Cevanine-type alkaloids from the bulbs of Fritillaria unibracteata var. wabuensis and their antifibrotic activities in vitro.

Steroidal alkaloids are the main bioactive components of the bulbs of Fritillaria, which have been used as traditional Chinese medicine, known as "Beimu", for the treatment of cough for thousands of years in China. Cough and dyspnea are the most common symptoms observed in patients with pulmonary fibrosis. However, the antifibrotic activity of steroidal alkaloids has not been reported yet. In this study, two previously unreported cevanine-type steroidal alkaloids (1 and 2), four previously undescribed cevanine-type alkaloid glycosides (3-6), and 19 known steroidal alkaloids (7-25) were isolated from the bulbs of Fritillaria unibracteata var. wabuensis. The structures of these compounds were elucidated by comprehensive HRESIMS and NMR spectroscopic data analysis, as well as DP4+ NMR calculations. The biological evaluation showed that compounds 2, 7-10, 14, 15, and 17 downregulated fibrotic markers induced by transforming growth factor-ß (TGF-ß) in MRC-5 cells. Moreover, compounds 14 and 17 dose dependently inhibited TGF-ß-induced epithelial-mesenchymal transition in A549 cells, alleviated TGF-ß-induced migration and proliferation of fibroblasts, and decreased the expression of fibrotic markers, fibronectin, and N-cadherin in TGF-ß-induced MRC-5 cells. The research showed the potential of cevanine-type alkaloids as a class of natural antifibrotic agents.

Composite Quasi-Solid-State Electrolytes with Organic-Inorganic Interface Engineering for Fast Ion Transport in Dendrite-Free Sodium Metal Batteries.

Quasi-solid-state electrolytes (QSSE) are a promising candidate for addressing the limitations of liquid and solid electrolytes. However, different ion transport capacities between liquid solvents and polymers can cause localized heterogeneous distribution of Na+ fluxes. In addition, the continuous side reactions occurring at the interface between QSSE and sodium anode lead to uncontrollable dendrites growth. Herein, a novel strategy is designed to integrate the composite electrospun membrane of Na3Zr2Si2PO12 and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) into QSSE, aiming to introduce new fast ion conducting channels at the organic-inorganic interface. The efficient ion transfer pathways can effectively promote the homogenization of ion migration, enabling composite QSSE to achieve an ultrahigh ionic conductivity of 4.1 mS cm-1 at room temperature, with a Na+ transference number as high as 0.54. Moreover, the PVDF-HFP is preferentially reduced upon contact with the sodium anode to form a "NaF-rich" solid electrolyte interphase, which effectively suppresses the growth of dendrites. The synergistic combination of multiple strategies can realize exceptional long-term cycling stability in both sodium symmetric batteries (≈700 h) and full batteries (2100 cycles). This study provides a new insight for constructing high performance and dendrite-free solid-state sodium metal batteries.

Cryptolepine suppresses breast adenocarcinoma via inhibition of HIF-1 mediated glycolysis.

As a characteristic transcription factor in solid tumors, hypoxia inducible factor-1 (HIF-1) acts as a master regulator in breast cancer progression. Cryptolepine, as a natural alkaloid, noticeably inhibited HIF-1 transcriptional activity and decreased the protein expression of hypoxia-induced HIF-1α in breast cancer cells. Further study showed that cryptolepine blocked HIF-1-mediated glycolysis and suppressed the expression of multiple glycolysis enzymes, resulting in a decrease in ATP production in hypoxic T47D and 4T1 cells. Meanwhile, cryptolepine displayed potent suppressive effect on tumor growth in a dose-dependent manner. In 4T1 tumor xenografts, cryptolepine reduced HIF-1α protein expression, and thus decreased the levels of both lactate acid and ATP productions. The mechanistic study revealed that cryptolepine could effectively suppress the process of HIF-1α mRNA translation rather than transcription, which was attributed to the inhibition on the phosphorylation of eIF4E regulated by both MAPK and mTOR signaling pathways. Collectively, current findings suggested that cryptolepine possesses the potential to treat breast cancers by modulating HIF-1 both in vitro and in vivo.

TfOH-Catalyzed Cascade C-H/N-H Chemo-/Regioselective Annulation of Indole-2-carboxamides with Benzoquinones for the Construction of Anticancer Tetracyclic Indolo[2,3-c]quinolinones.

An efficient TfOH-catalyzed cascade C-H/N-H annulation of indole-2-carboxamides with benzoquinones has been developed for the synthesis of tetracyclic indolo[2,3-c]quinolinones. This reaction exhibits excellent chemo-/regioselectivity, achieving functionalization of the C-3 of indole and N-H of the amide moiety to form the new C-C and C-N bonds. Various expected products were synthesized from readily available starting materials in good to high yields with a wide substrate scope and good functional group tolerance. Among all synthetic products, 3d showed the most potent cytotoxicity toward the 4T1 cancer cell line with an IC50 value of 0.62 ± 0.05 µM. In vivo study demonstrated that 3d remarkably suppressed 4T1 xenograft tumor growth without body weight loss.

I2-Catalyzed Carbonylation of α-Methylene Ketones to Synthesize 1,2-Diaryl Diketones and Antiviral Quinoxalines in One Pot.

An efficient approach for the synthesis of 1,2-diaryl diketones was developed from readily available α-methylene ketones by catalysis of I2. In the same oxidation system, a novel one-pot procedure was established for the construction of antiviral and anticancer quinoxalines. The reactions proceeded well with a wide variety of substrates and good functional group tolerance, affording desired compounds in moderate to excellent yields. Quinoxalines 4ca and 4ad inhibited viral entry of SARS-CoV-2 spike pseudoviruses into HEK-293T-ACE2h host cells as dual blockers of both human ACE2 receptor and viral spike RBD with IC50 values of 19.70 and 21.28 µM, respectively. In addition, cytotoxic evaluation revealed that 4aa, 4ba, 4ia, and 4ab suppressed four cancer cells with IC50 values ranging from 6.25 to 28.55 µM.

Novel 1,3,4-thiadiazole/oxadiazole-linked honokiol derivatives suppress cancer via inducing PI3K/Akt/mTOR-dependent autophagy.

Honokiol is a bioactive biphenolic component derived from Magnoliae officinalis Cortex (known as "Hou Po" in Chinese), a traditional Chinese herbal medicine. A series of novel 1,3,4-thiadiazole/oxadiazole-linked honokiol derivatives were synthesized and tested for anticancer activity against seven human cancer cell lines in this study. Among all derivatives, 8a had the most potent cytotoxic effect on all tested cancer cells, with IC50 values ranging from 1.62 ± 0.19 to 4.61 ± 0.51 µM, which were 10.38-34.36 folds more potent than the parental honokiol (IC50 values of 30.96 ± 1.81-55.67 ± 0.31 µM). On A549, HCT116, and MDA-MB-231 cell lines, 8a demonstrated 5.69-fold, 5.65-fold, and 4.83-fold greater cytotoxicity than cisplatin, respectively. Compound 8a also had higher selectivity (SI values of 8.41-49.38) towards seven cancer cell lines over the normal cell lines than cisplatin (SI values of 1.24-2.52). The analysis of structure-activity relationships (SARs) revealed that honokiol derivatives bearing 1,3,4-thiadiazoles (8a-j) possessed stronger anticancer activity than those containing 1,3,4-oxadiazoles. Further mechanistic investigation indicated that 8a induced cytotoxic autophagy in cancer cells in a time- and dose-independent manner via suppressing the PI3K/Akt/mTOR pathway. Molecular docking suggested that 8a could bind to the PI3Kα active sites. Additionally, 8a inhibited the migration and invasion of A549 and MDA-MB-231 cancer cells.

IRE1α/NOX4 signaling pathway mediates ROS-dependent activation of hepatic stellate cells in NaAsO2 -induced liver fibrosis.

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague-Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol-requiring enzyme 1α (IRE1α)-endoplasmic reticulum (ER)-stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2 . In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4-mediated ROS generation.

Programmed death 1, ligand 1 and 2 correlated genes and their association with mutation, immune infiltration and clinical outcomes of hepatocellular carcinoma.

BACKGROUND: The exact regulation network of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) signaling in immune escape is largely unknown. We aimed to describe the gene expression profiles related to PD-1 as well as its ligands PD-L1 and PD-L2, thus deciphering their possible biological processes in hepatocellular carcinoma (HCC). AIM: To find the possible mechanism of function of PD-1, PD-L1, and PD-L2 in HCC. METHODS: Based on the expression data of HCC from The Cancer Genome Atlas, the PD-1/PD-L1/PD-L2 related genes were screened by weighted correlation network analysis method and the biological processes of certain genes were enriched. Relation of PD1/PD-L1/PD-L2 with immune infiltration and checkpoints was investigated by co-expression analysis. The roles of PD-1/PD-L1/PD-L2 in determination of clinical outcome were also analyzed. RESULTS: Mutations of calcium voltage-gated channel subunit alpha1 E, catenin beta 1, ryanodine receptor 2, tumor suppressor protein p53, and Titin altered PD-1/PD-L1/PD-L2 expression profiles in HCC. PD-1, PD-L1, and PD-L2 related genes were mainly enriched in biological procedures of T cell activation, cell adhesion, and other important lymphocyte effects. In addition, PD-1/PD-L1/PD-L2 was related with immune infiltration of CD8 T cells, cytotoxic lymphocytes, fibroblasts, and myeloid dendritic cells. Immune checkpoints of CTLA4, CD27, CD80, CD86, and CD28 were significantly related to the PD-1/PD-L1/PD-L2 axis. Clinically, PD-1 and PD-L2 expression was correlated with recurrence (P = 0.005 for both), but there was no significant correlation between their expression and HCC patient survival. CONCLUSION: Mutations of key genes influence PD-1, PD-L1, and PD-L2 expression. PD-1, PD-L1, and PD-L2 related genes participate in T cell activation, cell adhesion, and other important lymphocyte effects. The finding that PD-1/PD-L1/PD-L2 is related to immune infiltration and other immune checkpoints would expand our understanding of promising anti-PD-1 immunotherapy.

Characteristics of Drug-Induced Liver Injury in Northeast China: Disease Spectrum and Drug Types.

BACKGROUND: The aim of this study was to determine the disease spectrum and drug types causing drug-induced liver injury (DILI) in northeast China, so that the affected population can be reminded of the need to increase their post-medication monitoring. METHODS: A total of 470 DILI patients hospitalized at Shengjing Hospital between 2013 and 2016 were involved in this retrospective study. RESULTS: There were significant differences in the disease spectrum of the different age groups (P < 0.001) and genders (P = 0.009). Drugs used to treat osteopathies, dermatitis and infections, as well as health care supplements, each accounted for > 10% of all drugs that caused DILI. The percentage of DILIs related to Chinese herbal medicines (CHMs) gradually increased with patient age (P = 0.002). The percentage of males taking health supplements or CHMs was significantly lower compared with females. Total bilirubin (ß = 0.01, OR = 1.01, P < 0.001) and INR (ß = 0.74, OR = 2.11, P < 0.001) were found to be independent predictors of liver damage. CONCLUSIONS: The main type of drug that causes DILI in northeast China is a CHM. There are differences in the disease spectrum found in DILI patients of different ages and gender. Making appropriate changes in the drug-taking habits of high-risk groups and the drugs used to treat high-risk underlying diseases, as well as increasing patient monitoring, may help to reduce the incidence of DILIs.

Data on chemical composition of alkaloids of Plumula nelumbinis and antioxidant activity from thirteen habitats in China.

Plumula nelumbinis is widely consumed as tea for its pharmacological properties, which is related to its chemical composition, so the identification of the major compounds of P. nelumbinis is valuable. The data described in this article is supported by the research article entitled "Chemical composition of alkaloids of Plumula nelumbinis and their antioxidant activity from different habitats in China" (Tian et al., 2018). Included are the MS-MS Spectrograms of seven alkaloid standards and thirty alkaloids identified in the P. nelumbinis, which is based on ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry method. Also included are the total alkaloids content and the antioxidant activity of total alkaloid in P. nelumbinis from 13 habitats in China, which was accomplished with three different antioxidant assays.

Date on identification of flavonoids in Plumula nelumbinis by UPLC-ESI-QTOF-MS and antioxidant activity from 13 habitats in China.

Plumula nelumbinis is a well-known health food and a traditional Chinese medicine, is used in many countries around the world. For its pharmacological properties are related to its chemical composition, a ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) method was used to identify the flavonoids in P. nelumbinis. The first set of data shows the MS-MS Spectrograms of 12 flavonoid standards and 38 flavonoids detected in the P. nelumbinis from Xiangtan, Hunan province. The second set of data shows the total flavonoids content and the antioxidant activity of total flavonoid in P. nelumbinis from 13 habitats. The antioxidant activity were accomplished with 1,1-diphenyl-2-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and ferric reducing ability of plasma (FRAP) assays.