS) have drawn much attention in recent years because of their potential medical and pharmaceutical applications. This study investigated the effects and mechanisms of combination treatment of DSW and FPS in improving IR in HepG2 hepatocytes induced by a high glucose concentration. The results elucidated that co-treatment with DSW and FPS could synergistically repress hepatic glucose production and increase the glycogen level in IR-HepG2 cells. In addition, they stimulated the phosphorylation levels of the components of the insulin signaling pathway, including tyrosine phosphorylation of IRS-1, and serine phosphorylation of Akt and GSK-3ß. Furthermore, they increased the phosphorylation of AMPK and ACC, which in turn decreased the intracellular triglyceride level. Taken together, these results suggested that co-treatment with DSW and FPS had a greater improving effect than DSW or FPS alone on IR. They might attenuate IR by targeting Akt/GSK-3ß and AMPK pathways. These results may have some implications in the treatment of metabolic diseases.

Nortirucallane A, a new tirucallane-type nortriterpenoid isolated from Lonicerae japonicae flos.

One new tirucallane-type nortriterpenoid Nortirucallane A (1), together with Chrysoeriol (2) and Isorhamnetin (3), was isolated from the methylene chloride part of Lonicerae japonicae flos. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Compound 3 was isolated from the genus of Lonicera for the first time. The significance of 1 for the study of phytochemical taxonomy was discussed.

[Chemical Constituents of Lonicerae Japonicae Flos].

Objective: To study the chemical constituents of the methylene chloride extract of Lonicerae Japonicae Flos. Methods: The compounds were isolated and purified by silica gel column chromatography,Sephadex LH-20 gel column chromatography and recrystallization. The structures were elucidated by the physical and chemical properties,MS,1H-NMR and13C-NMR spectroscopy. Results: Nine compounds were isolated and their structures were identified as ß-sitosterol( 1),benzoic acid( 2),5-hydroxy-7,3',4'-trimethoxyflavone( 3),tetrapedic acid B( 4),tricin( 5),hydnocarpin D( 6),6,7,10-trihydroxy-8-octadecenoic acid( 7),5'-methoxyhydnocarpin-D( 8) and daucosterol( 9). Conclusion: Compound 2,4,7,8 are isolated from this plant,compounds 2,7,8 are isolated from Caprifoliaceae family for the first time.

The genus Litsea in traditional Chinese medicine: an ethnomedical, phytochemical and pharmacological review.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Litsea, mainly distributed in the tropical and subtropical regions, has been used in traditional and indigenous Chinese medicines for the treatment of diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, etc. for a long history. The present review aims to provide a comprehensive summary on the ethnomedical uses, phytochemistry, and pharmacology of the Litsea species used in traditional Chinese medicine (TCM). Based on these data, evidences supporting their ethnopharmacological effectiveness are illustrated, and opportunities for the future research and development as well as the therapeutic potential of this genus are analyzed to highlight the gaps in our knowledge that deserves further investigation. MATERIAL AND METHODS: Information on the Litsea species was collected via electronic search (using Pubmed, SciFinder, Google Scholar, Web of Science and CNKI) and a library search for articles published in peer-reviewed journals. Furthermore, information was also obtained from some local books on ethnopharmacology. RESULTS: Twenty plants of the genus Litsea are found to be important traditional medicines in China, and have a long medicinal application for diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, etc. Over 200 ingredients have been identified from these 20 Litsea species used in TCM, and flavonoids, terpenoids and alkaloids are considered as the characteristic and bioactive constituents. The crude extracts and the isolated metabolites of these medicinal plants have exhibited some in vitro and in vivo pharmacological effects, including antimicrobial, hepatoprotection, anti-inflammatory, antiasthmatic, immunomodulation, anti-diabetic, anticholelithogenic, as well as function on central nervous system, etc. CONCLUSIONS: The extensive literature survey reveals Litsea species to be a group of important medicinal plants used for the ethnomedical treatment of gastrointestinal diseases, diabetes, inflammatory disorders, and microbial infection in TCM. Pharmacological investigations have supported the use of some Litsea species in the traditional medicines. In addition, further researches targeting individual ingredients responsible for the pharmacological effects, as well as their mechanisms of action are necessary. The outcome of these studies will further support the therapeutic potential of the genus Litsea, and provide convincing evidences to its future clinical applications in modern medicine.

[Analysis of infrared spectra of 60 kinds of plant extract of traditional Chinese medicine and study on the identification and evaluation of characteristics of the regional markers associated with cold and heat nature].

By using the Fourier transform infrared spectroscopy and linear discriminant analysis (LDA), logistic discriminant analysis (Logistic-DA), principal component analysis-linear discriminant analysis (PCA-LDA), partial least-squares discriminant analysis (PLS-DA), random forest (RF), support vector machine (SVM), infrared spectra of 60 kinds of plant extract of Chinese traditional medicine were analyzed and the identification and evaluation of characteristics of the regional markers associated with cold and heat nature were studied. Results indicated that LDA and SVM are suitable for the recognition model of water extract infrared spectral data, LDA is suitable for the identification model of anhydrous ethanol extract infrared spectral data, SVM is suitable for the identification model of chloroform extract infrared spectral data, while petroleum ether extract group recognition effect is not ideal. According to the suitable characteristic parameters identification model, data were analyzed by infrared spectroscopy, and parameters and resistance characteristics of the traditional Chinese drug composition can be obtained. Regional characteristics of these two parameters can be used to identify drug ingredients, and can also be used to indicate different degrees of resistance characteristics of traditional Chinese medicine. Component parameter is model identification coefficient corresponding to the position of spectrum and infrared, with a value greater than zero it is cold nature marker, while with a value less than zero it is heat nature marker; model identification score is a parameter reflecting the degree of cold and heat nature, the greater the score (positive), the more it is cold, while the smaller the score, the more it is hot. a parameter reflecting the degree of cold and heat,the greater the score (positive) is cold more strong, the score is small (negative) heat stronger.

[Pattern recognition for traditional Chinese medicine nature of 60 kinds of herbal medicine based on high performance capillary electrophoresis fingerprint].

OBJECTIVE: To establish signature pattern recognition model of cold-hot nature of herbal medicine. METHODS: High performance capillary electrophoresis fingerprints of 60 kinds of herbal medicine (30 kinds of cold, 30 of hot) were established, features of wavelength were screened, 6 analysis methods such as linear discriminant analysis (LDA), logistic discriminant analysis (Logistic-DA), principal component and linear discriminant analysis (PCA-LDA), partial least-squares discriminant analysis (PLS-DA), random forest (RF) and support vector machine (SVM) were used to establish and evaluate recognition model of cold-hot nature after data processing. RESULTS: SVM was proved to be a suitable means of recognition model of herbal medicine cold-hot nature based on data of HPCE fingerprints. Characteristic parameters of nature could be screened according to theoretical spectra signature of nature model, the characteristic regions of components of herbs with cold-heat nature could be identified in the HPCE fingerprint. The characteristic parameters of cold-hot nature were the identifying coefficient for specific retention time of the theoretical spectra of recognition model, identification coefficients greater than zero were for the cold marker, while that less than zero for the hot marker. CONCLUSION: The results imply that HPCE is a feasible and effective means for identification of cold-hot nature of Traditional Chinese medicine.

[Biotransformation of cycloartane-type triterpenoid from myrrh].

OBJECTIVE: To study the biotransformation of cycloartan-24-ene-1alpha,2alpha, 3beta-triol isolated from myrrh and find new antitumor bioactive cycloartane-type derivatives. METHODS: Fourteen microbial strains were cultured in potato medium at 27.8 degrees C for 7 days. The strain of Penicillium janthinellum was selected for preparative transform assay, and cultured in potato medium at 27.8 degrees C for 10 days. The medium was extracted by EtOAc, and then EtOAc layer was purified by the silica gel column chromatography. The product was structurally elucidated by MS and NMR spectra, and their anti-proliferative effects against human prostate cancer PC3 and DU145 cells were evaluated using MTT assay. RESULTS: The substrate was transformed to two new hydroxyl substituted triterpenoids, with a yield of 21.15%; The products displayed anti-proliferative effect against PC3 and DU145 cells with IC50 values of 14.5 micromol/L and 27.8 micromol/L, respectively. CONCLUSION: Cycloartane-type triterpenoid can be bio-transformed by Penicillium janthinellum, and leading to the isolation of two new hydroxyl substituted derivatives.

Design, synthesis and biological evaluation of novel 4-hydroxybenzene acrylic acid derivatives.

A series of 4-hydroxybenzene acrylic acid derivatives were designed and synthesized based on the ferulic acid of natural active ingredients. The tested compound 5a, 5f and 6a have significant anti-inflammatory activity with suppression rates of 45.29%, 44.75% and 24.11%, respectively, compared with that of indomethacin, and their cardiac toxicity was not observed. The structure-function relationship shows that the p-hydroxyl group on the α-position benzene ring, particularly if acetylated, contributes to the considerable anti-inflammatory activity; that the carboxyl group on the double bond, if esterified, also contributes to the anti-inflammatory activity; that the p-methylsulfonyl group on the other benzene ring, whose introduction is due to the COX-2 selectivity, also contributes to anti-inflammatory activity surprisingly.