A Carbon 21 Steroidal Glycoside with Pregnane Skeleton from Cynanchum atratum Bunge Promotes Megakaryocytic and Erythroid Differentiation in Erythroleukemia HEL Cells through Regulating Platelet-Derived Growth Factor Receptor Beta and JAK2/STAT3 Pathway.

Erythroleukemia is a rare form of acute myeloid leukemia (AML). Its molecular pathogenesis remains vague, and this disease has no specific therapeutic treatments. Previously, our group isolated a series of Carbon 21 (C-21) steroidal glycosides with pregnane skeleton from the root of Cynanchum atratum Bunge. Among them, we found that a compound, named BW18, can induce S-phase cell cycle arrest and apoptosis via the mitogen-activated protein kinase (MAPK) pathway in human chronic myeloid leukemia K562 cells. However, its anti-tumor activity against erythroleukemia remains largely unknown. In this study, we aimed to investigate the anti-erythroleukemia activity of BW18 and the underlying molecular mechanisms. Our results demonstrated that BW18 exhibited a good anti-erythroleukemia activity in the human erythroleukemia cell line HEL and an in vivo xenograft mouse model. In addition, BW18 induced cell cycle arrest at the G2/M phase and promoted megakaryocytic and erythroid differentiation in HEL cells. Furthermore, RNA sequencing (RNA-seq) and rescue assay demonstrated that overexpression of platelet-derived growth factor receptor beta (PDGFRB) reversed BW18-induced megakaryocytic differentiation in HEL cells, but not erythroid differentiation. In addition, the network pharmacology analysis, the molecular docking and cellular thermal shift assay (CETSA) revealed that BW18 could inactivate Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, which might mediate BW18-induced erythroid differentiation. Taken together, our findings elucidated a novel role of PDGFRB in regulating erythroleukemia differentiation and highlighted BW18 as an attractive lead compound for erythroleukemia treatment.

Three rare anti-inflammatory sesquiterpene lactones from Magnolia grandiflora.

Four new sesquiterpene lactones (SLs) (1-4), along with a biosynthetically related SL (5), have been isolated from the leaves of Magnolia grandiflora. Magrandate A (1) is notable as the first C18 homogemarane type SL, featuring a unique 1,7-dioxaspiro[4.4]nonan-6-one core. Compounds 2 and 3, representing the first instances of chlorine-substituted gemarane-type SL analogs in natural products, were also identified. The structures of these isolates were elucidated through a combination of spectroscopic data analysis, electronic circular dichroism calculations, and X-ray single-crystal diffraction analysis. All isolates demonstrated anti-inflammatory activity in lipopolysaccharide-stimulated RAW264.7 cells. Notably, 3-5 showed a significant inhibitory effect on nitric oxide production, with IC50 values ranging from 0.79 to 4.73 µmol·L-1. Additionally, 4 and 5 exhibited moderate cytotoxic activities against three cancer cell lines, with IC50 values between 3.09 and 11.23 µmol·L-1.

Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli-1.

Rocaglaol, embedding a cyclopenta[b]benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC50 values between 0.11 ± 0.07 and 0.88 ± 0.02 µM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC50 = 0.19 ± 0.01 µM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.

Bioassay-guided isolation of anti-leukemic steroids from Aglaia abbreviata by inducing apoptosis.

The strategy of bioactivity-guided isolation is widely used to obtain active compounds as quickly as possible. Thus, the inhibitory effects on human erythroleukemia cells (HEL) were applied to guide the isolation of the anti-leukemic compounds from Aglaia abbreviata. As a result, 19 compounds (16 steroids, two phenol derivatives, and a rare C12 chain nor-sesquiterpenoid), including 13 new compounds, were isolated and identified based on spectroscopic data analysis, single-crystal X-ray diffraction data, and electronic circular dichroism (ECD) calculations. Among them, 9 steroids exhibited good selective anti-leukemic activity against HEL and K562 (human chronic myeloid leukemia cells) cells with IC50 values between 2.29 ± 0.18 µM and 19.58 ± 0.13 µM. Notably, all the active compounds had relatively lower toxicity on the normal human liver cell line (HL-7702). Furthermore, five compounds (1, 4, 8, 10, and 19) displayed good anti-inflammatory effects, with IC50 values between 7.15 ± 0.16 and 27.1 ± 0.37 µM. An α,ß-unsaturated ketone or a 5,6Δ double bond was crucial for improving anti-leukemic effect from the structure-activity relationship analysis. The compound with the most potential, 14 was selected for the preliminary mechanistic study. Compound 14 can induce apoptosis and cause cell cycle arrest. The expression of the marker proteins, such as PARP and caspase 3, were notably effected by this compound, thus inducing apoptosis. In conclusion, our investigation implied that compound 14 may serve as a potential anti-leukemia agent.

UPLC-Q-Orbitrap-MS/MS-Guided Isolation of Bioactive Withanolides from the Fruits of Physalis angulata.

Physalis angulata Linn. is an exotic Amazonian fruit that is commonly recognized as wild tomato, winter cherry, and gooseberry. While its fruit is known to contain many nutrients, such as minerals, fibers, and vitamins, few papers have investigated withanolide derivatives from its fruits. UPLC-Q-Orbitrap-MS/MS, which produces fragmentation spectra, was applied for the first time to guide the isolation of bioactive withanolide derivatives from P. angulata fruits. As a result, twenty-six withanolide derivatives, including two novel 1,10-secowithanolides (1 and 2) and a new derivative (3), were obtained. Compounds 1 and 2 are rare rearranged 1,10-secowithanolides with a tetracyclic 7/6/6/5 ring system. All structures were assigned through various spectroscopic data and quantum chemical calculations. Nine withanolide derivatives exhibited significant inhibitory effects on three tumor cell lines with IC50 values of 0.51-13.79 µM. Moreover, three new compounds (1-3) exhibited potential nitric oxide inhibitory effects in lipopolysaccharide-stimulated RAW264.7 cells (IC50: 7.51-61.8 µM). This investigation indicated that fruits of P. angulata could be applied to treat and prevent cancer and inflammatory-related diseases due to their potent active withanolide derivatives.

Bioassay-guided isolation of α-Glucosidase inhibitory constituents from Hypericum sampsonii.

This study employed the α-glucosidase inhibitory activity model as an anti-diabetic assay and implemented a bioactivity-guided isolation strategy to identify novel natural compounds with potential therapeutic properties. Hypericum sampsoniiwas investigated, leading to the isolation of two highly modified seco-polycyclic polyprenylated acylphloroglucinols (PPAPs) (1 and 2), eight phenolic derivatives (3-10), and four terpene derivatives (11-14). The structures of compounds 1 and 2, featuring an unprecedented octahydro-2H-chromen-2-one ring system, were fully characterized using extensive spectroscopic data and quantum chemistry calculations. Six compounds (1, 5-7, 9, and 14) exhibited potential inhibitory effects against α-glucosidase, with IC50 values ranging from 0.050 ± 0.0016 to 366.70 ± 11.08 µg·mL-1. Notably, compound 5 (0.050 ± 0.0016 µg·mL-1) was identified as the most potential α-glucosidase inhibitor, with an inhibitory effect about 6900 times stronger than the positive control, acarbose (IC50 = 346.63 ± 15.65 µg·mL-1). A docking study was conducted to predict molecular interactions between two compounds (1 and 5) and α-glucosidase, and the hypothetical biosynthetic pathways of the two unprecedented seco-PPAPs were proposed.

Discovery of diverse sesquiterpenoids from Magnolia grandiflora with cytotoxic activities by inducing cell apoptosis.

Phytochemical study of Magnolia grandiflora led to the isolation of 39 sesquiterpenoids, including 15 new compounds (1-15). Compounds 1 and 2 are discovered to be the first 13-norgermacrane type sesquiterpenoids in natural products. Compound 15 is a rare 5,6-seco-guaiane type sesquiterpene and its possible biogenic precursor is presumed to be compound 20. Subsequent structural modification for compound 28 led to 21 derivatives, among which 15 derivatives were new compounds. All compounds were tested for the inhibitory effects on three tumor cell lines, and 17 compounds were active with the IC50 values ranging from 1.91 ± 0.39 µM to 12.29 ± 1.68 µM. The structure-activity relationships implied that an α, ß-unsaturated lactone group was an important active group for the cytotoxicity. Two most active compounds (19 and 29) with low toxicity on normal human liver cell line were selected for further mechanism study. Compound 29 could induce apoptosis on Colo320DM cells through influencing the key apoptotic related proteins, such as PARP, Cleaved PARP, cleaved Caspase-3, and pro-Caspase 3. In addition, compound 19 with the best cytotoxic activity on HEL cells also could induce the apoptosis in dose- and time-dependent manners. In summary, our investigation implied that compounds 19 and 29 are two new potential anti-cancer candidates for ongoing study in the future.

A Novel Derivative of Curcumol, HCL-23, Inhibits the Malignant Phenotype of Triple-Negative Breast Cancer and Induces Apoptosis and HO-1-Dependent Ferroptosis.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer. Curcumol, as a natural small molecule compound, has potential anti-breast cancer activity. In this study, we chemically synthesized a derivative of curcumol, named HCL-23, by structural modification and explored its effect on and underlying mechanism regarding TNBC progression. MTT and colony formation assays demonstrated that HCL-23 significantly inhibited TNBC cells proliferation. HCL-23 induced G2/M phase cell cycle arrest and repressed the capability of migration, invasion, and adhesion in MDA-MB-231 cells. RNA-seq results identified 990 differentially expressed genes including 366 upregulated and 624 downregulated genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that these differentially expressed genes were obviously enriched in adhesion, cell migration, apoptosis, and ferroptosis. Furthermore, HCL-23 induced apoptosis via the loss of mitochondrial membrane potential and the activation of the caspase family in TNBC cells. In addition, HCL-23 was verified to trigger ferroptosis through increasing cellular reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation levels. Mechanistically, HCL-23 markedly upregulated the expression of heme oxygenase 1 (HO-1), and the knockdown of HO-1 could attenuate ferroptosis induced by HCL-23. In animal experiments, we found that HCL-23 inhibited tumor growth and weight. Consistently, the upregulation of Cleaved Caspase-3, Cleaved PARP, and HO-1 expression was also observed in tumor tissues treated with HCL-23. In summary, the above results suggest that HCL-23 can promote cell death through activating caspases-mediated apoptosis and HO-1-dependent ferroptosis in TNBC. Therefore, our findings provide a new potential agent against TNBC.

Patients with advanced pancreatic and biliary cancer appear vulnerable to SARS-CoV-2 Omicron variant: An observational study during the COVID-19 outbreak in Shanghai.

Background: The COVID-19 pandemic has spread rapidly across the globe. Cancer patients have a higher risk of severe infections and associated mortality than the general population. However, the lethal effect of Omicron-variant affection on advanced pancreatic and biliary cancer patients is still not clear. Herein, we designed an observational study to shed light on the influence of the Omicron variant on this so-called "King of Cancer" and improve management of these patients with COVID-19 in the future. Methods: Omicron-infected patients with advanced pancreatic and biliary cancer were enrolled from 15 April to 31 May 2022. Four groups were set up in this study: Group 1, Omicron-infected cancer patients (N = 4); Group 2, non-infected cancer patients (N = 4); Group 3, infected non-cancer-afflicted subjects (N = 4); Group 4, non-infected non-cancer-afflicted subjects (N = 4). On Days 0, 7, and 14 after infection, the blood samples were collected dynamically from all subjects. The primary endpoints were disease severity and survival. Results: At the endpoint of this observational study, Patient Nos. 2, 3, and 4 died separately on Days 11, 25, and 13 after viral infection. All of them had advanced cancer, with a death rate of up to 75%. Group 1 presented an overall T-cell exhaustion status compared with other groups. Group 1 had obviously lower T-cell populations and higher B-cell percentages and CD4+T/CD8+T ratios (P <0.05). Time-course cytokine monitoring results showed that IL-1ß was significantly decreased in Group 1 (P <0.05) and generally kept at a low level without obvious fluctuation. IL-6 was markedly increased in infected cancer patients (P <0.01) but remained at a low level and had no apparent change during the whole infection process in non-cancer-afflicted subjects. Furthermore, several inflammatory parameter indexes indicated a tight association of Omicron infection with the disease course and prognosis of Omicron-infected cancer patients. Conclusions: Advanced pancreatic and biliary cancer patients with Omicron infection have severe symptoms and poor outcomes. More attention, protective measures, and routine healthcare services should be recommended to these vulnerable populations in clinical practice during the pandemic in the foreseeable future.

Potential roles and molecular mechanisms of bioactive ingredients in Curcumae Rhizoma against breast cancer.

BACKGROUND: Breast cancer is the most prevalent cancer worldwide, with high morbidity and mortality. Despite great advances in the therapeutic strategies, the survival rate in the past decades of patients with breast cancer remains unsatisfactory. Growing evidence has demonstrated that Curcumae Rhizoma, called Ezhu in Chinese, showed various pharmacological properties, including anti-bacterial, anti-oxidant, anti-inflammatory and anti-tumor activities. It has been widely used in Chinese medicine to treat many types of human cancer. PURPOSE: To comprehensively summarize and analyze the effects of active substances in Curcumae Rhizoma on breast cancer malignant phenotypes and the underlying mechanisms, as well as discuss its medicinal value and future perspectives. METHOD: We used "Curcumae Rhizoma" or the name of crude extracts and bioactive components in Curcumae Rhizoma in combination with "breast cancer" as key words. Studies focusing on their anti-breast cancer activities and mechanisms of action were extracted from Pubmed, Web of Science and CNKI databases up to October 2022. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guideline was followed. RESULTS: Crude extracts and 7 main bioactive phytochemicals (curcumol, ß-elemene, furanodiene, furanodienone, germacrone, curdione and curcumin) isolated from Curcumae Rhizoma have shown many anti-breast cancer pharmacological properties, including inhibiting cell proliferation, migration, invasion and stemness, reversing chemoresistance, and inducing cell apoptosis, cycle arrest and ferroptosis. The mechanisms of action were involved in regulating MAPK, PI3K/AKT and NF-κB signaling pathways. In vivo and clinical studies demonstrated that these compounds exhibited high anti-tumor efficacy and safety against breast cancer. CONCLUSION: These findings provide strong evidence that Curcumae Rhizoma acts as a rich source of phytochemicals and has robust anti-breast cancer properties.

Natural history of isolated abdominal aortic dissection: A prospective cohort study.

Objectives: Isolated abdominal aortic dissection (IAAD) is extremely rare, with its optimal treatment and intervention timing remaining poorly understood. We aimed to study the natural history of IAAD and facilitate better clinical decision. Methods: Consecutive patients admitted to our institution from January 2016 to April 2021 were enrolled and followed up prospectively. All-cause death was taken as the primary endpoint. Results: A total of 68 patients with IAAD were included. The mean age at presentation was 61.2 ± 14.8 (Range: 26.0, 93.0) years and 55 (80.9%) were male. A total of 38 (55.9%) patients were treated conservatively, 27 (39.7%) received endovascular aneurysm repair (EVAR), and 3 (4.4%) underwent open surgery. After a mean follow-up of 2.4 years (Range: 0.1, 5.5), 9 (13.2%) patients died, 8 of whom (21.0%) were treated conservatively and 1 EVAR (3.7%). Compared with EVAR/open surgery, patient treated conservatively had a much worse survival (p = 0.043). There was no significant difference between different IAAD aortic sizes regarding mortality (p = 0.220). Patients with completely thrombosed false lumen fared improved survival rate, followed by partial thrombosis and patency, respectively, although not significantly (p = 0.190). No significant difference was observed between male and female concerning survival rate (p = 0.970). Patients without symptoms had a significantly improved survival (p = 0.048). Conclusion: On the basis of patients' preference and surgeons' experience, a more aggressive treatment regimen for IAAD should be considered, with EVAR being the first choice, especially for those with persistent symptoms and patent false lumen, regardless of sex, age, or aortic size.

Safety and Efficacy of the Passeo-18 Lux Drug-Coated Balloon Catheter in Atherosclerotic Femoropopliteal Lesions: The Multicenter BIOLUX P-IV China Study.

BACKGROUND: The purpose of this trial was to assess the safety and effectiveness of a paclitaxel-coated balloon catheter in Chinese patients with de novo or nonstented restenotic femoropopliteal atherosclerotic lesions. METHODS: BIOLUX P-IV China is a prospective, independently adjudicated, multicenter, single-arm trial conducted in China. Patients with Rutherford class 2-4 were eligible, excluded were patients in which predilation resulted in severe (≥ grade D) flow-limiting dissection or residual stenosis > 70%. Follow-up assessments were conducted at 1, 6, and 12 months. The primary safety end point was 30-day major adverse event rate and the primary effectiveness end point was primary patency at 12 months. RESULTS: We enrolled 158 patients with 158 lesions. Mean age was 67.6 ± 9.6 years, diabetes was present in 53.8% (n = 85), and previous peripheral intervention/surgeries in 17.1% (n = 27). Lesions were 4.1 ± 0.9 mm in diameter and 74 ± 50 mm long with a mean diameter stenosis of 91 ± 13%; 58.2% (n = 92) were occluded (core laboratory analysis). Device success was achieved in all patients. The rate of major adverse events was 0.6% (95% confidence interval: 0.0; 3.5) at 30 days, consisting of 1 target lesion revascularization. At 12 months, binary restenosis was present in 18.7% (n = 26) and target lesion revascularization was performed in 1.4% (n = 2, all clinically driven), resulting in a primary patency of 80.0% (95% confidence interval: 72.4, 85.8); no major target limb amputation occurred. Clinical improvement at 12 months, defined as improvement of at least 1 Rutherford class, was 95.3% (n = 130). The median walking distance per 6-minute walk test was 279 m at baseline and improved by 50 m at 30 days and by 60 m at 12 months; the visual analogue scale changed from 76.6 ± 15.6 at baseline to 80.0 ± 15.0 at 30 days and 78.6 ± 14.6 at 12 months. CONCLUSIONS: Our results confirmed the clinical effectiveness and safety of a paclitaxel-coated peripheral balloon dilatation catheter for the treatment of de novo and nonstented restenotic lesion of the superficial femoral and proximal popliteal artery in Chinese patients (NCT02912715).

Hyperpatone A, a polycyclic polyprenylated acylphloroglucinol with a rare 8/6/5/6/5 pentacyclic skeleton from Hypericum patulum.

Hyperpatone A (1), a highly oxidated polycyclic polyprenylated acylphloroglucinol (PPAP), along with a biosynthesized related PPAP (2) was isolated from Hypericum patulum under the guidance of LC-MS investigation. Architecturally, compound 1 represents the first PPAP with an unprecedented 8/6/5/6/5 pentacyclic skeleton and an intramolecular peroxy bridge, which might be derived from the [3.3.1]-type bicyclic polyprenylated acylphloroglucinol via the critical Baeyer-Villiger oxidation, decarboxylation, and intramolecular cyclization. The structures were established by extensive spectroscopic analysis, ACD software calculation, and quantum chemical computations. A plausible biogenetic pathway of 1 and 2 was also proposed. Importantly, both compounds exhibited moderate cytotoxic activities against the HEL cell line with the IC50 values ranging from 10.2 to 19.2 µM. Moreover, compound 1 showed an inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells at a lower concentration of 5 or 1 µM.

Early and midterm results of valve-sparing aortic root reconstruction with a bovine pericardium patch for patients with acute type a aortic dissection.

Objectives: We evaluated the feasibility, effectiveness, and safety of valve-sparing aortic root reconstruction with a bovine pericardium patch for patients with acute type A aortic dissection (ATAAD). Methods: From January 2016 to January 2021, 895 consecutive patients with ATAAD received surgical treatment at our hospital. After applying our exclusion criteria, 508 patients were included in this research. Based on the attending surgeon's judgment and preference, 192 patients underwent our novel surgical novel surgical technique of valve-sparing aortic root reconstruction (repair group [RG]) and 316 patients underwent the Bentall procedure (Bentall group [BG]). Results: In the RG, the early mortality rate was 4.2% (8/192). In the BG, the early mortality rate was 5.1% (16/316). There were no significant differences between groups. The incidence of postoperative renal failure in the BG was significantly higher than that in the RG. The mean follow-up time was 2.93 years (standard deviation, ±1.38 years). There were no significant differences between groups regarding ATAAD-related mortality and reoperation. In the RG, the rate of freedom from aortic root reoperation at 5 years was 98.2%, and the grade of aortic regurgitation 6 months later was significant less than that before surgery, and it did not worsen during later follow-up. Conclusions: Valve-sparing aortic root reconstruction with a bovine pericardium patch can be successfully performed for selected patients with ATAAD and is associated with low in-hospital and late mortality rates and low root reoperation rates during early and midterm follow-up.

Garmultin-A Incites Apoptosis in CB3 Cells Through miR-17-5p by Attenuating Poly (ADP-Ribose) Polymerase-1.

Background: Leukemia accounts for a large number of deaths, worldwide, every year. Treating this ailment is always a challenging job. Recently, oncogenic miRNA leading to apoptosis are highly promising targets of many natural products. In this study, Garmultin-A (GA), isolated from the bark of Garcinia multiflora, was elucidated for its anti-leukemic effect in CB3 cells. Methods: The effect of the compound on CB3 cell viability was detected by MTT assay and apoptosis by FITC Annexin V/PI and Hochest 33258 staining. The western blot analysis assessed the BAX, BCL2, cMYC, pERK, and PARP-1 protein levels. Autodock analysis predicted the ligand-protein interactions. q-RT-PCR quantified the miR-17-5p expression. Luciferase assay confirmed the interaction between PARP-1 and miR-17-5p. Results: We uncover that GA leads to apoptosis by inducing overexpression of miR-17-5p and significantly downregulate PARP-1 protein levels in CB3 cells. The overexpression of miR-17-5p promotes apoptosis, and the miR-17-5p antagomirs restore GA-triggered apoptosis. Notably, we disclose that PARP-1 is a direct target of miR-17-5p. Increased pro-apoptotic and reduced anti-apoptosis protein levels were also observed in GA-treated CB3 cells. Conclusion: These results provide critical insights that GA could induce apoptosis in CB3 cells through targeting miR-17-5p by attenuating PARP-1. Thus, GA could act as a novel therapeutic agent for erythroleukemia.

Surgical treatment strategies for patients with type A aortic dissection involving arch anomalies.

Objective: The aim of the study was to investigate surgical modalities and outcomes in patients with type A aortic dissection involving arch anomalies. Method: Patients with type A aortic dissection who underwent surgical treatment at our center between January 2017 and 31 December 2020 were selected for this retrospective analysis. Data including computed tomography (CT), surgical records, and cardiopulmonary bypass records were analyzed. Perioperatively survived patients were followed up, and long-term mortality and aortic re-interventions were recorded. Result: A total of 81 patients with arch anomalies were included, 35 with "bovine" anomalies, 23 with an aberrant right subclavian artery, 22 with an isolated left vertebral artery, and one with a right-sided arch + aberrant left subclavian artery. The strategies of arch management and cannulation differed according to the anatomic variation of the aortic arch. In total, seven patients (9%) died after surgery. Patients with "bovine" anomalies had a higher perioperative mortality rate (14%) and incidence of neurological complications (16%). Overall, four patients died during the follow-up period, with a 6-year survival rate of 94.6% (70/74). A total of four patients underwent aortic re-intervention during the follow-up period; before the re-intervention, three received the en bloc technique (13.6% 3/22) and one received hybrid therapy (11.1% 1/9). Conclusion: With complete preservation and reconstruction of the supra-arch vessels, patients with type A aortic dissection combining arch anomalies can achieve a favorable perioperative prognostic outcome. Patients who received the en bloc technique are more likely to require aortic re-intervention than patients who underwent total arch replacement with a four-branched graft vessel. Cannulation strategies should be tailored according to the variation of anatomy, but routine cannulation with the right axillary artery can still be performed in most patients with arch anomalies, even for patients with an aberrant right subclavian artery.

Isolation and synthesis of rocaglaol derivatives by inhibiting Wnt/ß-catenin and MAPK signaling pathways against colorectal cancer.

Eight rocaglaol derivatives with good cytotoxic activity (IC50: 0.013 âˆ¼ 5.82 µM) were isolated from Aglaia odorata. Then, a series of novel derivatives with modifications on C3 of rocaglaol were designed, synthesized, and screened for their antitumor activities against three tumor cell lines (HEL, MDA-MB-231, and HCT116). A total of 44 derivatives exhibited significant cytotoxic activity with IC50 values lower than 1 µM. In particular, four derivatives (14, 20, 22j, and 22r) exhibited the best cytotoxic activity against HCT116 cells, with an IC50 value of 70 nM. Compound 22r with relatively low toxicity against normal cells and the best cytotoxic activity against HCT116 cells was selected for further study. Subsequent cellular mechanism studies showed that compound 22r induced apoptosis and G1 cell cycle arrest in HCT116 cells. Moreover, compound 22r inhibited both the Wnt/ß-catenin and MAPK signaling pathways via key proteins, such as the phosphorylation of p38 and JNK, GSK-3ß, Axin-2, etc. Therefore, our present results suggest that compound 22r is a potential candidate for developing novel anti-colorectal cancer agents in the future.

Maillard Reaction Products with Anti-Tobacco Mosaic Virus Activities Generated in Processed Thermopsis lanceolata R. Br. Seed Extract.

Six novel Maillard reaction products (MRPs) (1-6) were isolated from the processed Thermopsis lanceolata R. Br. seed extract, along with one biogenetically related intermediate (7). Compounds 1-4 possessed three rare dimerization patterns constructed by cytisine, whereas compounds 5 and 6 represented the first example of the addition products of cytisine and 5,6-dihydroxy-4-hexanolide. Their structures were elucidated by comprehensive spectroscopic data analysis and quantum chemistry calculations including GIAO 13C{1H} NMR and ECD calculation, combined with single-crystal X-ray diffraction analysis. Biologically, compound 3 displayed significant anti-tobacco mosaic virus activity compared with the positive control ningnanmycin.

Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin'gan Capsules against Breast Cancer.

In the theory of traditional Chinese medicine (TCM), "liver-qi" stagnation and heat-induced toxicity represent the main etiologies of breast cancer. Recently, several TCMs with heat-clearing and detoxification efficacy have shown inhibitory effects on breast cancer. Jin'gan capsules (JGCs), initially approved to treat colds in China, are a heat-clearing and detoxification TCM formula. However, the anticancer activity of JGCs against breast cancer and its underlying mechanisms remain unclear. First, we assessed the antiproliferative activity of JGCs in breast cancer cell lines and evaluated their effects on cell apoptosis and the cell cycle by flow cytometry. Furthermore, we identified the potential bioactive components of JGCs and their corresponding target genes and constructed a bioactive compound-target interaction network by ultra-performance liquid chromatography-high-resolution tandem mass spectrometry (UPLC-HR-MS/MS) and network pharmacology analysis. Finally, the underlying mechanism was investigated through gene function enrichment analysis and experimental validation. We found that JGCs significantly inhibited breast cancer cell growth with IC50 values of 0.56 ± 0.03, 0.16 ± 0.03, and 0.94 ± 0.09 mg/mL for MDA-MB-231, MDA-MB-468, and MCF-7, respectively. In addition, JGC treatment dramatically induced apoptosis and S phase cell cycle arrest in breast cancer cells. Western blot analysis confirmed that JGCs could regulate the protein levels of apoptosis- and cell cycle-related genes. Utilizing UPLC-HR-MS/MS analysis and network pharmacology, we identified 7 potential bioactive ingredients in JGCs and 116 antibreast cancer targets. Functional enrichment analysis indicated that the antitumor effects of JGCs were strongly associated with apoptosis and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Western blot analysis validated that JGC treatment markedly decreased the expression levels of p-JAK2, p-STAT3, and STAT3. Our findings suggest that JGCs suppress breast cancer cell proliferation and induce cell cycle arrest and apoptosis partly by inhibiting the JAK2/STAT3 signaling pathway, highlighting JGCs as a potential therapeutic candidate against breast cancer.

Hypersampones A-C, Three Nor-Polycyclic Polyprenylated Acylphloroglucinols with Lipid-Lowering Activity from Hypericum sampsonii.

Hypersampones A-C (1-3), three unprecedented nor-polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum sampsonii. These compounds represent the first nor-PPAPs with an unexpected tetracyclic 6/5/5/6 ring system. Their structures were assigned through the analysis of detailed spectroscopic data, X-ray crystallography, and electronic circular dichroism calculations. Compound 1 significantly inhibited the accumulation of lipid in an oleic acid-treated HepG2 cell model by suppressing the protein expression of FAS and ACACA at 5 µM.