Isolation and Anticancer Progression Evaluation of the Chemical Constituents from Bridelia balansae Tutcher.

The dichloromethane extract of the roots of Bridelia balansae Tutcher (Phyllanthaceae) was found to show potential anticancer activity against HCT116 colorectal cancer cell. Our bioassay-guided phytochemical investigation of the roots of B. balansae led to the identification of 14 compounds including seven lignans (1-7), three phenylbenzene derivatives (8-10), two flavanone (11-12), and two triterpenoids (13-14). Among them, 4'-demethyl-4-deoxypodophyllotoxin (1) is the first aryltetralin lignan compound identified from this plant species. In addition, the stereochemistry of 1 was validated by X-ray crystallography for the first time, and its distinguished cytotoxic effect on HCT116 cells with an IC50 value at 20 nM was induced via an apoptosis induction mechanism. Compound 1 could also significantly decrease the migration rate of HCT116 cells, indicating its potential application against cancer metastasis. The western blot analysis showed that 1 has the potential to inhibit cell proliferation and metastasis. Treatment of 1 resulted in the downregulation of matrix metalloproteinases 2 (MMP2) and p-Akt, while p21 was upregulated. Collectively, the present study on the phytochemical and biological profile of B. balansae has determined the plant as a useful source to produce promising anticancer lead compounds.

Comparing the clinical outcomes of single vs. systematic dual stenting strategies for unprotected left main bifurcation lesion: a systematic review and meta-analysis.

Introduction: The optimal percutaneous coronary intervention (PCI) strategy for coronary left main (LM) bifurcation lesions remains controversial. This meta-analysis compared the medium and long-term follow-up clinical outcomes of single vs. systematic dual stenting strategies of LM bifurcation lesions. Methods: We systematically identified studies published within 5 years comparing single vs. systematic double stenting strategies for LM bifurcation lesions. The primary endpoint was medium-term (1 year) and long-term (at least 3 years) all-cause death. Secondary outcomes included major adverse cardiovascular events (MACEs), target lesion revascularization (TLR), overall occurrence of stent thrombosis (ST), cardiovascular (CV) mortality, and myocardial infarction (MI). Results: Two randomized controlled trials and nine observational studies with 7,318 patients were included in this meta-analysis. In terms of the medium-term follow-up clinical outcomes, our pooled analysis showed that use of the systematic dual stenting strategy was associated with a lower ST risk (odds ratio [OR] = 0.43, 95% confidence interval [CI]: 0.20-0.89, P = 0.02) and cardiac death risk (OR = 0.43, 95% CI: 0.21-0.89, P = 0.02) compared to the single stenting strategy; there was no significant difference between the two strategies regarding rates of all-cause death, MACE, TLR, and MI. Patients with long-term follow-up showed comparable observed clinical outcomes between the two strategies. Most importantly, for patients with true LM bifurcation, the risk of all-cause death, ST, and CV mortality following the systematic dual stenting strategy was significantly lower than the single stenting strategy. Conclusions: For patients with LM bifurcation lesions, both the systematic dual stenting strategy and single stenting strategy demonstrated comparable results in terms of all-cause mortality during medium-term and long-term follow-up. However, the systematic dual stenting strategy showed a tendency towards lower incidence of ST and CV mortality compared to the single stenting strategy during medium-term follow-up. Consequently, the systematic dual stenting strategy yielded superior clinical outcomes for patients with LM bifurcation lesions.

Copper/TEMPO-Promoted Denitrogenation/Oxidation Reaction for Synthesis of Primary α-Ketoamides Using α-Azido Ketones.

A copper(II)-promoted denitrogenation/oxidation reaction for the preparation of primary α-ketoamides was developed using α-azido ketones as a substrate and TEMPO as an oxidant. α-Azido ketones were denitrogenated in situ to form an imino ketone intermediate, which underwent a radical addition process and radical migration to form α-ketoamides. It is worth noting that the imino ketone intermediate is the key to this reaction.

Bioactive isopimarane and 3,4-seco isopimarane diterpenoids from Isodon amethystoides.

Isodon amethystoides (Lamiaceae) is a popular plant in folk medicine in the southern provinces of China. Our phytochemical investigation of the twigs and leaves of this plant led to the discovery of five new diterpenoids with isopimarane and 3,4-seco isopimarane scaffolds [isoamethinols A-E (1-5)], along with the known compound 3,4-seco isopimara-4(18),7,15-triene-3-oic acid methylester (6). The chemical structures of these compounds, including the absolute configurations of the new diterpenoids, were determined by comprehensive spectroscopic analyses and single crystal X-ray diffraction measurements. These compounds were evaluated for their biological activities against a panel of human cancer cell lines, gram-positive bacterial strains and HIV. Notably, the 3,4-seco-isopimarane isoamethinol D (4) showed toxicity to the cervical Hela cancer (Hela) cells with an IC50 value of 27.21 µM and the lung (A549) cancer cells with an IC50 value of 21.47 µM. Compound 4 also exhibited mild antimicrobial activity against the oral bacterial strain Streptococcus mutans. These findings suggested that the diterpenoids with a 3,4-seco-isopimarane diterpenoids isolated from I. amethystoides could provide a novel structure scaffold for the discovery of anticancer and antimicrobial compounds.

Association of renin-angiotensin system inhibitors use with short- and long-term mortality in patients with aortic stenosis: A systematic review and meta-analysis.

Purpose: The present study aimed to investigate the association of renin-angiotensin system inhibitors (RASi) with short- and long-term mortality in patients with aortic stenosis (AS). Methods: A systematic search was performed in PubMed, Embase, and Cochrane library databases for relevant studies published before March 2022. Studies meeting the inclusion criteria were included to assess the effect of RASi on short-term (≤30 days) and long-term (≥1 year) mortality in patients with AS. Results: A total of 11 studies were included in the meta-analysis. Our results demonstrated that RASi reduced short-term mortality (OR = 0.76, 95% CI 0.63-0.93, p = 0.008) after aortic valve replacement (AVR). Subgroup analysis revealed that RASi was still associated with lower short-term mortality after transcatheter aortic valve replacement (TAVR); however, the association was relatively weak in patients who underwent surgical aortic valve replacement (SAVR). For long-term mortality, the pooled OR was 1.04 (95% CI 0.88-1.24, p = 0.63) after sensitivity analysis in patients who did not undergo AVR. In addition, our study confirmed that RASi significantly reduced long-term mortality (OR = 0.57, 95% CI 0.44-0.74, p < 0.0001) in patients who underwent AVR. Subgroup analysis showed that both TAVR and SAVR groups treated with RASi had lower long-term mortality. Conclusion: Renin-angiotensin system inhibitors did not change long-term mortality in AS patients who did not undergo AVR. However, RASi reduced short- and long-term mortality in patients who underwent AVR.

Efficacy and Safety of Non-recommended Dose of New Oral Anticoagulants in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Introduction: The real-world treatment of atrial fibrillation (AF) often involves the prescription of new oral anticoagulants (NOACs) using dosing both lower and higher than recommended guidelines. Our study aimed to evaluate the efficacy and safety of non-recommended dosage of NOACs in AF patients. Methods: A systematic search was performed for relevant studies across multiple electronic databases (PubMed, Embase, Cochrane Library, Clinical Trials Registry) from inception to May 1, 2021. Multicenter randomized trials and observational studies were selected with key reporting measures for inclusion involved efficacy outcomes including stroke or systemic thromboembolism along with safety endpoints assessing major or clinically relevant bleeding events. Results: A total of 11 eligible studies were included involving 48,648 patients receiving recommended dose of NOACs and 50,116 patients receiving non-recommended dosage. Compared to AF patients treated with recommended dose regimens, administration of low dose of NOACs was associated with higher risk of stroke/systemic embolism (RR = 1.24, 95% CI 1.14-1.35, P < 0.00001), but without reducing bleeding risk (RR = 1.18, 95% CI 0.91-1.53, P = 0.21) and a higher risk of all-cause mortality (RR = 1.58, 95% CI 1.25-1.99, P = 0.0001). Moreover, high dose of NOACs was associated with higher risk of stroke and systemic embolism efficacy (RR = 1.71, 95% CI 1.06-2.76, P = 0.03) and a non-significant trend to a greater risk of major or clinically relevant bleeding (RR = 1.57, 95% CI 0.96-2.58, P = 0.07). Conclusions: AF patients treated with low dose of NOACs showed equivalent safety but with worse efficacy compared with recommended dose. High dose of NOACs was not superior to recommended dose regimens in preventing stroke/systemic embolism outcomes in AF patients.

Efficacy based ginger fingerprinting reveals potential antiproliferative analytes for triple negative breast cancer.

Ginger (Zingiber officinale) is one of the most widely consumed dietary supplements worldwide. Its anticancer potential has been demonstrated in various studies. However, ginger roots obtained from different geographical locations showed extensive variability in their activities, mainly due to differences in the levels of bioactive compounds. Here we evaluated the effect of these differences on the anticancer activity of ginger by performing efficacy-based fingerprinting. We characterized the fingerprint profiles of 22 ginger samples using liquid chromatography-mass spectroscopy, followed by a principal component analysis (PCA) and pearson correlation analysis. We also evaluated the anti-proliferative effects (IC50) of these samples on triple-negative breast cancer cells using the MTT assays. The supervised PCA identified a subset of analytes whose abundance strongly associated with the IC50 values of the ginger extracts, providing a link between ginger extract composition and in vitro anticancer efficacy. This study demonstrated that variation in the ginger fingerprint profiles resulting from differences in their chemical composition could have a significant impact on efficacy and bioactivity of ginger extracts. Also, this first-of-a-kind efficacy-based fingerprinting approach proposed here can identify potent anticancer candidates from the ginger fingerprint without the need for isolating individual components from the extracts.

IRF9 Affects the TNF-Induced Phenotype of Rheumatoid-Arthritis Fibroblast-Like Synoviocytes via Regulation of the SIRT-1/NF-κB Signaling Pathway.

OBJECTIVE: To discuss how IRF9 affects the fibroblast-like synoviocytes (FLS) in TNF-induced rheumatoid arthritis (RA) via the SIRT-1/NF-κB signaling pathway. METHODS: RA-FLS were isolated and divided into control, sh-IRF9, TNF, TNF + sh-Ctrl, TNF + sh-IRF9, TNF + sh-SIRT1, and TNF + sh-IRF9 + sh-SIRT1 groups. Biological features of FLS were evaluated by MTT, wound healing, and Transwell assays, respectively. Cell apoptosis and cycle were assessed flow cytometrically. Inflammatory cytokines were determined through enzyme-linked immunosorbent assay (ELISA), while IRF9 expression and SIRT1/NF-κB signaling pathway activity were measured by Western blotting. RESULTS: TNF increased IRF9 expression as well as NF-κB signaling activity and down-regulated SIRT1 of RA-FLS. Silencing IRF9 resulted in up-regulation of SIRT1 and blocked NF-κB signaling, with significant decreases in TNF-induced cell viability, migration, and invasion, prominent enhancement in apoptosis and the proportion of cells in G0/G1 phase, but a decrease in the proportion of cells in S and G2/M phases, and reduced levels of inflammatory cytokines. However, these changes were totally abolished after silencing SIRT1, i.e., the IRF9 shRNA-induced inhibitory effect on the growth of RA-FLS was reversed. CONCLUSION: Silencing IRF9 curbs the activity of the NF-κB signaling pathway via up-regulating SIRT-1, to further suppress TNF-induced changes in the malignant features of RA-FLS, and the secretion of inflammatory cytokines, with the promoted apoptosis.

Inhibition of STAT3 signalling contributes to the antimelanoma action of atractylenolide II.

Our previous studies showed that atractylenolide II (AT-II) has antimelanoma effects in B16 melanoma cells. In this study, we investigated the involvement of STAT3 signalling in the antimelanoma action of AT-II. Daily administration of AT-II (12.5, 25 mg/kg, i.g.) for 14 days significantly inhibited tumor growth in a B16 xenograft mouse model and inhibited the activation/phosphorylation of STAT3 and Src in the xenografts. In B16 and A375 cells, AT-II (20, 40 µm) treatment for 48 h dose-dependently reduced protein expression levels of phospho-STAT3, phospho-Src, as well as STAT3-regulated Mcl-1 and Bcl-xL. Overexpression of a constitutively active variant of STAT3, STAT3C in A375 cells diminished the antiproliferative and apoptotic effects of AT-II. These data suggest that inhibition of STAT3 signalling contributes to the antimelanoma action of AT-II. Our findings shed new light on the mechanism of action underlying the antimelanoma effects of AT-II and provide further pharmacological basis for developing AT-II as a novel melanoma chemopreventive/chemotherapeutic agent.

Enhanced polyhydroxybutyrate production in transgenic sugarcane.

Polyhydroxybutyrate (PHB) is a bacterial polyester that has properties similar to some petrochemically produced plastics. Plant-based production has the potential to make this biorenewable plastic highly competitive with petrochemical-based plastics. We previously reported that transgenic sugarcane produced PHB at levels as high as 1.8% leaf dry weight without penalty to biomass accumulation, suggesting scope for improving PHB production in this species. In this study, we used different plant and viral promoters, in combination with multigene or single-gene constructs to increase PHB levels. Promoters tested included the maize and rice polyubiquitin promoters, the maize chlorophyll A/B-binding protein promoter and a Cavendish banana streak badnavirus promoter. At the seedling stage, the highest levels of polymer were produced in sugarcane plants when the Cavendish banana streak badnavirus promoter was used. However, in all cases, this promoter underwent silencing as the plants matured. The rice Ubi promoter enabled the production of PHB at levels similar to the maize Ubi promoter. The maize chlorophyll A/B-binding protein promoter enabled the production of PHB to levels as high as 4.8% of the leaf dry weight, which is approximately 2.5 times higher than previously reported levels in sugarcane. This is the first time that this promoter has been tested in sugarcane. The highest PHB-producing lines showed phenotypic differences to the wild-type parent, including reduced biomass and slight chlorosis.