Synthesis and in†vitro Anti-Inflammatory Activity of Novel Dendrobine Amide/Sulfonamide Derivatives.

A traditional Chinese medicine ingredient, dendrobine, has been demonstrated to have anti-inflammatory properties. However, due to its poor anti-inflammatory properties, its clinical use is limited. Consequently, we have designed and synthesized 32 new amide/sulfonamide dendrobine derivatives and screened their anti-inflammatory activities in vitro. Experiments showed that nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW264.7 cells was strongly reduced by derivative 14, with an IC50 of 2.96 µM. Western blot research revealed that 14 decreased the concentration-dependent expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (INOS). Molecular docking was used to predict the binding of the inflammation-associated proteins COX-2 and INOS to compound 14.

Structurally Diverse Coumarins from Peucedanum praeruptorum and their Anti-Inflammatory Activities via NF-κB Signaling Pathway.

The phytochemical study of Peucedanum praeruptorum led to the isolation of twenty-five coumarins (1-25). Of which, (±) praeruptol A (±1), one pair of previous undescribed seco-coumarin enantiomers were obtained. Their structures were established according to HR-ESI-MS, NMR, X-ray single crystal diffraction analysis, as well as ECD calculation. All compounds were tested for anti-inflammatory activity in the RAW264.7 macrophage model, and eight compounds (7-10, and 13-16) exhibited significant inhibitory effects with IC50 values ranging from 9.48 to 34.66 µM. Among them, compound 7 showed the strongest inhibitory effect, which significantly suppressed the production of IL-6, IL-1ß, and TNF-α, as well as iNOS and COX-2 in a concentration-dependent manner. Further investigated results showed that compound 7 exerted an anti-inflammatory effect via the NF-κB signaling pathway.

Limonoids from the Branches and Leaves of Aglaia lawii and Their Cytotoxic Activities.

Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6 µM.

Copper-Catalyzed Oxygenative Skeletal Rearrangement of Tetrahydro-ß-carbolines Using H2 O and O2 as Oxygen Sources.

Herein, we report an unprecedented skeletal rearrangement reaction of tetrahydro-ß-carbolines enabled by copper-catalyzed single-electron oxidative oxygenation, in which H2 O and O2 act as oxygen sources to generate a unique 2-hydroxyl-3-peroxide indoline intermediate. The synthetic reactivity of 2-hydroxyl-3-peroxide indoline species was demonstrated by a unique multi-step bond cleavage and formation cascade. Using a readily available copper catalyst under open-air conditions, highly important yet synthetically difficult spiro[pyrrolidone-(3,1-benzoxazine)] products were obtained in a single operation. The synthetic utility of this methodology is demonstrated by the efficient synthesis of the natural products donaxanine and chimonamidine, as well as the 3-hydroxyl-pyrroloindoline scaffold, in just one or two steps.

Red Room-Temperature Phosphorescence Supramolecular Assemblies Based on Cucurbit[7]uril: Reversible Temperature Stimulation Response and Cell-Specific Silver Ion Imaging.

Solid-state materials with efficient room-temperature phosphorescence (RTP) emission have been widely used in materials science, and organic RTP-emitting systems with heavy-metal doping in aqueous solutions have attracted much attention in recent years. A novel supramolecular interaction was induced by host-guest assembly using cucurbit[7]uril (Q[7]) as the host and brominated naphthalimide phosphor as the guest. This interaction was further enhanced through synergistic chelation stimulated by analytical silver ion complexation. This approach facilitated the system's structural rigidity, intersystem crossing, and oxygen shielding. We achieved deep red phosphorescence emission in aqueous solution and ambient conditions along with quantitative determination of silver ions. The new complex exhibited good reversible thermoresponsive behavior and was successfully applied for the first time to target phosphorescence imaging of silver ions in the mitochondria of A549 cancer cells. These results are beneficial for constructing novel RTP systems with stimulus-responsive luminescence in aqueous solution, contributing to future research in bioimaging, detection, optical sensors, and thermometry materials.

Unusual triterpenoids and steroids from Cipadessa baccifera and their biological activities.

Five undescribed triterpenoids and steroids (1-5), as well as ten known compounds, were purified from the branches and leaves of Cipadessa baccifera. Notably, 1 and 2 are rare cipadesin-type limonoids with an unusual 8,30-epoxide ring and 1,8-ether linkage, respectively. Compound 5 possessed pregnane steroid skeleton with an uncommon 5/6/6/6/5-fused ring system. Their structures were constructed by extensive spectroscopic analysis (NMR, IR, UV, and HRESIMS), and their absolute configurations were confirmed by ECD calculations and quantum chemical calculations. All the isolates were in vitro assayed for their antimicrobial potentials against 6 pathogenic microorganisms and antiproliferation activities against five human cancer cell lines. As a result, compounds 5, 12, 13, and 14 exhibited moderate antibacterial activities (MIC: 25-50 µg/mL). Moreover, 5 showed cytotoxicity against five cancer cell lines with IC50 values ranging from 8.0 to 19.9 µM.

Three New Constituents with Anti-Inflammatory and Antimicrobial Activities in Vitro from the Roots of Capsicum annuum L.

Three new compounds, including two new sesquiterpenes (1-2), named Annuumine E-F, and one new natural product, 3-hydroxy-2,6-dimethylbenzenemethanol (3), together with seventeen known compounds (4-20) were isolated from the ethanol extract of the roots of Capsicum annuum L. Among them, five compounds (4, 5, 9, 10 and 20) were isolated from this plant for the first time. The structures of new compounds (1-3) were determined via detailed analysis of the IR, HR-ESI-MS and 1D and 2D NMR spectra. The anti-inflammatory activities of the isolated compounds were evaluated by their ability to reduce NO release by LPS-induced RAW 264.7 cells. Notably, compound 11 exhibited moderate anti-inflammatory activity (IC50 =21.11 µM). Moreover, the antibacterial activities of the isolated compounds were also evaluated.

Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin.

BACKGROUND: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance. AIM: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC. METHODS: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively. RESULTS: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone. CONCLUSION: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Construction and Validation of a Novel Prognosis Model in Colon Cancer Based on Cuproptosis-Related Long Non-Coding RNAs.

Colon cancer (CC) is one of the most common (6%) malignancies and leading cause of cancer-associated death (more than 0.5 million) worldwide, which demands reliable prognostic biomarkers. Cuproptosis is a novel modality of regulated cell death triggered by the accumulation of intracellular copper. LncRNAs have been reported as prognostic signatures in different types of tumors. However, the correlation between cuproptosis-related lncRNAs (CRLs) and CC remains unclear. Data of CC patients were downloaded from public databases. The prognosis-associated CRLs were identified by co-expression analysis and univariate Cox. Least absolute shrinkage and selection operator were utilized to construct the CRLs-based prognostic signature in silico for CC patients. CRLs level was validated in human CC cell lines and patient tissues. ROC curve and Kaplan-Meier curve results revealed that high CRLs-risk score was associated with poor prognosis in CC patients. Moreover, the nomogram revealed that this model possessed a steady prognostic prediction capability with C-index as 0.68. More importantly, CC patients with high CRLs-risk score were more sensitive to eight targeted therapy drugs. The prognostic prediction power of the CRLs-risk score was further confirmed by cell lines, tissues and two independent CC cohorts. This study constructed a novel ten-CRLs-based prognosis model for CC patients. The CRLs-risk score is expected to serve as a promising prognostic biomarker and predict targeted therapy response in CC patients.

A Novel m7G-Related Gene Signature Predicts the Prognosis of Colon Cancer.

Colon cancer (CC), one of the most common malignancies worldwide, lacks an effective prognostic prediction biomarker. N7-methylguanosine (m7G) methylation is a common RNA modification type and has been proven to influence tumorigenesis. However, the correlation between m7G-related genes and CC remains unclear. The gene expression levels and clinical information of CC patients were downloaded from public databases. Twenty-nine m7G-related genes were obtained from the published literature. Via unsupervised clustering based on the expression levels of m7G-related genes, CC patients were divided into three m7G clusters. Based on differentially expressed genes (DEGs) from the above three groups, CC patients were further divided into three gene clusters. The m7G score, a prognostic model, was established using principal component analysis (PCA) based on 15 prognosis-associated m7G genes. KM curve analysis demonstrated that the overall survival rate was remarkably higher in the high-m7G score group, which was much more significant in advanced CC patients as confirmed by subgroup analysis. Correlation analysis indicated that the m7G score was associated with tumor mutational burden (TMB), PD-L1 expression, immune infiltration, and drug sensitivity. The expression level of prognosis-related m7G genes was further confirmed in human CC cell lines and samples. This study established an m7G gene-based prognostic model (m7G score), which demonstrated the important roles of m7G-related genes during CC initiation and progression. The m7G score could be a practical biomarker to predict immunotherapy response and prognosis in CC patients.

Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer.

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC50 value of 0.57 µM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies.

Novel flavonolignans from the roots of Indigofera stachyodes.

Two pairs of new enantiomeric flavonolignans, ±stachyols A and B (±1 and ± 2), along with two novel isoflavanelignans, stachyols C and D (3 and 4) were isolated from the roots of Indigofera stachyodes. Their chemical structures and absolute configurations were determined using nuclear magnetic resonance and comparison of experimental and theoretical electronic circular dichroism (ECD) spectra, as well as quantum chemical calculations. Of those compounds, 1 and 2 represented the first examples of flavonolignans with 5-deoxyflavonoids adduct phenylpropanoids. Moreover, 3 and 4 possess an unprecedented skeleton with isoflavanes adduct phenylpropanoids. The antioxidant activity was evaluated for all compounds in terms of ABTS+ and DPPH bioassays. Compounds 3 and 4 exhibited significant radical-scavenging activity in the ABTS+ assay, with IC50 values of 15.15 and 5.83 µM, respectively.

Copper-Catalyzed Aerobic Selective Oxidation of Tetrahydrocarbolines.

We report a safe and convenient open-flask copper-catalyzed selective oxidation/functionalization methodology for tetrahydrocarbolines and tetrahydro-ß-carbolines that employs atmospheric O2 as the terminal oxidant. The system is applicable to oxidative rearrangement of tetrahydro-ß-carbolines, tetrahydrocarboline oxidation to α-alkoxy carbazoles and spirooxindoles, and Witkop oxidation. Mechanistic experiments indicated that a single-electron oxidation process is responsible for the tunable selectivity control. This copper-catalysis protocol represents a significant advance in the field of indole oxidation.

Cipacinerasins A-K, structurally diverse limonoids from Cipadessa baccifera.

Eleven undescribed limonoids, cipacinerasins A-K, involving of four diverse carbon skeletal types, along with fifteen known analogues, were isolated from the branches and leaves of Cipadessa baccifera. Within them, cipacinerasins A and B feature a rearranged tetrahydropyranyl ring B formed between C-8 and C-30, are unusual miscellaneous-type limonoids. Cipacinerasins E and F are rare trijugin-type limonoids, of which the D-ring δ-lactone is cleaved. Their structures were elucidated on the basis of extensive spectroscopic data (HRESIMS, NMR, UV and IR), electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. All compounds were evaluated in vitro cytotoxicity against five human tumor cell lines (K562, HeLa, PC3, LN-Cap and Hell), and cipacinerasin E showed moderate antitumor activity with IC50 values ranging from 8.0 to 24.8 µM.

Copper-Catalyzed Selective Oxidative Cross-Coupling of Tryptophols and Tryptamines To Access Heterocyclic 3a,3a'-Bisindolines.

The first example of cyclization cross-coupling of tryptophols and tryptamines has been realized by copper catalysis with air or oxone as the terminal oxidant, resulting in the direct construction of a new class of heterocyclic 3a,3a'-bisindolines in moderate to good yields with high chemoselectivities. A series of mechanistic control experiments were also conducted, indicating that the copper catalyst selectively coordinates with the nitrogen moiety of the tryptamine to initiate the oxidation, and a nucleophilic-alkylation process is proposed for the carbon-carbon bond-forming in the reaction. The novel synthetic strategies and molecular skeletons outlined in this work provide new ideas and concepts for the design of other useful reaction and potential drugs.

Profiling alkaloids in Aconitum pendulum N. Busch collected from different elevations of Qinghai province using widely targeted metabolomics.

Aconitum pendulum N. Busch (Ranunculaceae) is rich in alkaloids with anti-inflammatory and analgesic activities. Many studies have focused on the identification or quantification of alkaloid components using low-throughput tests. However, the metabolic differences of plants from environmentally distinct regions remain unclear. The present study profiled alkaloid chemical compounds in the rhizomes of A. pendulum from different regions. A total of 80 chemical compounds were identified using a widely targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach. Principal component, hierarchical clustering, and orthogonal partial least squares-discriminant analyses of the chemical compounds indicated that the plants from 6 regions clearly separated into distinct groups. A total of 19 compounds contributed the most to the metabolite differences between collection areas and were identified as potential metabolic markers. The anti-inflammatory activities of the A. pendulum extracts were also evaluated and the potential environmental effects on the regulation of metabolite composition and bioactivity were explored. These results improve our understanding of the variation in chemical composition of plants from different regions and will serve as a reference for evaluating the medicinal value of A. pendulum in different environments.

Microbial spectrum and drug resistance of pathogens cultured from gallbladder bile specimens of patients with cholelithiasis: A single-center retrospective study.

BACKGROUND: Bacterial infection is an important cause of cholelithiasis or gallstones and interferes with its treatment. There is no consensus on bile microbial culture profiles in previous studies, and identified microbial spectrum and drug resistance is helpful for targeted preventive and therapeutic drugs in the perioperative period. AIM: To analyze the bile microbial spectrum of patients with cholelithiasis and the drug susceptibility patterns in order to establish an empirical antibiotic treatment for cholelithiasis-associated infection. METHODS: A retrospective single-center study was conducted on patients diagnosed with cholelithiasis between May 2013 and December 2018. RESULTS: This study included 185 patients, of whom 163 (88.1%) were diagnosed with gallstones and 22 (11.9%) were diagnosed with gallstones and common bile duct stones (CBDSs). Bile culture in 38 cases (20.5%) was positive. The presence of CBDSs (OR = 5.4, 95%CI: 1.3-21.9, P = 0.03) and longer operation time (> 80 min) (OR = 4.3, 95%CI: 1.4-13.1, P = 0.01) were identified as independent risk factors for positive bile culture. Gram-negative bacteria were detected in 28 positive bile specimens, and Escherichia coli (E. coli) (19/28) and Klebsiella pneumoniae (5/28) were the most frequently identified species. Gram-positive bacteria were present in 10 specimens. The resistance rate to cephalosporin in E. coli was above 42% and varied across generations. All the isolated E. coli strains were sensitive to carbapenems, with the exception of one imipenem-resistant strain. K. pneumoniae showed a similar resistance spectrum to E. coli. Enterococcus spp. was largely sensitive to glycopeptides and penicillin, except for a few strains of E. faecium. CONCLUSION: The presence of common bile duct stones and longer operation time were identified as independent risk factors for positive bile culture in patients with cholelithiasis. The most commonly detected bacterium was E. coli. The combination of ß-lactam antibiotics and ß-lactamase inhibitors prescribed perioperatively appears to be effective against bile pathogens and is recommended. Additionally, regular monitoring of emerging resistance patterns is required in the future.

Copper-Catalyzed Cyclization/Dimerization of Tryptamines with O2/Air as the Sole Oxidant: Direct Access to Complex Bispyrrolidino[2,3-b]indoline.

The first transition metal catalytic one-step synthesis of the 3a, 3a'-bispyrrolidino [2,3-b] indoline scaffold via tandem cyclization/dimerization of tryptamines has been realized with the environmentally friendly O2/air as the sole oxidant. Different from the traditional direct oxidation of indole "N-H" group by excess amount of metal salts, a copper-catalyzed oxidative cyclization reaction is developed for the formation of the radical pyrrolidinoindoline intermediate in the current strategy. The robustness and practicality of this methodology is demonstrated by the step-economic, divergent total synthesis of natural products (±)-folicanthine and meso-folicanthine.

Dual and opposing roles of the androgen receptor in VETC-dependent and invasion-dependent metastasis of hepatocellular carcinoma.

BACKGROUND & AIMS: Contradictory roles of the androgen receptor (AR) in hepatocellular carcinoma (HCC) metastasis have been reported. We have shown that VETC (vessels encapsulating tumor clusters) mediates invasion-independent metastasis, whereas VETC- HCCs metastasize in an invasion-dependent manner. Herein, we aimed to reveal the roles of AR in HCC metastasis. METHODS: Mouse xenograft models, clinical samples, and cell models were used. RESULTS: AR expression was significantly lower in HCCs with a VETC pattern, portal vein tumor thrombus, endothelium-coated microemboli or high recurrence rates. Overexpressing AR in VETC+ hepatoma cells suppressed VETC formation and intrahepatic metastasis but promoted pulmonary metastasis of mouse xenografts. AR decreased the transcription of Angiopoietin-2 (Angpt2), a factor essential for VETC formation, by binding to the Angpt2 promoter. The roles of AR in inhibiting VETC formation and intrahepatic metastasis were attenuated by restoring Angpt2 expression, suggesting that AR may repress VETC-dependent intrahepatic metastasis by inhibiting Angpt2 expression and VETC formation. On the other hand, AR upregulated Rac1 expression, promoted lamellipodia formation and increased cell migration/invasion. A Rac1 inhibitor abrogated the AR-mediated promotion of migration/invasion and pulmonary metastasis of VETC+ hepatoma cells, but did not affect the AR-mediated inhibition of intrahepatic metastasis. Furthermore, an AR inhibitor decreased Rac1 expression and attenuated both intrahepatic and pulmonary metastasis of VETC- xenografts, an effect which was abrogated by restoring Rac1 expression. These data indicate that AR may facilitate the lung metastasis of VETC+ HCCs and both the liver/lung metastases of VETC- HCCs by upregulating Rac1 expression and then promoting migration/invasion. CONCLUSION: AR plays dual and opposing roles in VETC-dependent and invasion-dependent metastasis, which highlights the complex functions of AR and the importance of individualized cancer therapy. LAY SUMMARY: In this study, we uncovered the dual and opposing roles of the androgen receptor in VETC (vessels encapsulating tumor clusters)-dependent and invasion-dependent metastasis of hepatocellular carcinoma (HCC). We elucidated the underlying mechanisms of these processes, which provided novel insights into the complex regulatory network of the androgen receptor in HCC metastasis and may have important implications for precision medicine.

Geomagnetic field absence reduces adult body weight of a migratory insect by disrupting feeding behavior and appetite regulation.

The geomagnetic field (GMF) is well documented for its essential role as a cue used in animal orientation or navigation. Recent evidence indicates that the absence of GMF (mimicked by the near-zero magnetic field, NZMF) can trigger stress-like responses such as reduced body weight, as we have previously shown in the brown planthopper, Nilaparvata lugens. In this study, we found that consistent with the significantly decreased body weight of newly emerged female (-14.67%) and male (-13.17%) adult N. lugens, the duration of the phloem ingestion feeding waveform was significantly reduced by 32.02% in 5th instar nymphs reared under the NZMF versus GMF. Interestingly, 5th instar nymphs that exhibited reduced feeding had significantly higher glucose levels (+16.98% and +20.05%; 24 h and 48 h after molting), which are associated with food aversion, and expression patterns of their appetite-related neuropeptide genes (neuropeptide F, down-regulated overall; short neuropeptide F, down-regulated overall; adipokinetic hormone, up-regulated overall; and adipokinetic hormone receptor, down-regulated overall) were also altered under the absence of GMF in a manner consistent with diminishing appetite. Moreover, the expressions of the potential magnetosensor cryptochromes (Crys) were found significantly altered under the absence of GMF, indicating the likely upstream signaling of the Cry-mediated magnetoreception mechanisms. These findings support the hypothesis that strong changes in GMF intensity can reduce adult body weight through affecting insect feeding behavior and underlying regulatory processes including appetite regulation. Our results highlight that GMF could be necessary for the maintenance of energy homeostasis in insects.