Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Swieteliacates S-U, phragmalin limonoids, from the leaves of Swietenia macrophylla.

Three novel phragmalin-type limonoids, swieteliacates S-U (1-3), were isolated from Swietenia macrophylla leaves, alongside four previously identified limonoids (4-7). The structures, encompassing absolute configurations, were delineated through 1D and 2D NMR analyses, high-resolution mass spectrometry (HR-MS), and NMR and ECD calculations. Swieteliacate S (1) is a distinctive cryptate comprising a tricyclo[4.2.110,30.11,4]decane fragment and an additional five-membered oxygen ring. Compounds 3 and 5 exhibited inhibition rates of 26.08 ± 2.26% and 15.42 ± 3.66%, respectively, on triglyceride (TG) production in Hep G2 cells at 40 µM.

Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding.

Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.

The structure of a minimum amyloid fibril core formed by necroptosis-mediating RHIM of human RIPK3.

Receptor-interacting protein kinases 3 (RIPK3), a central node in necroptosis, polymerizes in response to the upstream signals and then activates its downstream mediator to induce cell death. The active polymeric form of RIPK3 has been indicated as the form of amyloid fibrils assembled via its RIP homotypic interaction motif (RHIM). In this study, we combine cryogenic electron microscopy and solid-state NMR to determine the amyloid fibril structure of RIPK3 RHIM-containing C-terminal domain (CTD). The structure reveals a single protofilament composed of the RHIM domain. RHIM forms three ß-strands (referred to as strands 1 through 3) folding into an S shape, a distinct fold from that in complex with RIPK1. The consensus tetrapeptide VQVG of RHIM forms strand 2, which zips up strands 1 and 3 via heterozipper-like interfaces. Notably, the RIPK3-CTD fibril, as a physiological fibril, exhibits distinctive assembly compared with pathological fibrils. It has an exceptionally small fibril core and twists in both handedness with the smallest pitch known so far. These traits may contribute to a favorable spatial arrangement of RIPK3 kinase domain for efficient phosphorylation.

Phlorizin, an Important Glucoside: Research Progress on Its Biological Activity and Mechanism.

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1ß/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.

CHI3L1 promotes myocardial fibrosis via regulating lncRNA TUG1/miR-495-3p/ETS1 axis.

Abnormal levels of CHI3L1 and lnc TUG1 are often associated with myocardial fibrosis, and their specific expressions may be closely related to the process of myocardial fibrosis. In addition, CHI3L1 was found to significantly up-regulate the expression of lncTUG1. Therefore, this study further explored the major role of CHI3L1 in regulating the progression of myocardial fibrosis. Myocardial fibrosis in mice was established using an angiotensin (Ang II) model, and the degree of myocardial fibrosis was assessed by qPCR, western blot and pathological techniques. HL-1 cells with overexpression and silencing of CHI3L1 were constructed, and the cell migration ability was detected using the Transwell method. Biological information was used to predict the potential target miRNA of lnc TUG1, and the interaction between them was verified by dual luciferase reporter assay. Using functional rescue assay and the rAAV9 technique, CHI3L1 was verified to affect the fibrotic process of myocardial cells by regulating the lnc TUG1/miR-495-3p/ETS1 axis in vitro and in vivo. The myocardial fibrosis index in the model group was significantly upregulated, and expression of both CHI3L1 and lnc TUG1 was upregulated. Pathological results revealed fibrosis and collagen deposition in the myocardium. Overexpression of lnc TUG1 reversed the inhibitory effect of CHI3L1 silencing on myocardial fibrosis. Mechanistically, CH3L1 upregulates the expression of lnc TUG1, and lnc TUG1 weakens the inhibition of ETS1 through sponge absorption of miR-495-3p, promoting the process of myocardial fibrosis.

Rearranged Lindenane Sesquiterpenoid Trimers from Chloranthus fortunei: Target Discovery and Biomimetic Conversion.

Seven lindenane-type sesquiterpenoid trimers, including four new ones (1-4) and three known analogues (5-7), were isolated from Chloranthus fortunei guided by high-performance liquid chromatography with photodiode array detection with characteristic absorption at 210 and 350 nm. Their structures, including absolute configurations, were achieved by high-resolution mass spectrometry, nuclear magnetic resonance, electronic circular dichroism, and quantum chemical calculations. Compound 1 was the first example of two lindenane units connected by a C-15-C-15' bond. The 5/7/5-fused ring system in 2 was presumably formed biogenetically by key keto-enol tautomerism and Cope rearrangement from 5. The 5/3/6 carbon skeleton in 3-5 and epi-cyclopropane in 3 and 6 might have originated from trishizukaol A (7) with a normal 3/5/6-fused ring system through vinylcyclopropane rearrangement. The biomimetic conversion from 7 to 3-6 was successfully achieved by adding a 365 nm ultraviolet lamp and a free radical initiator, and 2 was also spontaneously converted to 5 in methanol and CDCl3, which proved the correctness of the structural identification and the speculation described above. Compounds 1-7 exhibited anti-inflammatory activity with IC50 values in the range of 2.90-22.80 µmol/L.

Analysis of aerosol optical depth and relation to covariates during pre-monsoon season (2002-2019) over Pakistan using ARIMAX model and cross-wavelet analysis.

The pre-monsoon season heavily influences the precipitation amount in Pakistan. When hydrometeorological parameters interact with aerosols from multiple sources, a radiative climatic response is observed. In this study, aerosol optical depth (AOD) space-time dynamics were analyzed in relation to meteorological factors and surface parameters during the pre-monsoon season in the years 2002-2019 over Pakistan. Level-3 (L3) monthly datasets from Moderate Resolution Imaging Spectroradiometer (MODIS) and Multi-Angle Imaging Spectroradiometer (MISR) were used. Tropical Rainfall Measuring Mission (TRMM) derived monthly precipitation, Atmospheric Infrared Sounder (AIRS) derived air temperature, after moist relative humidity (RH) from Modern-Era Retrospective analysis for Research and Applications, Version-2 (MERRA-2), near-surface wind speed, and soil moisture data derived from Global Land Data Assimilation System (GLDAS) were also used on a monthly time scale. For AOD trend analysis, Mann-Kendall (MK) trend test was applied. Moreover, Autoregressive Integrated Moving Average with Explanatory variable (ARIMAX) technique was applied to observe the actual and predicted AOD trend, as well as test the multicollinearity of AOD with covariates. The periodicities of AOD were analyzed using continuous wavelet transformation (CWT) and the cross relationships of AOD with prevailing covariates on a time-frequency scale were analyzed by wavelet coherence analysis. A high variation of aerosols was observed in the spatiotemporal domain. The MK test showed a decreasing trend in AOD which was most significant in Baluchistan and Punjab, and the overall trend differs between MODIS and MISR datasets. ARIMAX model shows the correlation of AOD with varying meteorological and soil parameters. Wavelet analysis provides the abundance of periodicities in the 2-8 months periodic cycles. The coherency nature of the AOD time series along with other covariates manifests leading and lagging effects in the periodicities. Through this, a notable difference was concluded in space-time patterns between MODIS and MISR datasets. These findings may prove useful for short-term and long-term studies including oscillating features of AOD and covariates.

Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM.

Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson's disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

Financial performance of China's listed firms in presence of coronavirus: Evidence from corporate culture and corporate social responsibility.

Motivated from the shortage of the existing research studies on impacts of dangerously contagious diseases on firms' financial performance, this study sheds light on the impacts of Coronavirus (Covid-19) outbreak on financial performance upon on the quarterly data of 126 Chinese listed firms across 16 industries. Overall, the Covid-19 outbreak reduced Chinese listed firms' financial performance proxied by the revenue growth rate, ROA, ROE, and asset turnover. This outbreak's negative effects on Chinese firms' profitability were much smaller than that on their revenue growth rates. While this outbreak's negative effects on financial performance of Chinese listed firms were bigger for those that were seriously affected by this pandemic like airlines, travel, and entertainment (ATE), this pandemic's effects were positive for the medicine industry. In the meanwhile, Chinese listed firms that located in high-risk regions suffered a bigger financial loss during the outbreak, and especially there was a strong Hubei effect. The corporate culture and CSR moderated the inverse relationship between this outbreak and Chinese firms' financial performance. Findings of this study contribute to enrich the existing literature on impacts of the Covid-19 outbreak on firms' financial performance worldwide and suggest helpful practical and theoretical implications.

Research progress of meliaceous limonoids from 2011 to 2021.

Covering: July 2010 to December 2021Limonoids, a kind of natural tetranortriterpenoids with diverse skeletons and valuable insecticidal and medicinal bioactivities, are the characteristic metabolites of most plants of the Meliaceae family. The chemistry and bioactivities of meliaceous limonoids are a continuing hot area of natural products research; to date, about 2700 meliaceous limonoids have been identified. In particular, more than 1600, including thirty kinds of novel rearranged skeletons, have been isolated and identified in the past decade due to their wide distribution and abundant content in Meliaceae plants and active biosynthetic pathways. In addition to the discovery of new structures, many positive medicinal bioactivities of meliaceous limonoids have been investigated, and extensive achievements regarding the chemical and biological synthesis have been made. This review summarizes the recent research progress in the discovery of new structures, medicinal and agricultural bioactivities, and chem/biosynthesis of limonoids from the plants of the Meliaceae family during the past decade, with an emphasis on the discovery of limonoids with novel skeletons, the medicinal bioactivities and mechanisms, and chemical synthesis. The structures, origins, and bioactivities of other new limonoids were provided as ESI. Studies published from July 2010 to December 2021 are reviewed, and 482 references are cited.

Automatic MS/MS Data Mining Strategy for Discovering Target Natural Products: A Case of Lindenane Sesquiterpenoids.

Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a widely used method for discovering natural products (NPs); however, automatic MS/MS data mining for the discovery of NPs remains a challenge. In this work, LindenaneExtractor, a program based on characteristic MS/MS ions of lindenane sesquiterpenoids (LSs) was developed to automatically extract the LSs features for target LS discovery in plant extracts. To build this program, fragmentation mechanisms of characteristic ions of LSs were elucidated and confirmed by quantum chemical calculation and deuterium-labeled compounds. Subsequently, the information of characteristic ions was integrated and coded to develop LindenaneExtractor, which was further examined by standards and several public databases. Finally, the target LS features in Sarcandra hainanensis extract were automatically extracted by LindenaneExtractor and visualized by feature-based molecular networking and two-dimensional (2D) retention time-m/z plot, leading to the discovery of 96 target LSs in total, 37 of these compounds were potentially new NPs and one was confirmed by further isolation. This work proposed a new strategy for target NP analysis and discovery based on automatic MS/MS data mining, which could significantly improve the efficiency and accuracy of NP discovery.

CDK14/ß-catenin/TCF4/miR-26b positive feedback regulation modulating pancreatic cancer cell phenotypes in vitro and tumor growth in mice model in vivo.

INTRODUCTION: Chemotherapy and radiotherapy have been reported to be basically ineffective for pancreatic ductal adenocarcinoma patients; thus, gene therapy might provide a novel approach. CDK14, a new oncogenic member of the CDK family involved in the pancreatic cancer cell response to gemcitabine treatment, has been reported to be regulated by microRNAs. In the present study, we aimed to investigate whether miR-26b regulated CDK14 expression to affect the phenotype of pancreatic cancer cells. METHODS: Overexpression or knockdown of CDK14 or miR-26b was generated in pancreatic cancer cell lines and the function of CDK14 and miR-26b on cell phenotype and the Wnt signaling pathway was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine and transwell assays, as well as a xenograft model and western blotting. The predicted binding site between the 3'-untranslated region of CDK14 and miR-26b, miR-26b promoter and TCF4 was verified by luciferase or chromatin immunoprecipitation assays. RESULTS: CDK14 overexpression inhibited p-GSK3ß, whereas it promoted p-LRP6, the nuclear translocation of ß-catenin and the transactivation of TCF4 transcription factor, thus promoting pancreatic cancer cell aggressiveness. miR-26b directly targeted CDK14 and inhibited CDK14 expression. In vitro and in vivo, miR-26b overexpression inhibited, and CDK14 overexpression promoted, cancer cell aggressiveness; CDK14 overexpression partially attenuated the miR-26b overexpression effects on cancer cells. The effects of miR-26b overexpression on tumor growth and the Wnt/ß-catenin/TCF4 signaling were partially reversed by CDK14 overexpression. TCF4 inhibited the expression of miR-26b by targeting its promoter region. CONCLUSIONS: CDK14, ß-catenin, TCF4 and miR-26b form a positive feedback regulation for modulating pancreatic cancer cell phenotypes in vitro and tumor growth in vivo.

Sarglaromatics A-E: A Class of Naphthalene-Like Architecture Fused Norlindenane Sesquiterpene Dimers from Sarcandra glabra.

Sarglaromatics A-E (1-5, respectively), five unprecedented naphthalene-like architecture-fused norlindenane sesquiterpene dimers, were discovered from the roots of Sarcandra glabra. The unique naphthalene core skeleton was obtained from classical lindenane [4 + 2] dimers via a free-radical-mediated C11-C11' bond formation reaction and 12'-decarboxylation. The highly fused octonary ring skeleton was elucidated by HRMS, NMR, ECD, quantum chemical calculations, and biogenetic inspiration. Compounds 1 and 2 showed significant anti-nonalcoholic steatohepatitis (NASH) activity by inhibiting lipid deposition in L02 cells.

Sarcaglarone A, a lindenane-monoterpene heterodimer from the seeds of Sarcandra glabra.

Three novel lindenane-monoterpene heterodimers with different skeleton types (1-3), together with a known analogue (4), were obtained from the seeds of Sarcandra glabra. Their structures were elucidated on the basis of comprehensive spectroscopic analyses, single crystal X-ray diffraction, and calculations of ECD. Sarcaglarone A (1) displayed an unprecedented monocyclic monoterpene moiety formed by a free-radical-mediated C1'-C5' bond formation reaction. 6α-Hydroxysarglaperoxide A (2) and 7'-oxyisosarcaglabrin A (3) are C23 and C25 terpenes formed by [2 + 2 + 2] cycloaddition and the Diels-Alder reaction, respectively. Their inhibitory activities against nitric oxide (NO) production were evaluated.

Limonoids from Swietenia macrophylla and their antitumor activities in A375 human malignant melanoma cells.

Swietelinins A - C (1-3) and swieteliacates F - R (4-16), sixteen new limonoids and 18 known limonoids (17-34) were isolated from Swietenia macrophylla. The absolute configurations of these compounds were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. Swieteliacate J (10) is the first limonoid possessing an unusual 8ß, 9ß-epoxy ring system. All of the compounds were tested for cytotoxicity against four human tumor cell lines (SMMC-7721, SW620, A549, and A375). Compounds 10, 11, and 19 exhibited selectively moderate cytotoxicity against four tumor cell lines, especially 19 exhibited significant cytotoxic effects against A375 with IC50 an value of 9.8 µM and was more active than the positive control, dacarbazine with an IC50 value of 22.4 µM. Compound 19 effectively induced apoptosis of A375, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 19 significantly induced A375 cell apoptosis in a dose-dependent manner.

Giant Cardiac Cavernous Hemangioma Diagnosed with Contrast-Enhanced Ultrasound: A Case Report.

Presently, there are few reports in the database about a contrast-enhanced ultrasound-assisted diagnosis of cardiac cavernous hemangioma. We report a case of giant cavernous hemangioma of the heart, which was diagnosed using contrast-enhanced ultrasound. Finally, it was confirmed by surgical pathology. This case demonstrates that contrast-enhanced ultrasound can play an important role in the diagnosis of cardiac cavernous hemangioma.

Proteomic Analysis Reveals the Effect of Trichostatin A and Bone Marrow-Derived Dendritic Cells on the Fatty Acid Metabolism of NIH3T3 Cells under Oxygen-Glucose Deprivation Conditions.

Fibroblasts mediate acute wound healing and long-term tissue remodeling with scarring after tissue injury. Following myocardial infarction (MI), necrotized cardiomyocytes become replaced by secreted extracellular matrix proteins produced by fibroblasts. Dendritic cells (DCs) can migrate from the bone marrow to the infarct areas and infarct border areas to mediate collagen accumulation after MI. Trichostatin A (TSA) is known to regulate apoptosis and proliferation in fibroblasts and affect the functions of DCs under oxygen-glucose deprivation (OGD) conditions. In this study, we used label-free quantitative proteomics to investigate the effects of TSA and bone marrow-derived dendritic cells (BMDCs) on NIH3T3 fibroblasts under OGD conditions. The results showed that the fatty acid degradation pathway was significantly upregulated in NIH3T3 cells under OGD conditions and that the fatty acid synthesis pathway was significantly downregulated in NIH3T3 cells treated with conditioned media (CM) from BMDCs treated with TSA under OGD conditions [BMDCs-CM(TSA)]. In addition, BMDCs-CM(TSA) significantly decreased the levels of triglycerides and free fatty acids and mediated fatty acid metabolism-related proteins in NIH3T3 cells under OGD conditions. In summary, this proteomics analysis showed that TSA and BMDCs affect fatty acid metabolism in NIH3T3 cells under OGD conditions.

O-Glycosylation Induces Amyloid-ß To Form New Fibril Polymorphs Vulnerable for Degradation.

Brain accumulation of amyloid-ß (Aß) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression of Alzheimer's disease (AD). Aß peptides have diverse posttranslational modifications (PTMs) that variously modulate Aß aggregation into fibrils, but understanding the mechanistic roles of PTMs in these processes remains a challenge. Here, we chemically synthesized three homogeneously modified isoforms of Aß (1-42) peptides bearing Tyr10 O-glycosylation, an unusual PTM initially identified from the cerebrospinal fluid samples of AD patients. We discovered that O-glycans significantly affect both the aggregation and degradation of Aß42. By combining cryo-EM and various biochemical assays, we demonstrate that a Galß1-3GalNAc modification redirects Aß42 to form a new fibril polymorphic structure that is less stable and more vulnerable to Aß-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation modifications affect Aß42 aggregation at the molecular level, our study provides powerful experimental tools to support further investigations about how PTMs affect Aß42 fibril aggregation and AD-related neurotoxicity.

Aglatestine A, a Rearranged Limonoid with a 3/6/6 Tricarbocyclic Framework from the Fruits of Aglaia edulis.

Aglatestine A (1), an unprecedented 3/6/6 tricarbocyclic limonoid framework along with four biogenic A/D-seco limonoid analogues with rare ß-substituents at C-6 (2-5), was discovered from the fruits of Aglaia edulis. The structures of 1-5 along with their absolute configurations were clarified using methods of HRMS(ESI), NMR, electronic circular dichroism, X-ray diffraction crystallography, and quantum chemical calculations. The plausible biogenetic speculation suggested that an electrophilic cyclization between C-1 carbocation from acetolysis and electron-rich C-5 from enolization of C═O of 2 may play a key role. The biological evaluation showed that 5 exhibited anti-inflammatory activity indicated by inhibiting NO release in LPS-activated RAW 264.7 macrophages (IC50: 35.72 ± 1.96 µM).