Transcriptome profiling reveals dysregulation of inflammatory and protein synthesis genes in PCOS.

To analyze the differential expression genes of polycystic ovary syndrome (PCOS), clarify their functions and pathways, as well as the protein-protein interaction network, identify HUB genes, and explore the pathological mechanism. PCOS microarray datasets were screened from the GEO database. Common differentially expressed genes (co-DEGs) were obtained using GEO2R and Venn analysis. Enrichment and pathway analyses were conducted using the DAVID online tool, with results presented in bubble charts. Protein-protein interaction analysis was performed using the STRING tool. HUB genes were identified using Cytoscape software and further interpreted with the assistance of the GeneCards database. A total of two sets of co-DEGs (108 and 102), key proteins (15 and 55), and hub genes (10 and 10) were obtained. The co-DEGs: (1) regulated inflammatory responses and extracellular matrix, TNF, and IL-17 signaling pathways; (2) regulated ribosomes and protein translation, ribosome and immune pathways. The key proteins: (1) regulated inflammation, immunity, transcription, matrix metabolism, proliferation/differentiation, energy, and repair; (2) regulated ubiquitination, enzymes, companion proteins, respiratory chain components, and fusion proteins. The Hub genes: (1) encoded transcription factors and cytokines, playing vital roles in development and proliferation; (2) encoded ribosomes and protein synthesis, influencing hormone and protein synthesis, associated with development and infertility. The dysregulated expression of inflammation and protein synthesis genes in PCOS may be the key mechanism underlying its onset and progression.

Dauresorcinols A and B, two pairs of merosesquiterpenoid enantiomers with new carbon skeletons from Rhododendron dauricum.

Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A-E (1-5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh2(OCOCF3)4-induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1-5 are proposed involving key oxa-electrocyclization and Wagner-Meerwein rearrangement reactions. (+)/(-)-1 and 3-5 showed potent α-glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α-glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α-glycosidase inhibitors.

Structurally diverse analgesic diterpenoids from the flowers of Rhododendron molle.

Thirteen diterpenoids (1-13), classified into four structurally diverse carbon skeletons, including 1,5-seco-kalmane (1 and 6), grayanane (2-11), kalmane (12), and rhodomollane (13), were isolated from the flowers extract of Rhododendron molle. Among them, rhodomollinols A - E (1-5) were five new diterpenoids and their structures were elucidated by extensive spectroscopic methods including HRESIMS, UV, IR, 1D and 2D NMR, as well as quantum ECD calculations. Rhodomollinol A (1) is the first representative of a 6-deoxy-1,5-seco-kalmane diterpenoid. The abnormal NMR phenomenon of the presence of only 9 carbon resonances instead of 20 carbons in the 13C NMR spectrum of 1 was observed and elucidated by the quantum NMR calculations. All diterpenoids 1-13 showed significant analgesic activities in an acetic acid-induced writhing model. It's the first time to report the analgesic activity of a rhodomollane-type diterpenoid. At a dose of 1.0 mg/kg, diterpenoids 1-3, 6, 8, 9, and 12 reduced the writhe numbers with inhibition rates over 50%, and 9 exhibited stronger analgesic activity with a writhe inhibition rate of 89.7% than that of the positive control morphine. Importantly, even at the lowest dose of 0.04 mg/kg, rhodomollinols A (1) and B (2), rhodomollein X (7), and 2-O-methylrhodojaponin VI (9) still showed more potent analgesic effects than morphine with the writhe inhibition rates of 51.8%, 48.0%, 61.7%, and 60.0%, respectively. A preliminary structure-activity relationship might provide some clues to design potential analgesics on the basis of structurally diverse Ericaceae diterpenoids.

Discovery of highly functionalized grayanane diterpenoids from the flowers of Rhododendron molle as potent analgesics.

A systematical investigation on the chemical constituents of the flowers of Rhododendron molle (Ericaceae) led to the isolation and characterization of thirty-eight highly functionalized grayanane diterpenoids (1-38), including twelve novel analogues molleblossomins A-L (1-12). Their structures were elucidated by comprehensive methods, including 1D and 2D NMR analysis, calculated ECD, 13C NMR calculations with DP4+ probability analysis, and single crystal X-ray diffraction. Molleblossomins A (1), B (2), and E (5) are the first representatives of 2ß,3ß:9ß,10ß-diepoxygrayanane, 2,3-epoxygrayan-9(11)-ene, and 5,9-epoxygrayan-1(10),2(3)-diene diterpenoids, respectively. Molleblossomins G (7) and H (8) represent the first examples of 1,3-dioxolane-grayanane conjugates furnished with the acetaldehyde and 4-hydroxylbenzylidene acetal moieties, respectively. All grayanane diterpenoids 1-38 were screened for their analgesic activities in the acetic acid-induced writhing model, and all of them exhibited significant analgesic activities. Diterpenoids 6, 13, 14, 17, 20, and 25 showed more potent analgesic effects than morphine at a lower dose of 0.2 mg/kg, with the inhibition rates of 51.4%, 68.2%, 94.1%, 66.9%, 97.7%, and 60.0%, respectively. More importantly, even at the lowest dose of 0.04 mg/kg, rhodomollein X (14), rhodojaponin VI (20), and rhodojaponin VII (22) still significantly reduced the number of writhes in the acetic acid-induced pain model with the percentages of 61.7%, 85.8%, and 64.6%, respectively. The structure-activity relationship was summarized and might provide some hints to design novel analgesics based on the functionalized grayanane diterpenoids.

Bidirectional Interphase Modulation of Phosphate Electrolyte Enables Intrinsic Safety and Superior Stability for High-Voltage Lithium-Metal Batteries.

Developing advanced high voltage lithium-metal batteries (LMBs) with superior stability and intrinsic safety is of great significance for practical applications. However, the easy flammability of conventional carbonate solvents and inferior compatibility of commercial electrolytes for both highly reactive Li anodes and high-voltage cathodes severely hinder the implementation process. Hence, we rationally designed an intrinsically nonflammable and low-cost phosphate electrolyte toward stable high-voltage LMBs by bidirectionally modulating the interphases. Benefiting from the synergistic regulation of LiNO3 and DME dual-additives in the 1.5 M LiTFSI/Triethyl phosphate electrolyte, thin, dense and robust electrodes/electrolyte interphases were well constructed simultaneously on the surfaces of Li anode and Ni-rich cathode, dramatically improving the stability and compatibility between electrodes and electrolyte. Consequently, boosted kinetic and high Coulombic efficiency of 98.6% for Li metal plating/stripping over 400 cycles and superior cycling stability of exceeding 4,000 h in Li symmetric cell is achieved. More importantly, the Li∥LiNi0.6Mn0.2Co0.2O2 cell assembled with a thin Li anode and high mass-loading cathode at a high cutoff voltage of 4.6 V retains a 98.4% capacity retention after 500 cycles at 1C. This work affords a promising strategy to develop nonflammable electrolytes enabling the high safety, good cyclability, and low cost of high-energy LMBs.

Five new species of the genus Hermonassa Walker, 1865 from Xizang Autonomous Region, China (Lepidoptera, Noctuidae, Noctuinae).

Five new species of the genus Hermonassa Walker, 1865 (H.nigricanssp. nov., H.conusasp. nov., H.brunneocuprinasp. nov., H.albimaculasp. nov., and H.linzhiensis, sp. nov. are described from Autonomic Region Xizang, China (Tibet). Hermonassanigricanssp. nov. is distributed in Nepal and China, and the Himalayan species H.kalamantra Kovács, G. Ronkay & L. Ronkay, 2018 is reсorded for China for the first time. The occurrences of H.anthracina Boursin, 1967 in Nepal is questionable taking in the account the presence of two externally hardly distinguishable species, H.kalamantra and H.nigricanssp. nov. New collecting data for H.yixincheni Han & Li, 2007 and H.oleographa Hampson, 1911 in China are presented. Five species groups are reviewed, and three species groups are designated.

A Three-Dimensional (3D) Framework of Freestanding Vanadium Nitride Nanowires for Dendrite-Free and Long Life-Span Lithium Metal Anodes.

Lithium (Li) metal is a promising anode candidate for high-energy-density batteries owing to its high theoretical capacity and low electrochemical potential. However, uneven Li nucleation, uncontrollable dendritic growth, infinite voltage change and even safety issues hinder its commercial application. Herein, a three-dimensional (3D) framework of freestanding vanadium nitride nanowires (VN NWs) is established as Li host for dendrite-free Li metal anode. A lithiophilic Li3 N interlayer which in situ formed by the surface reaction between molten Li and VN NWs is utilized to guide a uniform Li nucleation and deposition within the skeleton, as well as avoid the dendrite formation. Meanwhile, VN NWs can decrease local current density, homogenize Li-ion flux and accommodate volume fluctuations of the anode due to its 3D structure with high electron conductivity. Thus, the corresponding composite Li metal anode delivers a long-life span of 500 cycles (1000 h) at a current density of 0.5 mA cm-2 , and exhibits lower nucleation over-potential and voltage hysteresis at different current densities from 0.5~5 mA cm-2 in carbonate electrolyte. In conclusion, this work provides a new type of scaffold with both high electronic conductivity and excellent lithiophilicity for stable Li anodes.

Structural and Interfacial Manipulation of Multifunctional Skeletons Enabled Shuttling-Free and Dendrite-Free Li-S Full Batteries.

Li-S batteries are regarded as promising devices for energy storage systems owing to high energy density, low cost, and environmental friendliness. However, challenges of polysulfides shuttling in sulfur cathode and dendrite growth of lithium anode severely hinder the practical application. Developing advanced skeletons simultaneously regulating the cathode and anode is significant and challenging. Hence, a novel and scalable strategy combining spray drying and topological nitriding is proposed, and hierarchically assembled rGO hollow microspheres encapsulated highly porous nanospheres consisted of ultrafine Nb4 N5 -Nb2 O5 or Nb4 N5 nanoparticles as multifunctional skeletons for S and Li are designed. In such unique architecture, a 3D highly porous structure provides abundant void space for loading of S and Li, and accommodates volume change during cycling. Moreover, Nb4 N5 -Nb2 O5 heterostructured interface promotes adsorption-conversion process of polysulfides, while strong lithophilic Nb4 N5 induces the selective infiltration of Li into the void of the skeleton and regulates the uniform deposition and growth. More interestingly, in situ generated Li3 N@Nb ion/electron conducting interfaces induced by the reaction of Nb4 N5 and Li reduce the nucleation overpotential and induce selective deposition of Li into the cavity. Consequently, the Li-S full cell exhibits superior cycling stability and impressive rate performance with a low capacity ratio of negative/positive.

Phytochemical interventions for post-traumatic stress disorder: A cluster co-occurrence network analysis using CiteSpace.

OBJECTIVE: This study investigated trends in the study of phytochemical treatment of post-traumatic stress disorder (PTSD). METHODS: The Web of Science database (2007-2022) was searched using the search terms "phytochemicals" and "PTSD," and relevant literature was compiled. Network clustering co-occurrence analysis and qualitative narrative review were conducted. RESULTS: Three hundred and one articles were included in the analysis of published research, which has surged since 2015 with nearly half of all relevant articles coming from North America. The category is dominated by neuroscience and neurology, with two journals, Addictive Behaviors and Drug and Alcohol Dependence, publishing the greatest number of papers on these topics. Most studies focused on psychedelic intervention for PTSD. Three timelines show an "ebb and flow" phenomenon between "substance use/marijuana abuse" and "psychedelic medicine/medicinal cannabis." Other phytochemicals account for a small proportion of the research and focus on topics like neurosteroid turnover, serotonin levels, and brain-derived neurotrophic factor expression. CONCLUSION: Research on phytochemicals and PTSD is unevenly distributed across countries/regions, disciplines, and journals. Since 2015, the research paradigm shifted to constitute the mainstream of psychedelic research thus far, leading to the exploration of botanical active ingredients and molecular mechanisms. Other studies focus on anti-oxidative stress and anti-inflammation. Please cite this article as: Gao B, Qu YC, Cai MY, Zhang YY, Lu HT, Li HX, Tang YX, Shen H. Phytochemical interventions for post-traumatic stress disorder: A cluster co-occurrence network analysis using CiteSpace. J Integr Med. 2023; 21(4):385-396.

Design, synthesis and biological evaluation of phosphoroxy quinazoline derivatives as potential EGFRT790M/C797S inhibitors.

Owing to the urgency and importance of developing fourth-generation EGFR inhibitors that can effectively overcome C797S site mutation in NSCLC, Brigatinib was used in this work as a lead compound to modify its structure to obtain a series of phosphoroxy quinazoline derivatives. Biological study indicated that the inhibitory activity and selectivity of the target compounds on EGFRL858R/T790M/C797S/EGFRDel19/T790M/C797S enzymes and EGFRDel19/T790M/C797S overexpressed Ba/F3 cells were significantly better than those of Brigatinib. Among the target compounds, 8a exhibited the best biological activity in vitro. More importantly, 8a presented acceptable pharmacokinetic behaviors and showed potent anti-tumor efficacy in the Ba/F3-EGFRDel19/T790M/C797S subcutaneous xenograft mice model with the tumor growth inhibition value of 82.60% at a dose of 30 mg/kg. These results indicated that 8a, as a drug candidate of the novel fourth-generation EGFR small-molecule inhibitor, has high potentials to treat with NSCLC on EGFR with C797S mutation.

A novel implant surface modification mode of Fe3O4-containing TiO2 nanorods with sinusoidal electromagnetic field for osteoblastogenesis and angiogenesis.

Implants made of Ti and its alloys are widely utilized in orthopaedic surgeries. However, insufficient osseointegration of the implants often causes complications such as aseptic loosening. Our previous research discovered that disordered titanium dioxide nanorods (TNrs) had satisfactory antibacterial properties and biocompatibility, but TNrs harmed angiogenic differentiation, which might retarded the osseointegration process of the implants. Magnetic nanomaterials have a certain potential in promoting osseointegration, electromagnetic fields within a specific frequency and intensity range can facilitate angiogenic and osteogenic differentiation. Therefore, this study used Fe3O4 to endow magnetism to TNrs and explored the regulation effects of Ti, TNrs, and Fe3O4-TNrs under 1 â€‹mT 15 â€‹Hz sinusoidal electromagnetic field (SEMF) on osteoblastogenesis, osseointegration, angiogenesis, and its mechanism. We discovered that after the addition of SEMF treatment to VR-EPCs cultured on Fe3O4-TNrs, the calcineurin/NFAT signaling pathway was activated, which then reversed the inhibitory effect of Fe3O4-TNrs on angiogenesis. Besides, Fe3O4-TNrs with SEMF enhanced osteogenic differentiation and osseointegration. Therefore, the implant modification mode of Fe3O4-TNrs with the addition of SEMF could more comprehensively promote osseointegration and provided a new idea for the modification of implants.

Estrogen-related genes influence immune cell infiltration and immunotherapy response in Hepatocellular Carcinoma.

Background: Immunotherapy has been the first-line treatment option in advanced Hepatocellular Carcinoma(HCC); but now, there are no established molecular markers that can predict immunotherapy response. Estrogen has a crucial role in the development of a variety of liver illnesses, including liver fibrosis, Nonalcoholic fatty liver disease (NAFLD), and HCC. Nonetheless, the significance of estrogen-related genes in HCC immunotherapy and the underlying molecular mechanisms are not yet fully understood. Method: In this study, we constructed a novel estrogen-related gene prognostic signature (ERGPS) by analyzing bulk RNA sequencing data from 365 HCC patients. Based on the median risk score, we divided 365 HCC patients into low- and high-risk groups. Tumor mutation burden (TMB), Microsatellite instability (MSI), T cell receptor (TCR) richness, B cell receptor (BCR) richness, single-nucleotide variants (SNV) Neoantigens, Cancer Testicular Antigens (CTA) scores, and Tumour Immune Dysfunction and Exclusion (TIDE) scores were used to evaluate the magnitude of immunotherapy response. Multiple external datasets validate the validity and robustness of the prognostic signature. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate estrogen-related gene overexpression in HCC tissue samples. Results: ERGPS is an independent risk factor affecting the prognosis of HCC patients and is superior to other clinical variables in predicting patient survival and immunotherapy response. Multiple independent external datasets confirmed the superior predictive efficacy of the prognostic signature. The prognostic signature was positively correlated with TMB score, MSI score, TCR richness, BCR richness, SNV Neoantigens score, CTA score, expression levels of immune checkpoint-related genes, and TIDE score. Patients with HCC in the high-risk group identified by the prognostic signature were likely to be more responsive to immunotherapy and more suitable for immunotherapy. qRT-PCR confirmed that estrogen-related genes of the construct signature were highly expressed in HCC tumor tissues. Conclusion: Estrogen-related genes are overexpressed in HCC tissues. Our novel prognostic signature can accurately predict not only the prognosis but also the immunotherapy response of HCC patients. In the future, prognostic signatures will be a useful tool for clinicians to screen patients with HCC who are suitable for immunotherapy.

Novel methylated flavoalkaloids from Echa 1 green tea inhibit fat accumulation and enhance stress resistance in Caenorhabditis elegans.

Methylation is a common structural modification of catechins in tea, which can improve the bioavailability of catechins. Flavoalkaloids are catechin derivatives with a nitrogen containing five-membered ring at the C-6 or C-8 position. Here we isolated three new methylated flavoalkaloids from Echa 1 green tea (Camellia sinensis cv. Echa 1) and synthesized another four new methylated flavoalkaloids. The structures of the new ester-type methylated catechins (etmc)-pyrrolidinone A-G (1-7) were elucidated by various spectroscopic techniques, including nuclear magnetic resonance (NMR), optical rotation, infrared, UV-vis, experimental and calculated circular dichroism (CD) spectra, and high-resolution mass. Among them, 6 and 7 showed the strongest α-glucosidase inhibitory activity and significantly lowered lipid content of Caenorhabditis elegans with 73.50 and 67.39% inhibition rate, respectively. Meanwhile, 6 and 7 also exhibited strong antioxidant activity in vitro and stress resistance to heat, oxidative stress, and UV irradiation in nematodes.

Understanding smart education continuance intention in a delayed benefit context: An integration of sensory stimuli, UTAUT, and flow theory.

Smart education is a combination of AI and education, and its benefits are delayed. Existing research lacks an understanding of smart education continuance intention in the context of this delayed benefit. Thus, this study aimed to examine users' continuance intention in a delayed benefit context by integrating sensory stimulus, the extended UTAUT, and flow theory. The study focused on a mobile-based smart education (MBSE) system (Liulishuo) and collected data on 494 MBSE users. The PLS-SEM analysis suggested that the model is largely supported. Identifying MBSE's technical attributes as sensory stimuli, the extended UTAUT as primary information processing, flow as secondary information processing, and continuance intention as a decision, this study verifies the relationships between various constructs and their influence on MBSE continuance intention. The results also indicate that a user's flow state plays a crucial role in strengthening continuance intention and realizing the delayed benefits of smart education. Thus, this study provides a deeper understanding of continuous usage mechanisms as they relate to smart education.

Highly oxygenated grayanane diterpenoids with structural diversity from the flowers of Rhododendron dauricum and their analgesic activities.

Twenty-eight grayanane diterpenoids (1-28) including 13 new ones, named daublossomins A-M (1-13), and two new natural products, 3-O-acetylgrayanotoxin II (14) and 10-epi-grayanotoxin III (15), were isolated from the flowers of Rhododendron dauricum L. (Ericaceae). Their structures were elucidated by means of comprehensive spectroscopic methods and quantum chemical calculations (13C NMR-DP4+ analysis and calculated ECD), and the absolute configurations of ten grayanane diterpenoids 1, 4, 5, 7, 8, 22, 23, 25, 27, and 28 were determined by X-ray crystallographic analysis. Daublossomin A (1) represents the first example of an 11,16-epoxygrayan-6-one diterpenoid. Daublossomins B (2) and C (3) are the first examples of 9ß,10ß-epoxygrayanane diterpenoids, and daublossomin I (9) is the second conjugated grayan-1(5),6(7),9(10)-triene diterpenoid. Compounds 1-11 and 13-27 were evaluated for their analgesic activities in the HOAc-induced writhing test in mice, and 1-8, 10, 11, 13, 15, 17, 18, 22-24, and 26 exhibited significant analgesic effects at a dose of 5.0 mg/kg (inhibition rates > 50%). Among them, daublossomins A (1) and F (6) still showed potent analgesic activity even at a lower dose of 0.2 mg/kg with the inhibition rates of 54.4% and 55.2%, respectively. Grayanotoxin III (20) showed more potent analgesic activities than the positive control, morphine, at a dose of 0.04 mg/kg. A preliminary structure-activity relationship for the analgesic grayanane diterpenoids was discussed, providing some useful clues to design and develop structurally novel potent analgesics.

Cellular senescence affects energy metabolism, immune infiltration and immunotherapeutic response in hepatocellular carcinoma.

Aging is an inevitable consequence of life, characterized by a progressive decline in tissue and organ function and an increased risk of death. There is growing evidence that aging is closely related to tumor development and immune regulation. However, in hepatocellular carcinoma, the relationship between cellular senescence and immune infiltration, energy metabolism, chemokines, and immunotherapeutic response is unclear and needs further study. We first analyzed 274 cellular senescence-associated genes by the NMF algorithm and identified two cellular senescence-associated clusters. Subsequently, we compared the differences between the two clusters, in terms of immune infiltration, energy metabolism, chemokines, and immunotherapeutic response to treatment. We further constructed risk models using cellular senescence-associated signature genes that could effectively identify the two subpopulations. Finally, we validated the validity and robustness of the risk model using an external dataset. We found significant differences in survival prognosis between two cellular senescence-associated clusters. In addition, we found significant differences in immune cell infiltration, expression of energy metabolism-related genes, expression of chemokine-related genes, expression of immune checkpoint-related genes, Tumor Immune Dysfunction and Exclusion between the two clusters. Also, a scoring system associated with cellular senescence was developed and validated as an independent prognostic indicator. It was validated as an independent prognostic factor and immunotherapeutic predictor for HCC. It was validated as an independent prognostic factor and immunotherapeutic predictor for HCC. The cellular senescence-related scoring system was validated as an independent prognostic factor and immunotherapy predictor for HCC, and patients with low CSS were characterized by prolonged survival time. Our study confirmed the relationship between cellular senescence and immune cell infiltration, energy metabolism, chemokines, expression of immune checkpoint-related genes, and response to immunotherapy. This enhances our understanding of cellular senescence and tumor immune microenvironment, energy metabolism, chemokines, and provides new insights to improve immunotherapy outcomes in HCC patients. It provides new insights to improve the outcome of immunotherapy in HCC patients.

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture.

Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A-D (1-4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.

Structurally diverse alkaloids with nine frameworks from Zephyranthes candida and their acetylcholinesterase inhibitory and anti-inflammatory activities.

Twenty-six structurally diverse Amaryllidaceae alkaloids, including ten undescribed compounds named zephyranines A-I and 6-O-ethylnerinine, two undescribed natural products zephyranthine-6-one and 3-O-deacetyl-sternbergine, were isolated from whole plants of Zephyranthes candida. Their structures were determined by HRESIMS, 1D and 2D NMR, CD data analysis, NMR and ECD calculations, and single-crystal X-ray diffraction analysis. All structures were classified into nine framework types: 10b,11-seco-crinine, graciline, crinine, homolycorine, trisphaeridine, lycorine, galasine, tazettine, and belladine. Zephyranine A represents the first naturally occurring 10b,11-seco-crinine type alkaloid, and zephyranine B is the sixth graciline type alkaloid. 6-O-ethylnerinine is an artifact from the extraction and isolation. All isolates were evaluated for their acetylcholinesterase (AChE) inhibitory and anti-inflammatory activities. Zephyranines A, G, and H exhibited moderate AChE inhibitory activities, with IC50 values of 8.2, 39.0, and 10.8 µM, respectively. Zephyranine B, haemanthamine, haemanthidine, 11-hydroxyvittatine, and 8-demethoxy-10-O-methylhostasine exhibited potent anti-inflammatory activity on the LPS-induced NO production in RAW264.7 mouse macrophages with IC50 values of 21.3, 4.6, 12.2, 5.6, and 17.4 µM, respectively. Structure-activity-relationship analysis and docking studies indicated that interactions with the key Trp286 and Tyr337 residues are required for potent AChE inhibitors.

Construction and validation of a novel signature based on epithelial-mesenchymal transition-related genes to predict prognosis and immunotherapy response in hepatocellular carcinoma by comprehensive analysis of the tumor microenvironment.

Immunotherapy has yielded encouraging results in the treatment of advanced hepatocellular carcinoma (HCC). However, the relationship between epithelial-mesenchymal transition (EMT) and immunotherapy for HCC has not been adequately explained. In this study, we comprehensively analyzed a bulk RNA sequence dataset of 365 HCC patients in The Cancer Genome Atlas (TCGA) dataset. Subsequently, we constructed a prognostic signature based on 6 EMT-related genes and divided 365 HCC patients into high- and low-risk groups. The predictive efficacy of the signature was well validated in different clinical subgroups and in two independent external datasets. We further explored the relationship between prognostic signature and immunotherapy response in terms of immune cell infiltration, somatic mutations, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint-associated gene expression, single-nucleotide variants (SNV) neoantigens, cancer testicular antigens (CTA) scores, and tumor immune dysfunction and exclusion (TIDE) scores. We validated the predictive efficacy of prognostic signature for immunotherapy response using external independent immunotherapy data. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate EMT-related gene overexpression in HCC tissue samples. Prognostic signature was an independent risk factor affecting the prognosis of HCC patients and has shown superiority in predicting patient survival compared to other clinical factors. Compared with the low-risk group, the proportion of Activated_CD4_T_cell, Type_2_T_helper_cel, and macrophages were higher in the tumor microenvironment of HCC patients in the high-risk group, while the Activated_CD8_T_cell and CD56bright_natural_killer_cell proportions were lower. The prognostic signature was positively correlated with TMB scores, MSI scores, SNV neoantigens scores, expression levels of immune checkpoint-related genes, and TIDE scores, and patients in the high-risk group were more suitable for immunotherapy. qRT-PCR confirms overexpression of 6 EMT-related genes in HCC tissues for the construction of prognostic signature. Our novel prognostic signature can effectively predict the prognosis and immunotherapy response of HCC patients. In the future, it will be an effective tool for physicians to screen suitable immunotherapy populations and improve response rates and overall survival (OS).

MoO2 nanosheets anchored with Co nanoparticles as a bifunctional electrocatalytic platform for overall water splitting.

Electrochemical water splitting is one of the potential commercial techniques to produce clean hydrogen energy because of the high efficiency and environmental friendliness. However, development of low-cost bifunctional electrocatalysts that can replace Pt-based catalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is challenging. Herein, Co nanoparticles (NPs) are anchored on MoO2 nanosheets (Co/MoO2) by thermal reduction of the CoMoO4 nanosheet array in Ar/H2. The uniformly distributed Co NPs improve the electron transfer capability and modulate the surface states of the MoO2 nanosheets to enhance hydrogen desorption and HER kinetics. Moreover, the Co/MoO2 composite is beneficial to the interfacial structure and the MoO2 nanosheets prevent aggregation of Co NPs to improve the intrinsic OER characteristics in the alkaline electrolyte. As a result, the Co/MoO2 electrocatalyst shows low HER and OER overpotentials of 178 and 318 mV at a current density of 10 mA cm-2 in 1 M KOH. The electrolytic cell consisting of the bifunctional Co/MoO2 electrodes shows a small voltage of 1.72 V for a current density of 10 mA cm-2 in overall water splitting.