Study on Quality Characteristic of Chebulae Fructus and Its Adulterants and Degradation Pathway of Hydrolyzable Tannins.

Chebulae Fructus (CF) is known as one of the richest sources of hydrolyzable tannins (HTs). In this study, ultra-performance liquid chromatography coupled with a photodiode array detector method was established for simultaneous determination of the 12 common phenolcarboxylic and tannic constituents (PTCs). Using this method, quantitative analysis was accomplished in CF and other four adulterants, including Terminaliae Belliricae Fructus, Phyllanthi Fructus, Chebulae Fructus Immaturus, and Canarii Fructus. Based on a quantitative analysis of the focused compounds, discrimination of CF and other four adulterants was successfully accomplished by hierarchical cluster analysis and principal component analysis. Additionally, the total contents of the 12 compounds that we focused on in this study were unveiled as 148.86 mg/g, 96.14 mg/g, and 18.64 mg/g in exocarp, mesocarp, and endocarp and seed of CF, respectively, and PTCs were witnessed to be the most abundant in the exocarp of CF. Noticeably, the HTs (chebulagic acid, chebulanin acid, chebulinic acid, and punicalagin) were observed to be ultimately degraded to chebulic acid, gallic acid, and ellagic acid during sunlight-drying of the fresh fruits. As a result, our study indicated that CF and its adulterants could be distinguished by the observed 12 PTCs, which were mainly distributed in the exocarp of the fruits. The HTs were prone to degrade into the three simple phenolcarboxylic acids during drying or processing, allowing us to obtain a more comprehensive understanding of the PTCs, with great significance in the improved quality of CF and related products.

Comprehensive metabolome characterization and comparison between two sources of Dragon's blood by integrating liquid chromatography/mass spectrometry and chemometrics.

Dragon's Blood (DB) serves as a precious Chinese medicine facilitating blood circulation and stasis dispersion. Daemonorops draco (D. draco; Qi-Lin-Jie) and Dracaena cochinchinensis (D. cochinchinenesis; Long-Xue-Jie) are two reputable plant sources for preparing DB. This work was designed to comprehensively characterize and compare the metabolome differences between D. draco and D. cochinchinenesis, by integrating liquid chromatography/mass spectrometry and untargeted metabolomics analysis. Offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (2D-LC/IM-QTOF-MS), by utilizing a powerful hybrid scan approach, was elaborated for multicomponent characterization. Configuration of an XBridge Amide column and an HSS T3 column in offline mode exhibited high orthogonality (A0 0.80) in separating the complex components in DB. Particularly, the hybrid high-definition MSE-high definition data-dependent acquisition (HDMSE-HDDDA) in both positive and negative ion modes was applied for data acquisition. Streamlined intelligent data processing facilitated by the UNIFI™ (Waters) bioinformatics platform and searching against an in-house chemical library (recording 223 known compounds) enabled efficient structural elucidation. We could characterize 285 components, including 143 from D. draco and 174 from D. cochinchinensis. Holistic comparison of the metabolomes among 21 batches of DB samples by the untargeted metabolomics workflows unveiled 43 significantly differential components. Separately, four and three components were considered as the marker compounds for identifying D. draco and D. cochinchinenesis, respectively. Conclusively, the chemical composition and metabolomic differences of two DB resources were investigated by a dimension-enhanced analytical approach, with the results being beneficial to quality control and the differentiated clinical application of DB.

Global Profiling of the Antioxidant Constituents in Chebulae Fructus Based on an Integrative Strategy of UHPLC/IM-QTOF-MS, MS/MS Molecular Networking, and Spectrum-Effect Correlation.

An integrative strategy of UHPLC/IM-QTOF-MS analysis, MS/MS molecular networking (MN), in-house library search, and a collision cross-section (CCS) simulation and comparison was developed for the rapid characterization of the chemical constituents in Chebulae Fructus (CF). A total of 122 Constituents were identified, and most were phenolcarboxylic and tannic compounds. Subsequently, 1,3,6-tri-O-galloyl-ß-d-glucose, terflavin A, 1,2,6-tri-O-galloyl-ß-d-glucose, punicalagin B, chebulinic acid, chebulagic acid, 1,2,3,4,6-penta-O-galloyl-ß-d-glucose, and chebulic acid, among the 23 common constituents of CF, were screened out by UPLC-PDA fingerprinting and multivariate statistical analyses (HCA, PCA, and OPLS-DA). Then, Pearson's correlation analysis and a grey relational analysis were performed for the spectrum-effect correlation between the UPLC fingerprints and the antioxidant capacity of CF, which was finally validated by an UPLC-DPPH• analysis for the main antioxidant constituents. Our study provides a global identification of CF constituents and contributes to the quality control and development of functional foods and preparations dedicated to CF.

Steroidal Saponins from Solanum lyratum Thunb.

Four undescribed steroidal compounds along with twenty known compounds were isolated from n-butanol extracted fraction of the whole plants of Solanum lyratum Thunb (SLNF). Their structures were assigned based on analyses of the extensive spectroscopic data (including MS, 1D/2D NMR, and ECD) or comparisons of the NMR data with those reported. Among the knowns, three compounds were isolated from Solanum plants for the first time, while one compound was isolated from S. lyratum for the first time. In addition, the cytotoxicities of these isolates against human colon SW480 and hepatoma Hep3B cells were evaluated by a MTT assay. And, nine of them and SLNF exhibited significant activities against both SW480 and Hep3B cells, while twelve of them significantly inhibited the activities of SW480 cells. This study allows for the exploitation of chemical markers with potential significance in discrimination of Solanum plants, and uncovers the diverse steroidal constituents from S. lyratum dedicated for its future application in cancer treatment.

A rare tetrahydroimidazopyridine from the marine-derived fungus Paraconiothyrium sp. YK-03.

A new tetrahydroimidazopyridine named butyl (5R,6R,7S,8S)-5,6,7,8-tetrahydro-6,7,8-trihydroxy-5-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate(1), together with eight known compounds (2-9), were isolated from the fermentation broth of a marine-derived fungus Paraconiothyrium sp. YK-03. Their chemical structures were elucidated by extensive analysis of one-dimensional and two-dimensional NMR spectroscopy, HR-ESIMS and optical rotation. Among these compounds, compound 1 represented a rare tetrahydroimidazopyridine, and compounds 2-7 were isolated from the Paraconiothyrium species for the first time. A plausible biosynthetic pathway for compound 1 was proposed.

Carotenoid-derived norsesquiterpenoids and sesquiterpenoids from Tagetes erecta L.

Tagetes erecta L. (marigold), a common landscaping flower widely cultivated in America, Africa, Asia and Europe, is the fundamental source of carotenoids (especially lutein) in food and pharmaceutical industry. Carotenoids are well-known to possess various healthy and beneficial biological activities such as eye protection, anti-aging, and anti-inflammatory. In our exploitation of carotenoid-derived products from T. erecta, nine previously undescribed compounds including seven megastigmane-type norsesquiterpenoids (1-7), one carotenoid-derived sesquiterpenoid (8), and one natural 3-hydroxyl-α-ionylideneacetic acid derivative (9), along with twelve known compounds (10-21), were afforded from the 95% ethanol extract of the petals of T. erecta. Their planar chemical structures and the absolute configurations were established by analysis of the extensive spectroscopic data including HRESI-MS, 1D/2D NMR and the simulation of ECD. Further, a plausible biosynthesis pathway for compounds 1-20 is proposed.

Furfural Derivatives and Phenolic Constituents in Stemona tuberosa Lour.

Chemical investigation on the water-soluble constituents of Stemona tuberosa Lour. resulted in the isolation of a previously undescribed furfural derivative namely (S)-5-((R)-hydroxy(5-(hydroxymethyl)furan-2-yl)methyl)-5-methylfuran-2(5H)-one and twenty-five known compounds from the water decoction of the dried root tubers. Their structures were determined by analysis of the extensive spectroscopic data, including 1D/2D NMR, HR-ESI-MS, and ORD, as well as the ECD simulation and comparison. Most of them were phenolic and among them, four compounds were isolated from Stemona plants for the first time. This study uncovers diverse constituents from water decoction of S. tuberosa dedicated for its quality control and allows for the exploitation of chemical markers with potential significance for discrimination of Stemona plants.

Degradation Profiling of Nardosinone at High Temperature and in Simulated Gastric and Intestinal Fluids.

Nardosinone, a predominant bioactive product from Nardostachys jatamansi DC, is well-known for its promising therapeutic applications, such as being used as a drug on anti-inflammatory, antidepressant, cardioprotective, anti-neuroinflammatory, anti-arrhythmic, anti-periodontitis, etc. However, its stability under varying environmental conditions and its degradation products remain unclear. In this study, four main degradation products, including two previously undescribed compounds [2-deoxokanshone M (64.23%) and 2-deoxokanshone L (1.10%)] and two known compounds [desoxo-narchinol A (2.17%) and isonardosinone (3.44%)], were firstly afforded from the refluxed products of nardosinone in boiling water; their structures were identified using an analysis of the extensive NMR and X-ray diffraction data and the simulation and comparison of electronic circular dichroism spectra. Compared with nardosinone, 2-deoxokanshone M exhibited potent vasodilatory activity without any of the significant anti-neuroinflammatory activity that nardosinone contains. Secondly, UPLC-PDA and UHPLC-DAD/Q-TOF MS analyses on the degradation patterns of nardosinone revealed that nardosinone degraded more easily under high temperatures and in simulated gastric fluid compared with the simulated intestinal fluid. A plausible degradation pathway of nardosinone was finally proposed using nardosinonediol as the initial intermediate and involved multiple chemical reactions, including peroxy ring-opening, keto-enol tautomerization, oxidation, isopropyl cleavage, and pinacol rearrangement. Our findings may supply certain guidance and scientific evidence for the quality control and reasonable application of nardosinone-related products.

Steroidal constituents from Solanum nigrum.

Three previously undescribed steroidal constituents including two sterols (1-2) and one pregnane-type steroidal glycoside (6), along with nineteen known ones (3-5, 7-22), were isolated from the 80% alcohol extraction of Solanum nigrum L. Their structures and the absolute configurations were established by analysis of the extensive spectroscopic data (1H/13 NMR, 1H1H COSY, HSQC, HMBC, and NOESY), and/or by comparisons of the experimental electronic circular dichroism (ECD) spectra with those calculated ones by TDDFT method. Further, a MTT assay was applied to demonstrate that compounds 1-4, 6-12, 18, and 22 exhibited significant cytotoxic activities against SW480 cells, and compounds 1-4, 6-14, and 16-22 showed significant cytotoxic activities against Hep3B cells.

Phytochemistry, data mining, pharmacology, toxicology and the analytical methods of Cyperus rotundus L. (Cyperaceae): a comprehensive review.

Cyperus rotundus L. has been widely used in the treatment and prevention of numerous diseases in traditional systems of medicine around the world, such as nervous, gastrointestinal systems diseases and inflammation. In traditional Chinese medicine (TCM), its rhizomes are frequently used to treat liver disease, stomach pain, breast tenderness, dysmenorrheal and menstrual irregularities. The review is conducted to summarize comprehensively the plant's vernacular names, distribution, phytochemistry, pharmacology, toxicology and analytical methods, along with the data mining for TCM prescriptions containing C. rotundus. Herein, 552 compounds isolated or identified from C. rotundus were systematically collated and classified, concerning monoterpenoids, sesquiterpenoids, flavonoids, phenylpropanoids, phenolics and phenolic glycosides, triterpenoids and steroids, diterpenoids, quinonoids, alkaloids, saccharides and others. Their pharmacological effects on the digestive system, nervous system, gynecological diseases, and other bioactivities like antioxidant, anti-inflammatory, anti-cancer, insect repellent, anti-microbial activity, etc. were summarized accordingly. Moreover, except for the data mining on the compatibility of C. rotundus in TCM, the separation, identification and analytical methods of C. rotundus compositions were also systematically summarized, and constituents of the essential oils from different regions were re-analyzed using multivariate statistical analysis. In addition, the toxicological study progresses on C. rotundus revealed the safety property of this herb. This review is designed to serve as a scientific basis and theoretical reference for further exploration into the clinical use and scientific research of C. rotundus. Supplementary Information: The online version contains supplementary materials available at 10.1007/s11101-023-09870-3.

Santalane-type sesquiterpenoids and isobenzofuranones from cultures of Paraconiothyrium sporulosum YK-03.

Three undescribed santalane-type sesquiterpenoids (parasantalenoic acids A-C) and two undescribed epimeric isobenzofuranones (paraphthalides A and B) were isolated from cultures of the marine mud-associated fungus Paraconiothyrium sporulosum YK-03. Their structures were elucidated by analysis of the extensive spectroscopic and crystal X-ray diffraction data, combined with ECD calculations and comparison. Santalane-type sesquiterpenoids have been firstly found in the Paraconiothyrium species. Parasantalenoic acids A-C represent three rare polyhydroxylated santalane-type sesquiterpenoid carboxylic acids, and parasantalenoic acid A represents the first example of 2-chlorinated santalane-type sesquiterpenoid. A plausible biosynthetic pathway for parasantalenoic acids A-C was proposed. Additionally, the anti-neuroinflammatory activities of parasantalenoic acids A-C were investigated by evaluating their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells. Among them, parasantalenoic acid C showed significant anti-neuroinflammatory activity with an inhibition of 86.45 ± 2.45% at 10 µM.

NO Release Inhibitory Activity of Flavonoids from Aesculus Wilsonii Seeds through MAPK (P38), NF-κB, and STAT3 Cross-Talk Signaling Pathways.

The flavonoid constituents of Aesculus wilsonii, a source of the Chinese medicinal drug Suo Luo Zi, and their in vitro anti-inflammatory effects were investigated. Fifteen flavonoids, including aeswilflavonosides IA-IC (1:  - 3: ) and aeswilflavonosides IIA-IIE (4:  - 8: ), along with seven known derivatives were isolated from a seed extract. Their structures were elucidated by extensive spectroscopic methods, acid and alkaline hydrolysis, and calculated electronic circular dichroism spectra. Among them, compounds 3: and 7: possess a 5-[2-(carboxymethyl)-5-oxocyclopent-yl]pent-3-enylate or oleuropeoylate substituent, respectively, which are rarely reported in flavonoids. Compounds 2, 3, 7: , and 12:  - 15: were found to inhibit lipopolysaccharide-induced nitric oxide production in RAW 264.7 cell lines. In a mechanistic assay, the flavonoid glycosides 2, 3: , and 7: reduced the expressions of interleukin-6 and tumor necrosis factor-alpha induced by lipopolysaccharide. Further investigations suggest that 2: and 3: downregulated the protein expression of tumor necrosis factor-alpha and interleukin-6 by inhibiting the phosphorylation of p38. Compound 7: was found to reduce the production of inducible nitric oxide synthase, and the secretion of tumor necrosis factor-alpha and interleukin-6 through inhibiting nuclear factor kappa-light-chain-enhancer of activated B signaling pathway. Compounds 2, 3: , and 7: possessed moderate inhibitory activity on the expression of signal transducer and activator of transcription-3. Taken together, the data indicate that the flavonoid glycosides of A. wilsonii seeds exhibit nitric oxide release inhibitory activity through mitogen-activated protein kinase (p38), nuclear factor kappa-light-chain-enhancer of activated B, and signal transducer and activator of transcription-3 cross-talk signaling pathways.

Sesquiterpenoids and monoterpenoids from the water decoction of Valeriana officinalis L.

Nine previously undescribed compounds including three sesquiterpenoids, three iridoids, two monoterpenoids and a furan fatty acid, along with seventeen known ones, were isolated from the water decoction of roots and rhizomes of Valeriana officinalis L. Structure elucidation of the twenty-six compounds were accomplished by analysis of the extensive spectroscopic data, and the absolute configurations of the nine previously undescribed ones were established by NOESY experiment and the electronic circular dichroism (ECD) simulations. Among them, ß-patchoulene-8-O-ß-D-glucopyranoside, 11-methoxyl-viburtinal, and protocatechuic acid showed anti-neuroinflammatory potentials by significantly inhibiting the secretion of nitric oxide (NO) on BV-2 cells upon LPS stimulation (p < 0.001) without affecting the cell viability.

Phytochemical and pharmacological studies on Solanum lyratum: a review.

Solanum lyratum is one of the temperate plants, broadly distributed in Korea, China, Japan, India, and South-East Asia and well-documented in those oriental ethnic medicine systems for curing cancers, jaundice, edema, gonorrhea, cholecystitis, phlogosis, rheumatoid arthritis, etc. This review systematically summarized the research progress on S. lyratum respecting the botany, traditional uses, phytochemistry, pharmacology, and toxicology to increase people's in-depth understanding of this plant, by data retrieval in a series of online or off-line electronic databases as far as we can reach. Steroidal saponins and alkaloids, terpenoids, nitrogenous compounds, and flavonoid compounds are the main chemical constituents in S. lyratum. Among them, steroidal alkaloids and saponins are the major active ingredients ever found in S. lyratum, exerting activities of anti-cancer, anti-inflammation, anti-microbial, anti-allergy, and anti-oxidation in vivo or in vitro. As a result, S. lyratum has been frequently prescribed for the abovementioned therapeutic purposes, and there are substantial traditional and modern shreds of evidence of its use.

Aristolone in Nardostachys jatamansi DC. induces mesenteric vasodilation and ameliorates hypertension via activation of the KATP channel and PDK1-Akt-eNOS pathway.

BACKGROUND: Nardostachys jatamansi DC. is a common medicinal herb used to treat cardiovascular diseases, particularly hypertension. Previously, our lab characterized the chemical compounds of N. jatamansi. However, the bioactive compounds of N. jatamansi and their mechanisms of action on blood pressure and blood vessels are unknown. PURPOSE: The vasorelaxant effects of the methanolic extract (MeOH ext.) of the roots and rhizomes of N. jatamansi, its main compounds, and their underlying mode of action, were investigated. METHODS: The main compounds of N. jatamansi were isolated and identified using UHPLC-TOF MS. The antihypertensive effect of N. jatamansi extracts and (-)-aristolone were determined using spontaneously hypertensive rats. The extracts, fractions, and compounds were also evaluated for their vasorelaxant effects on U46619 contractile responses in isolated thoracic aortic and mesenteric arterial rings. The endothelial-dependent relaxation, as well as the regulatory pathways and targets of (-)-aristolone, were studied in-vitro and ex-vivo. Molecular docking and biophysical characterization (Surface plasmon resonance) studies were utilized to investigate the molecular interaction between (-)-aristolone and the target protein. RESULTS: MeOH ext. (200 mg/kg) reduces the systolic and diastolic blood pressure in spontaneously hypertensive rats. MeOH ext. and its ethyl acetate fraction (EtOAc Fr.), but not the H2O fraction, had a significant relaxing effect on the thoracic aorta. (-)-aristolone and kanshone H from EtOAc Fr. induced vasorelaxation of the thoracic aorta and mesenteric artery. In human umbilical vein endothelial cells, (-)-aristolone treatment upregulated phosphorylation of Akt (T308) and eNOS. Molecular docking and surface plasmon resonance experiments revealed an interaction between (-)-aristolone and phosphoinositide-dependent protein kinase 1 (PDK1), an upstream protein kinase that phosphorylates Akt at T308. Treatment with PDK1 inhibitor PHT-427 and eNOS inhibitor L-NAME consistently inhibited (-)-aristolone-induced vasorelaxation. In addition, KATP channel inhibitor glibenclamide dramatically inhibited the vasorelaxant effects of (-)-aristolone and kanshone H in the endothelium-denuded thoracic aorta. Finally, (-)-aristolone lowers hypertensive rats' systolic and diastolic blood pressure. CONCLUSIONS: The extracts of N. jatamansi promote vasorelaxation and alleviate hypertension. The essential chemicals responsible for producing vasorelaxation effects are (-)-aristolone and kanshone H, which activate the PDK1-Akt-eNOS-NO relaxing pathway and stimulate the opening of the KATP channel. These findings point to N. jatamansi and aristolone as possible antihypertensive agents.

Polyhydroxylated bergamotane-type sesquiterpenoids from cultures of Paraconiothyrium sporulosum YK-03 and their absolute configurations.

Eight undescribed polyhydroxylated bergamotane-type sesquiterpenoids with bicyclic, tricyclic and tetracyclic systems, namely sporulamides A-D, sporulosoic acids A-B and sporuloketals A-B, along with three known analogs were isolated from cultures of the marine mud-associated fungus Paraconiothyrium sporulosum YK-03. The chemical structures of these sesquiterpenoids were elucidated by the extensive spectroscopic techniques of NMR and HR-ESI-MS. Assisted by the X-ray crystallography analysis and electronic circular dichroism (ECD) spectroscopic calculation and comparison, their absolute configurations were established. Sporuloketals A-B represent two rare tetracyclic bergamotanes. It's the first time that ECD empirical rules have been successfully verified and applied for determining the absolute configurations of these bergamotane-type sesquiterpenoids.

A review on traditional uses, phytochemistry, pharmacology, toxicology and the analytical methods of the genus Nardostachys.

ETHNOPHARMACOLOGICAL RELEVANCE: The plants of the genus Nardostachys (Caprifoliaceae) have been used for a long history in different cultural systems of medicine, including Chinese, Ayurvedic, Korean folk medicine and Islamic, for treatments of disorders in nervous, digestive, cardiovascular and integumentary systems. AIM OF THE REVIEW: This review aims to provide comprehensive information on Nardostachys plants including botany update, traditional uses, data mining of uses in traditional Chinese medicine (TCM) and current Chinese medicinal patents, chemical constituents, pharmacological effects, toxicity and analytical method studies. MATERIALS AND METHODS: Studies of the genus Nardostachys were collected via Google Scholar and Baidu Scholar, ScienceDirect, SciFinder, Wiley Online Library, ACS Publications, NLM/NCBI, Web of Science, CNKI, WANFANG DATA, EMBASE, Huabeing database and Traditional Chinese Medicine Resource Network and libraries. Some local books, PhD or MS's dissertations were also included. The literatures cited in this review covered the period from 1962 to March 2021. The Plant List and Kew Herbarium Catalogue databases were used to authenticate the scientific name. RESULTS: Botany description of Nardostachys genus is updated. Analysis of the literatures indicates that Nardostachys species are valuable herbs with therapeutic potentials for various disorders. Data mining on ancient TCM prescriptions and current Chinese medicinal patents containing Nardostachys revealed its common compatibility with other herbs in China. Phytochemical studies identified terpenoids and phenolic compounds as the main constituents in the genus Nardostachys and sesquiterpenoids as the major bioactive components. Experimental studies demonstrated that crude extracts, major fractions and the main constituents from Nardostachys species mainly exhibited pharmacological activities on nervous, digestive, cardiovascular and skin systems. Further, in vivo and in vitro toxicological studies demonstrated that Nardostachys plants showed either no or low toxicities, except at high doses. Finally, methods of qualitative and quantitative analyses on chemical constituents of genus Nardostachys were summarized, including TLC/HPTLC, GC and HPLC/UPLC methods, combined with common detectors including PDA, DAD and MS. CONCLUSIONS: This review summarizes the progress on phytochemistry, pharmacology, toxicology and analytical methods of the genus Nardostachys. Studies demonstrate traditional uses of the genus Nardostachys, and reveal novel bioactive effects for clinical uses. These achievements expand our knowledge on the genus Nardostachys and its clinical value.

Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer.

BACKGROUND: To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. METHODS: The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. RESULTS: LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. CONCLUSION: LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC. Video Abstract.

Antidepressant activities and regulative effects on serotonin transporter of Nardostachys jatamansi DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Nardostachys jatamansi (D.Don) DC. (family Caprifoliaceae, NJ) is well-documented and commonly used in the systems of traditional medicine in China, Tibet, Nepal, Bhutan, India and Japan for curing digestive and neuropsychiatric disorders with a long history of medication. However, the possible action mechanisms of antidepressant effects of NJ remain unraveled. AIM OF THE STUDY: The aim of this study was to systematically investigate chemical substances of NJ and their effects on serotonin transporter (SERT) in antidepressant activity. MATERIALS AND METHODS: Antidepressant effects of total methanol extract of NJ were evaluated by tail suspension test (TST) and open field test (OFT). Then the total extract was analyzed by ultra-high-performance liquid chromatography (UHPLC) method, and its effect on SERT activity was evaluated by high content assay (HCA) to determine half maximal effective concentration (EC50). This total extract was subfractioned into twenty subfractions by preparative high-performance liquid chromatography (p-HPLC) method, and 'subfraction-SERT activity' relationship curve was fitted with medians of the retention time of those subfractions and their SERT activity values. Then, the fraction NJFr.01 enriched with SERT enhancers was optimized, prepared and analyzed by UHPLC method. Antidepressant effects of the fraction NJFr.01 were evaluated by TST and OFT. Further, major constituents of the total extract and fraction NJFr.01 were isolated by p-HPLC and identified by extensive nuclear magnetic resonance (NMR) analyses and comparisons with those reported data, and their SERT activities were also evaluated. Finally, antagonistic effects of chlorogenic acid and desoxo-narchinol A against fluoxetine on SERT were evaluated. RESULTS: Results of TST and OFT demonstrated antidepressant effects of toatal extract of NJ. The EC50 of total extract on SERT enhancement was 31.63 µg/mL. The fitted 'subfraction-SERT activity' relationship curve revealed that fraction NJFr.01 was enriched with SERT enhancing constituents. Both total extract and fraction NJFr.01 significantly enhanced SERT activity, while the rest fraction NJFr.02 didn't show any SERT activity. Then, antidepressant effects of fraction NJFr.01 were demonstrated by TST and OFT. Further, phytochemistry investigation and UHPLC analyses confirmed the identification of fourteen constituents in the total extract of NJ, including 7-oxonardinoperoxide (1), desoxo-narchinol A (2), kanshone B (3), narchinol B (4), nardosinonediol (5), kanshone A (6), 1-hydroxylaristolone (7), debilon (8), nardosinone (9), kanshone H (10), 1,8,9,10-tetradehydroaristolan-2-one (11), (-)-aristolone (12), 1(10)-aristolene-2-one (13) and jatamol A (14), and seven constituents in the fraction NJFr.01, including chlorogenic acid (15), 8α-dihydrogeniposide (16), 7-deoxy-8-epi-loganic acid (17), adoxosidic acid (18), 8-epi-loganic acid (19), 8α-6,7-dihydroapodantheroside acetate (20) and 6″-acetylpatrinalloside (21). Their structures were established by NMR analyses and comparisons with those reported data. HCA results of these constituents demonstrated the major components of fraction NJFr.01 enhanced SERT activity. Antagonistic results showed that chlorogenic acid and desoxo-narchinol A reversed inhibition effect of fluoxetine on SERT activity. CONCLUSION: This study first systematically expatiated the roles of SERT activity in antidepressant effects of NJ, including total methanol extract and the water-soluble fraction NJFr.01 enriched with SERT enhancing constituents. This is the first report of natural SERT enhancing extract and fractions with antidepressant potential in NJ.

Prunus cerasoides Extract and Its Component Compounds Upregulate Neuronal Neuroglobin Levels, Mediate Antioxidant Effects, and Ameliorate Functional Losses in the Mouse Model of Cerebral Ischemia.

Prunus cerasoides (PC) has been reported to have antimicrobial and anti-inflammatory properties, but its potential as a neuroprotective agent in a mouse model of cerebral ischemia has not been explored. Considering neuroglobin (Ngb), an endogenous neuroprotective factor, as a novel approach to neuroprotection, in this study, Ngb promoter activity, Ngb expression changes, and antioxidant protection by PC extract (PCE) and PC component compounds (PCCs) were analyzed in oxygen-glucose deprivation (OGD)-treated neurons. In vivo analysis involved transient middle cerebral artery occlusion (tMCAO) in mice with pre- and post-treatment exposure to PCE. Following ischemic stroke induction, neurological behavior scores were obtained, and cellular function-related signals were evaluated in the ischemic infarct areas. In addition to PCE, certain component compounds from PCE also significantly increased Ngb levels and attenuated the intracellular ROS production and cytotoxicity seen with OGD in primary neurons. Administration of PCE reduced the infarct volume and improved neurological deficit scores in ischemic stroke mice compared with the vehicle treatment. Increased Ngb levels in infarct penumbra with PCE treatment were also accompanied by decreased markers of apoptosis (activated p38 and cleaved caspase-3). Our findings point to the benefits of Ngb-mediated neuroprotection via PCE and its antioxidant activity in an ischemic stroke model.