Hyperoside ameliorates cerebral ischaemic-reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway.

CONTEXT: Hyperoside (Hyp), one of the active flavones from Rhododendron (Ericaceae), has beneficial effects against cerebrovascular disease. However, the effect of Hyp on vasodilatation has not been elucidated. OBJECTIVE: To explore the effect of Hyp on vasodilatation in the cerebral basilar artery (CBA) of Sprague-Dawley (SD) rats suffering with ischaemic-reperfusion (IR) injury. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into sham, model, Hyp, Hyp + channel blocker and channel blocker groups. Hyp (50 mg/kg, IC50 = 18.3 µg/mL) and channel blocker were administered via tail vein injection 30 min before ischaemic, followed by 20 min of ischaemic and 2 h of reperfusion. The vasodilation, hyperpolarization, ELISA assay, haematoxylin-eosin (HE), Nissl staining and channel-associated proteins and qPCR were analysed. Rat CBA smooth muscle cells were isolated to detect the Ca2+ concentration and endothelial cells were isolated to detect apoptosis rate. RESULTS: Hyp treatment significantly ameliorated the brain damage induced by IR and evoked endothelium-dependent vasodilation rate (47.93 ± 3.09% vs. 2.99 ± 1.53%) and hyperpolarization (-8.15 ± 1.87 mV vs. -0.55 ± 0.42 mV) by increasing the expression of IP3R, PKC, transient receptor potential vanilloid channel 4 (TRPV4), IKCa and SKCa in the CBA. Moreover, Hyp administration significantly reduced the concentration of Ca2+ (49.08 ± 7.74% vs. 83.52 ± 6.93%) and apoptosis rate (11.27 ± 1.89% vs. 23.44 ± 2.19%) in CBA. Furthermore, these beneficial effects of Hyp were blocked by channel blocker. DISCUSSION AND CONCLUSIONS: Although Hyp showed protective effect in ischaemic stroke, more clinical trial certification is needed due to the difference between animals and humans.

A comprehensive quality control evaluation for standard decoction of Smilax glabra Roxb based on HPLC-MS-UV/CAD methods combined with chemometrics analysis and network pharmacology.

An effective, sensitive, and rapid method was developed for the quality control evaluation of the standard decoction of Smilax glabra Roxb (SGR). SGR is a primary ingredient of the traditional functional foods of turtle jelly and SGR tea. Chemometrics, Network Pharmacology, and molecular docking were used to screen for six quality markers. Multiple extraction parameters were optimized. HPLC-UV/CAD-QAMS was used to rapidly quantify the six quality markers (neoastilbin, astilbin, neoisoastilbin, isoastilbin, quercitrin, and isoengeletin) in 10 batches of the standard decoction of SGR samples. The relative correction factor (RCF) values of the five compounds were close to 1, demonstrating that the charged aerosol detection (CAD) showed a consistent response to compounds with similar parent nucleus structures. This method can serve as a guide for rapid quantitative analysis of the multi-components of the SGR standard decoction and all the traditional functional foods of turtle jelly with the homology of medicine.

Bioactive constituents from Gerbera piloselloides with anti-inflammatory and antiproliferative activities.

A phytochemical investigation of the 95% ethanol extract from Gerbera piloselloides obtained fourteen compounds, including three undescribed phenone-monoterpenes (1a/1b and 2), seven undescribed chromone-monoterpenes (3a/3b-5a/5b and 6), and one undescribed coumarin-monoterpene (8). Among them, four pairs of enantiomers (1a/1b and 3a/3b-5a/5b) were successfully isolated by the chiral-phase HPLC resolution. The structures and absolute configurations were unambiguously determined based on comprehensive spectroscopic data, electronic circular dichroism (ECD) data, and X-ray diffraction analysis. Structurally, compound 1 is the first 5-methylphenone monoterpene formed through a circular 6-membered carbocycle. And their anti-inflammatory and antiproliferative activities were evaluated via LPS stimulated RAW 264.7 cells and five human cancer lines (HepG2, MDA-MB-231, SCG-7901, A549 and MCF-7), respectively. Compounds 4b, 5a and 5b showed moderate inhibitory effect against nitric oxide (NO) production with IC50 values ranging from 12.52 to 15.75 µM. Compound 8 significantly inhibited the proliferation of MDA-MB-231 human cancer line in a dose-dependent manner. Furthermore, the connection between phenone-monoterpenes, chromone-monoterpenes, and coumarin-monoterpenes in biosynthesis were also discussed.

Naturally occurring physalins from the genus Physalis: A review.

Physalins, including physalins and neophysalins, are a class of highly oxygenated ergostane-type steroids. They are commonly known by the name of 16,24-cyclo-13,14-seco steroids, in which the disconnection of C-13 and C-14 produces an eight or nine-membered ring and the carbocyclization of C-16 and C-24 generates a new six-membered ring. Meanwhile, the oxidation of C-18 methyl to carboxyl group forms a 18,20-lactone, and the oxidation of C-14 and C-17 gets a heterocyclic oxygen acrossing rings C and D. Additionly, physalins frequently form an oxygen bridge to connect C-14 to C-27. Physalins are a kind of characteristic constituents from the species of the genus Physalis (Solanaceae), which are reported with a wide array of pharmacological activities, including anticancer, anti-inflammatory, immunoregulatory, antimicrobial, trypanocidal and leishmanicidal, antinociceptive, antidiabetic and some other activities. Herein,the research progress of physalins from the genus Physalis during the decade from 1970 to 2021 on phytochemistry, pharmacology, pharmacokinetics and application in China are systematically presented and discussed for the first time.

Five new 5,6-ß-epoxywithanolides from Physalis minima.

Five new 5,6-ß-epoxywithanolides (1-5) were isolated from the whole plants of Physalis minima L. Their structural elucidations were achieved by the extensive spectroscopic analysis (IR, UV, HR-ESI-MS, 1D-NMR, and 2D-NMR). The isolates were evaluated for their anti-inflammatory activities on lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells and cytotoxic activities against three cancer cell lines, viz. A549 lung adenocarcinoma cells, SMMC-7721 hepatic carcinoma cells and MCF-7 breast cancer cells by using the MTT-based assay. All of them possessed moderate inhibition to the production of nitric oxide with IC50 values from 42.18 to 73.26 µM, and the IC50 values of the cytotoxic activities were in the range of 31.25 to 80.14 µM.

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors.

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT (n = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) (n = 11) and HT + ACT + CT (n = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR = CR + PR + SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p < 0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p < 0.05). Peripheral blood CD8+/CD28+ T cells increased (p = 0.002), while the CD4+/CD25+/CD127+Treg cells decreased after therapy (p = 0.012). TCR diversity was substantially increased among the clinical responders.Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.

Association of maternal folate intake during pregnancy with infant asthma risk.

Several studies assessed the association of maternal folate intake with infant asthma risk, but the findings are controversial. We performed a meta-analysis to clarify the association between maternal folate intake and infant asthma risk. PubMed and SCOPUS databases were searched for related studies published until August 2018. Fixed-effects models were applied to pool relative risks (RRs) and their corresponding 95% confidence intervals (CIs) due to the low heterogeneity. We also adopted generalized least-squares trend (GLST) estimation for the dose-response analysis. In our study, a total of 10 studies with maternal folate intake and 5 studies with blood folate concentration were included. We found that maternal folate intake during pregnancy was significantly related to the risk of infant asthma (RR = 1.11; 95% CI = 1.06-1.17). Similar results were found for geographic region from Europe (RR = 1.08; 95% CI = 1.01-1.16) and North America (RR = 1.20; 95% CI = 1.11-1.30) in subgroup analyses. Meanwhile, the dose-response analysis showed a linear relationship between maternal folic acid intake during pregnancy and infant asthma risk. This meta-analysis indicates that maternal folate intake during pregnancy could increase infant asthma risk. Therefore, the adverse effect of folic acid on infant asthma should not be ignored when it is supplemented during pregnancy to prevent birth defects.

Anti-inflammatory and cytotoxic withanolides from Physalis minima.

Six undescribed withanolides were isolated and characterized during the investigation of anti-inflammatory and cytotoxic constituents from the whole plants of Physalis minima L. Their structures were elucidated by extensive spectroscopic analyses (IR, UV, HR-ESI-MS, 1D-NMR, and 2D-NMR), and their anti-inflammatory and cytotoxic activities were evaluated in vitro. All the compounds exhibited anti-inflammatory ability via inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. Moderate cytotoxic activities against A549 lung adenocarcinoma cells, SMMC-7721 hepatic carcinoma cells and MCF-7 breast cancer cells with IC50 values in the range of 40.01-82.17 µM were observed for these withanolides.

Cartilage-specific deletion of ephrin-B2 in mice results in early developmental defects and an osteoarthritis-like phenotype during aging in vivo.

BACKGROUND: Ephrins and their related receptors have been implicated in some developmental events. We have demonstrated that ephrin-B2 (EFNB2) could play a role in knee joint pathology associated with osteoarthritis (OA). Here, we delineate the in vivo role of EFNB2 in musculoskeletal growth, development, and in OA using a cartilage-specific EFNB2 knockout (EFNB2(Col2)KO) mouse model. METHODS: EFNB2(Col2)KO was generated with Col2a1-Cre transgenic mice. The skeletal development was evaluated using macroscopy, immunohistochemistry, histomorphometry, radiology, densitometry, and micro-computed tomography. Analyses were performed at P0 (birth) and on postnatal days P15, P21, and on 8-week- and 1-year-old mice. RESULTS: EFNB2(Col2)KO mice exhibited significant reduction in size, weight, length, and in long bones. At P0, the growth plates of EFNB2(Col2)KO mice displayed increased type X collagen, disorganized hyphertrophic zone, and decreased mineralization. At P15, mutant mice demonstrated a significant reduction in VEGF and TRAP at the chondro-osseous junction and a delay in the secondary ossification, including a decrease in bone volume and trabecular thickness. At P21 and 8 weeks old, EFNB2(Col2)KO mice exhibited reduced bone mineral density in the total skeleton, femur and spine. One-year-old EFNB2(Col2)KO mice demonstrated OA phenotypic features in both the knee and hip. By P15, 27 % of the EFNB2(Col2)KO mice developed a hip locomotor phenotype, which further experiments demonstrated reflected the neurological midline abnormality involving the corticospinal tract. CONCLUSION: This in vivo study demonstrated, for the first time, that EFNB2 is essential for normal long bone growth and development and its absence leads to a knee and hip OA phenotype in aged mice.

Two new 28-nor-oleanane-type triterpene saponins from roots of Camellia oleifera and their cytotoxic activity.

Two new 28-nor-oleanane-type triterpene saponins, oleiferoside U (1), and oleiferoside V (2) were isolated from the 50% EtOH extract of the roots of Camellia oleifera C. Abel. Their structures were elucidated as camellenodiol 3ß-O-ß-d-galactopyranosyl-(1→2)-ß-d-xylopyranosyl-(1→2)-[ß-d-galactopyranosyl-(1→3)]-ß-d-glucuronopyranoside and camellenodiol 3ß-O-ß-d-galactopyranosyl-(1→3)-ß-d-xylopyranosyl-(1→2)-[ß-d-galactopyranosyl-(1→3)]-ß-d-glucuronopyranoside. Their chemical structures were established mainly on the basis of integrated spectroscopic techniques. In vitro, cytotoxic activities of the two new triterpene saponins were evaluated against three human tumor cell lines (A549, SMMC-7721, and MCF-7) using the MTT assay. Both of them showed a certain cytotoxic activities toward the tested cell lines and gave IC50 values in the range of 45.04-63.22 µM.