Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. METHODS: Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. RESULTS: Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model). CONCLUSIONS: This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

Ultrasound-guided microwave ablation versus surgery for solitary T1bN0M0 papillary thyroid carcinoma: a prospective multicenter study.

OBJECTIVE: Microwave ablation (MWA) has emerged as a minimally invasive technology for papillary thyroid microcarcinoma (PTMC), but it has not been widely applied to treat T1bN0M0 PTC with high-level evidence. This study was designed to compare the real-world efficacy and safety of MWA or surgery for treating T1bN0M0 PTC. METHODS: From December 2019 to April 2021, 123 continuous unifocal T1bN0M0 PTC patients without lymph node metastasis (LNM) or distant metastasis (DM) were included from 10 hospitals. Patients were allocated into the MWA or surgery group based on their willingness. The main outcomes were local tumour progression (LTP), new thyroid cancer, LNM, and DM. The secondary outcomes included changes in tumour size and volume, complications, and cosmetic results. Subgroup analyses were conducted to identify influencing factors. RESULTS: Fifty-two patients chose MWA, and 71 patients chose surgery. Patients had similar demographic information and tumour characteristics in the two groups. The follow-up durations after MWA and surgery were 10.6 ± 4.2 and 10.4 ± 3.4 months, respectively. The LNM rate was 5.8% in the MWA group and 1.4% in the surgery group (p = 0.177). No LTP, new thyroid cancer, or distant metastasis (DM) occurred in either group. Five (9.6%) of the 52 patients in the MWA group and 8 (11.3%) of the 71 patients in the surgery group had complications (p = 0.27). Better cosmetic results were found in the MWA group (p < 0.01). CONCLUSION: MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. CLINICAL RELEVANCE STATEMENT: MWA achieved comparable short-time treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC. KEY POINTS: • MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. • The complication rate in the surgery group was higher than that in the MWA group without a significant difference. • There was no statistically significant difference in the LNM rate between the MWA and surgery groups.

circZNF532 promotes endothelial-to-mesenchymal transition in diabetic retinopathy by recruiting TAF15 to stabilize PIK3CD.

Endothelial-to-mesenchymal transition (EndMT) is a pivotal event in diabetic retinopathy (DR). This study explored the role of circRNA zinc finger protein 532 (circZNF532) in regulating EndMT in DR progression. Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) to induce the DR cell model. Actinomycin D-treated HRMECs were used to confirm the mRNA stability of phosphoinositide-3 kinase catalytic subunit δ (PIK3CD). The interaction between TATA-box-binding protein-associated factor 15 (TAF15) and circZNF532/PIK3CD was subsequently analyzed using RNA immunoprecipitation (RIP), RNA pull-down. It was found that HG treatment accelerated EndMT process, facilitated cell migration and angiogenesis, and enhanced PIK3CD and p-AKT levels in HRMECs, whereas si-circZNF532 transfection neutralized these effects. Further data showed that circZNF532 recruited TAF15 to stabilize PIK3CD, thus elevating PIK3CD expression. Following rescue experiments suggested that PIK3CD overexpression partially negated the inhibitory effect of circZNF532 silencing on EndMT, migration, and angiogenesis of HG-treated HRMECs. In conclusion, our results suggest that circZNF532 recruits TAF15 to stabilize PIK3CD, thereby facilitating EndMT in DR.

Dihydrophenanthro[b]furan derivatives from the tubers of Bletilla striata.

Two pairs of new dihydrophenanthro[b]furan enantiomers blephebibnols G-H (1-2), one new dihydrophenanthro[b]furan derivative blephebibnol I (3), along with four known analogues (4-7), were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined by the combination of spectroscopic data analysis, ECD and NMR calculations. Compounds 1a, 1b, and 2b showed inhibition of NO production in LPS-stimulated BV-2 cells, with IC50 values ranging from 4.11 to 14.65 µM. Further mechanistic study revealed that 1a suppressed the phosphorylation of p65 subunit to regulate the NF-κB signaling pathway. In addition, some compounds displayed selective cytotoxic activities against HCT-116, HepG2, A549, or HGC27 cancer cell lines with IC50 values ranging from 0.1 to 8.23 µM.

Observation of Robust and Long-Ranged Superperiodicity of Electronic Density Induced by Intervalley Scattering in Graphene/Transition Metal Dichalcogenide Heterostructures.

Two-dimensional (2D) h-BN and transition metal dichalcogenides (TMDs) are widely used as substrates of graphene because they are insulating, atomically flat, and without dangling bonds. Usually, it is believed that such insulating substrates will not affect the electronic properties of graphene, especially when the moiré pattern generated between them is quite small. Here, we present a systematic study of the electronic properties of graphene/TMD heterostructures with the period of the moiré pattern <1 nm, and our results reveal an unexpected sensitivity of electronic properties in graphene to the 2D insulating substrates. We demonstrate that there is a robust and long-ranged superperiodicity of electronic density in graphene, which arises from the scattering of electrons between the two valleys of graphene in the graphene/TMD heterostructures. By using scanning tunneling microscope and spectroscopy, three distinct atomic-scale patterns of the electronic density are directly imaged in every graphene/TMD heterostructure.

Single-cell RNA sequencing to identify cellular heterogeneity and targets in cardiovascular diseases: from bench to bedside.

The mechanisms of cardiovascular diseases (CVDs) remain incompletely elucidated. Single-cell RNA sequencing (scRNA-seq) has enabled the profiling of single-cell transcriptomes at unprecedented resolution and throughput, which is critical for deciphering cardiovascular cellular heterogeneity and underlying disease mechanisms, thereby facilitating the development of therapeutic strategies. In this review, we summarize cellular heterogeneity in cardiovascular homeostasis and diseases as well as the discovery of potential disease targets based on scRNA-seq, and yield new insights into the promise of scRNA-seq technology in precision medicine and clinical application.

Up-regulation of miR-192-5p inhibits the ELAVL1/PI3Kδ axis and attenuates microvascular endothelial cell proliferation, migration and angiogenesis in diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes mellitus that poses a threat to adults. MicroRNAs (miRNAs) play a key role in DR progression. However, the role and mechanism of miR-192-5p in DR remain unclear. We aimed to investigate the effect of miR-192-5p on cell proliferation, migration and angiogenesis in DR. METHODS: Expression of miR-192-5p, ELAV-like RNA binding protein 1 (ELAVL1) and phosphoinositide 3-kinase delta (PI3Kδ) in human retinal fibrovascular membrane (FVM) samples and human retinal microvascular endothelial cells (HRMECs) was assessed using RT-qPCR. ELAVL1 and PI3Kδ protein levels were evaluated by Western blot. RIP and dual luciferase reporter assays were performed to confirm the miR-192-5p/ELAVL1/PI3Kδ regulatory networks. Cell proliferation, migration and angiogenesis were assessed by CCK8, transwell and tube formation assays. RESULTS: MiR-192-5p was decreased in FVM samples from DR patients and high glucose (HG)-treated HRMECs. Functionally, overexpressed miR-192-5p inhibited cell proliferation, migration and angiogenesis in HG-treated HRMECs. Mechanically, miR-192-5p directly targeted ELAVL1 and decreased its expression. We further verified that ELAVL1 bound to PI3Kδ and maintained PI3Kδ mRNA stability. Rescue analysis demonstrated that the suppressive effects of HG-treated HRMECs caused by miR-192-5p up-regulation were overturned by overexpressed ELAVL1 or PI3Kδ. CONCLUSION: MiR-192-5p attenuates DR progression by targeting ELAVL1 and reducing PI3Kδ expression, suggesting a biomarker for the treatment of DR.

USP14 Regulates ATF2/PIK3CD Axis to Promote Microvascular Endothelial Cell Proliferation, Migration, and Angiogenesis in Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of blindness in diabetic patients. However, the pathogenesis of DR is complex, and no firm conclusions have been drawn so far. It has become a hot spot in ophthalmology research to deeply study the mechanism of DR pathological changes and find effective treatment options. Human retinal microvascular endothelial cells (HRMECs) were induced by high glucose (HG) to construct DR cell model. CCK-8 assay was used to detect the viability of HRMECs. Transwell assay was used to detect the migration ability of HRMECs. Tube formation assay was used to identify the tube formation ability of HRMECs. The expressions of USP14, ATF2 and PIK3CD were detected by Western blot analysis and qRT-PCR assay. Immunoprecipitation (IP) was used to ascertain the relationship of USP14 and ATF2. To explore the regulatory relationship between ATF2 and PIK3CD by dual-luciferase reporter gene assay and Chromatin immunoprecipitation (ChIP) assay. High glucose treatment promoted the proliferation, migration, and tube formation of HRMEC, and the expressions of USP14, ATF2 and PIK3CD were significantly up-regulated. USP14 or ATF2 knockdown inhibited HG-induced HRMECs proliferation, migration, and tube formation. USP14 regulated the expression of ATF2, and ATF2 promoted PIK3CD expression. PIK3CD overexpression attenuated the inhibitory effectiveness of USP14 knockdown on proliferation, migration and tube formation of DR cell model. Here, we revealed that USP14 regulated the ATF2/PIK3CD axis to promote proliferation, migration, and tube formation in HG-induced HRMECs.

Fiber Optic Sensing Technology and Vision Sensing Technology for Structural Health Monitoring.

Structural health monitoring is currently a crucial measure for the analysis of structural safety. As a structural asset management approach, it can provide a cost-effective measure and has been used successfully in a variety of structures. In recent years, the development of fiber optic sensing technology and vision sensing technology has led to further advances in structural health monitoring. This paper focuses on the basic principles, recent advances, and current status of applications of these two sensing technologies. It provides the reader with a broad review of the literature. It introduces the advantages, limitations, and future directions of these two sensing technologies. In addition, the main contribution of this paper is that the integration of fiber optic sensing technology and vision sensing technology is discussed. This paper demonstrates the feasibility and application potential of this integration by citing numerous examples. The conclusions show that this new integrated sensing technology can effectively utilize the advantages of both fields.

Transcriptomics Reveals the Effect of Short-Term Freezing on the Signal Transduction and Metabolism of Grapevine.

Low temperature is an important factor limiting plant growth. Most cultivars of Vitis vinifera L. are sensitive to low temperatures and are at risk of freezing injury or even plant death during winter. In this study, we analyzed the transcriptome of branches of dormant cv. Cabernet Sauvignon exposed to several low-temperature conditions to identify differentially expressed genes and determine their function based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)enrichment analyses. Our results indicated that exposure to subzero low temperatures resulted in damage to plant cell membranes and extravasation of intracellular electrolytes, and that this damage increased with decreasing temperature or increasing duration. The number of differential genes increased as the duration of stress increased, but most of the common differentially expressed genes reached their highest expression at 6 h of stress, indicating that 6 h may be a turning point for vines to tolerate extreme low temperatures. Several pathways play key roles in the response of Cabernet Sauvignon to low-temperature injury, namely: (1) the role of calcium/calmodulin-mediated signaling; (2) carbohydrate metabolism, including the hydrolysis of cell wall pectin and cellulose, decomposition of sucrose, synthesis of raffinose, and inhibition of glycolytic processes; (3) the synthesis of unsaturated fatty acids and metabolism of linolenic acid; and (4) the synthesis of secondary metabolites, especially flavonoids. In addition, pathogenesis-related protein may also play a role in plant cold resistance, but the mechanism is not yet clear. This study reveals possible pathways for the freezing response and leads to new insights into the molecular basis of the tolerance to low temperature in grapevine.

Clinical effect of glucosamine hydrochloride combined with compound osteopeptide injection for knee osteoarthritis.

Objective: To investigate the clinical efficacy of glucosamine hydrochloride combined with compound osteopeptide injection for knee osteoarthritis (KOA). Methods: We retrospectively collected clinical data of 82 patients with KOA admitted to Shandong Weifang People's Hospital from April 2019 to September 2022. According to the treatment records, 35 patients received an intramuscular injection of compound osteopeptide (control group), and 47 patients received an injection of glucosamine hydrochloride combined with compound osteopeptide (observation group). We compared clinical efficacy, WOMAC scores, inflammatory factor and CD4+ and CD8+ levels, and the incidence of adverse reactions between the two groups. Results: The observation group's total efficacy (95.74%) was significantly higher than the control group's (80.00%; P<0.05). Treatment led to a significant reduction in WOMAC scores in both groups. In addition, the levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) in the observation group were significantly lower than those in the control group (P<0.05); while the levels of CD4+ and CD8+ were significantly higher in the observation group (P<0.05). Conclusions: Compared with compound osteopeptide injection alone, glucosamine hydrochloride combined with compound osteopeptide injection is more effective for patients with KOA, with improved level of inflammatory factors and immune function.

The effect of SNPs in lncRNA as ceRNA on the risk and prognosis of hepatocellular carcinoma.

BACKGROUND: Most susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies (GWAS) are located in non-coding regions, and the mechanism of action remains unclear. The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) on long non-coding RNAs (lncRNAs) that affect competing endogenous RNAs (ceRNA) regulation mechanism with the risk and prognosis of HCC. METHODS: Based on a set of bioinformatics strategies, eight lncRNA genes that affect HCC through the mechanism of lncRNA-mediated ceRNA were systematically screened, and 15 SNPs that affect microRNA (miRNA) binding in these lncRNA genes were annotated. Genotyping was performed in 800 HCC cases and 801 healthy controls to examine associations of these SNPs with HCC in a northeastern Chinese Han population. RESULTS: The GG, GC and GG + GC genotypes of HOTAIR rs7958904 were associated with a 0.65, 0.59 and 0.63-fold decreased HCC risk, respectively. In addition, HCC patients with PVT1 rs3931282 AA + GA genotypes were less prone to develop late-stage cancers in a stratified analysis of clinical characteristics. When stratified by clinical biochemical indexes, rs1134492 and rs10589312 in PVT1 and rs84557 in EGFR-AS1 showed significant associations with aspartate aminotransferase (AST), alanine aminotransferase (ALT) or AST/ALT ratio in HCC patients. Furthermore, we constructed potential ceRNA regulatory axes that might be affected by five positive SNPs to explain the causes of these genetic associations. CONCLUSIONS: HOTAIR rs7958904, PVT1 rs3931282, rs1134492 and rs10589312, and EGFR-AS1 rs84557 might be predictors for HCC risk or prognosis. Our results provide new insights into how SNPs on lncRNA-mediated ceRNAs confer interindividual differences to occurrence and progression of HCC.

Venous Size Discrepancy Is a Critical Factor When Using Superficial Temporal Vessels as Recipient Vessels for Free Flaps.

BACKGROUND: Superficial temporal vessels have been used successfully as recipient vessels for head and neck reconstruction. This study evaluates the impact of several treatment variables on flap failure and take-back rate when using these recipient vessels. METHODS: We conducted a retrospective study of all microsurgical reconstructions using superficial temporal vessels as recipient vessels in a period of 10 years. Variables collected included previous treatments (radiotherapy, chemotherapy, neck dissection, free flap reconstruction), type of flaps used (soft tissue, osteocutaneous), and vessel size discrepancy between donor and recipient vessels. RESULTS: A total of 132 patients were included in the study. The flap success rate was 98.5%. The take-back rate was 10.6%. The most frequent reason for take-back was venous congestion secondary to thrombosis. None of the studied variables was associated with flap failure. Reconstructions using osteocutaneous flaps and vein diameter discrepancy (ratio ≥ 2:1) had significantly higher take-back rates. CONCLUSION: Flaps with a significant size discrepancy between donor and recipient veins (ratio ≥ 2:1) and fibula flaps (compared with soft tissue flaps) were associated with a higher risk of take-back. It is crucial to minimize venous engorgement during flap harvest and anastomosis, and limit vein redundancy during flap in-setting.

Mechanism of CNP-mediated DG-PKC and IP4 signaling pathway in diabetic rats with gastric motility disorder.

In the precedent research conducted by the same team, it concluded that the activities in C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP)/ß-type phospholipase C (PLCß) pathways of rat antral smooth muscle were changed due to diabetes, which was the key pathogenetic mechanism for diabetic gastric dysmotility. As the follow-on step, this study was designed to probe into the downstream signaling pathway of CNP/PLCß. The results showed that level of α-type protein kinase C (PKCα),cell membrane to cytoplasm ratio of PKCα, cell membrane to cytoplasmic ratio of ßI-type protein kinase C (PKCßI) and level of Phosphor-PKCα (P-PKCα) were significantly reduced in diabetes rat antral smooth muscle samples. The content of tetraphosphate inositol (IP4) in gastric antral smooth muscle of diabetic rats reduced, and the content of diacyl-glycerol (DG) was unchanged. CNP significantly decreased the content of IP4 and DG, this effect was more obvious in diabetic rats. Subsequent to the addition of protein kinase A (PKA) blocker N-[2- (p-Bromocin-namylamino)ethyl]-5 -isoquinolinesulfonamide dihydrochloride (H-89) before CNP treatment, the inhibitory effect of CNP was reduced; subsequent to the addition of protein kinase G (PKG) blocker KT5823 before CNP treatment, the inhibitory effect of CNP was also reduced. With the addition of the combination of H-89 and KT5823 before CNP treatment, the inhibition by CNP could be offset. These results were concluded that CNP inhibited the activity of PKC family in rat smooth muscle and reduced the levels of IP4 and DG through the PKG/PKA-PLCß pathways, causing inhibited muscular contractions, which may be a key pathogenetic factor for diabetic gastroparesis.

Integrated bioinformatics analyses identified SCL3-induced regulatory network in Arabidopsis thaliana roots.

OBJECTIVES: To uncover key genes and pathways regulated by SCL3, a GRAS transcription factor, in the context of gibberellin (GA) in the roots of the model plant Arabidopsis thaliana. RESULTS: Gene expression profiles of ga1-3 mutant and ga1-3 and scl3 double mutant are considerably similar to each other, revealed by Principal Component Analysis (PCA). More than 400 significantly Differentially Expressed Genes (DEGs) among the Arabidopsis thaliana roots of ga1-3 mutant, ga1-3 and scl3 double mutant and GA loss/SCL3 gain mutant were uncovered by comprehensive bioinformatics analyses. Protein synthesis pathway, including RPL proteins, RPS proteins, etc., and flavonoid biosynthesis pathway, including TT4, F3H, TT5, CHIL, etc. were significantly increased when SCL3 expression was higher than normal by means of pathway enrichment analysis and protein-protein interaction analysis, which is further supported by comparison analyses between wild type samples and SCL3 overexpressed roots. CONCLUSION: Protein synthesis and flavonoid biosynthesis were regulated by SCL3 in the context of GA in Arabidopsis thaliana root system identified by comprehensive bioinformatic analyses.

Effects of insulin-like growth factor-1 on endoplasmic reticulum stress and autophagy in rat gastric smooth muscle cells cultured at different glucose concentrations in vitro.

The purpose of the study was to observe changes in endoplasmic reticulum stress (ERS)- and autophagy-related proteins in gastric smooth muscle tissues of diabetic rats with gastroparesis, investigate the effect of insulin-like growth factor 1 (IGF-1) on ERS and autophagy in rat gastric smooth muscle cells cultured under different glucose concentrations, and explore the influence of IGF-1 on development of diabetic gastroparesis (DGP). After establishing a rat model of DGP, rats were divided into normal control (NC) and 6-week diabetic model (DM6W) groups. Expression of ERS-related and autophagy-related proteins was detected by western blot analysis and immunofluorescence assay in rat gastric smooth muscle tissue and in vitro-cultured rat gastric smooth muscle cells exposed to different glucose concentrations and treatment with IGF-1 for 24 or 48 h. Changes in glucose-regulated-protein-78 (GRP78), growth arrest and DNA damage-inducible gene 153 (CHOP), and microtubule-associated protein 1A/1B light chain 3B (LC3) expression levels were detected by western blot analysis, and GRP78 and LC3 expression were examined by confocal laser-scanning microscopy. In vivo expression levels of GRP78, CHOP, and LC3 were significantly higher in the DM6W group compared with the NC group (p < 0.001). Twenty-four hours after cells were cultured at different glucose concentrations in vitro, expression of GRP78, CHOP, and LC3II/I was significantly higher in the high glucose-treated group compared with the normal glucose group (p < 0.05). After IGF-1 intervention, CHOP and GRP78 expression were significantly higher in the normal glucose + IGF-1 group compared with the normal glucose group (p < 0.01), while no significant difference was found between high glucose and high glucose + IGF-1 groups. LC3II/I expression was significantly lower in the normal glucose + IGF-1 group compared with the normal glucose group, and was significantly lower in the high glucose and high glucose + IGF-1 groups (p < 0.05). After 48 h of culture, CHOP expression was significantly higher and LC3II/I expression was significantly lower in the high glucose group compared with the normal glucose group (p < 0.05), but no significant change in GRP78 expression was observed between these two groups. After IGF-1 intervention, there was no difference in CHOP or GRP78 expression between normal glucose + IGF-1 and normal glucose groups. However, CHOP and GRP78 expression were significantly lower in the high glucose + IGF-1 group compared with the high glucose group (p < 0.05). There was no significant difference in LC3II/I expression between normal glucose + IGF-1 and normal glucose groups, or high glucose + IGF-1 and high glucose groups. Results of confocal laser-scanning microscopy showed significantly lower expression of LC3II/I in the high glucose + IGF-1 group compared with the high glucose group (p < 0.05). ERS and autophagy were involved in the occurrence of DGP. IGF-1 exerted an inhibitory effect on ERS in rat gastric smooth muscle cells cultured under high glucose conditions, and this inhibitory effect increased with time. IGF-1 inhibited the level of autophagy in rat gastric smooth muscle cells cultured under high glucose conditions at early stages, which may be achieved through inhibition of ERS.

Phenanthrenequinone enantiomers with cytotoxic activities from the tubers of Pleione bulbocodioides.

Eight new phenanthrenequinones (four pairs of enantiomers), named bulbocodioidins A-D (1-4), have been isolated from the ethanolic extract of tubers of Pleione bulbocodioides. Their structures, including absolute configurations, were determined by extensive NMR analysis combined with experimental and calculated ECD (electronic circular dichroism) data analyses. Compounds 1-4 possessed a 9(10)H-phenanthren-10(9)-one structure, which is a rarely reported instance from natural sources. Their possible biosynthetic pathway was discussed in the text. The cytotoxic effects of the isolated phenanthrenequinones were evaluated in several human cancer cell lines, and compounds 1a and 4a exhibited marked cytotoxic activities.

Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists.

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.