Anti-necroptosis and anti-ferroptosis compounds from the Deep-Sea-Derived fungus Aspergillus sp. MCCC 3A00392.

Eight undescribed (1-8) and 46 known compounds (9-54) were isolated from the deep-sea-derived Aspergillus sp. MCCC 3A00392. Compounds 1-3 were three novel oxoindolo diterpenoids, 4-6 were three bisabolane sesquiterpenoids, while 7 and 8 were two monocyclic cyclopropanes. Their structures were established by exhaustive analyses of the HRESIMS, NMR, and theoretical calculations of the NMR data and ECD spectra. Compounds 10, 33, 38, and 39 were able to inhibit tumor necrosis factor (TNF)-induced necroptosis in murine L929 cell lines. Functional experiments verified that compounds 10 and 39 inhibited necroptosis by downregulating the phosphorylation of RIPK3 and MLKL. Moreover, compound 39 also reduced the phosphorylation of RIPK1. Compounds 10, 33, and 34 displayed potent inhibitory activities against RSL-3 induced ferroptosis with the EC50 value of 3.0 µM, 0.4 µM, and 0.1 µM, respectively. Compound 10 inhibited ferroptosis by the downregulation of HMOX1, while compounds 33 and 34 inhibited ferroptosis through regulation of NRF2/SLC7A11/GCLM axis. However, these compounds only showed weak effect in either the necroptosis or ferroptosis relative mouse disease models. Further studies of pharmacokinetics and pharmacodynamics might improve their in vivo bioactivities.

Scalable Multipartite Entanglement Created by Spin Exchange in an Optical Lattice.

Ultracold atoms in optical lattices form a competitive candidate for quantum computation owing to the excellent coherence properties, the highly parallel operations over spins, and the ultralow entropy achieved in qubit arrays. For this, a massive number of parallel entangled atom pairs have been realized in superlattices. However, the more formidable challenge is to scale up and detect multipartite entanglement, the basic resource for quantum computation, due to the lack of manipulations over local atomic spins in retroreflected bichromatic superlattices. In this Letter, we realize the functional building blocks in quantum-gate-based architecture by developing a cross-angle spin-dependent optical superlattice for implementing layers of quantum gates over moderately separated atoms incorporated with a quantum gas microscope for single-atom manipulation and detection. Bell states with a fidelity of 95.6(5)% and a lifetime of 2.20±0.13 s are prepared in parallel, and then connected to multipartite entangled states of one-dimensional ten-atom chains and two-dimensional plaquettes of 2×4 atoms. The multipartite entanglement is further verified with full bipartite nonseparability criteria. This offers a new platform toward scalable quantum computation and simulation.

Chemical Constituents of the Deep-sea Gammarid Shrimp-Derived Fungus Penicillium citrinum XIA-16.

One new alkaloid, (S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid (1), was isolated from the deep-sea-derived Penicillium citrinum XIA-16, together with 25 known compounds including ten polyketones (2-11), eight alkaloids (12-19), six steroids (20-25), and a fatty acid (26). Their planar and relative structures were determined by an analysis of 1D and 2D nuclear magnetic resonance (NMR) as well as high resolution electrospray ionization mass spectroscopy (HR-ESI-MS) data. The absolute configuration of 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Penicitrinol B (6) significantly inhibited RSL3-induced ferroptosis (EC50 =2.0 µM) by reducing lipid peroxidation and heme oxygenase 1 (HMOX1) expression. Under the concentration of 10 µM, penicitrinol A (7) was able to inhibit cuproptosis with the cell viabilities of 68.2 % compared to the negative control (copper and elesclomol) with the cell viabilities of 14.8 %.

High sensitivity pH sensing by using a ring resonator laser integrated into a microfluidic chip.

We present a chip-scale integrated pH sensor with high sensitivity by using an optofluidic ring resonator (OFRR) laser. An optical fiber with a high refractive index (RI) is employed both as an optical cavity and the sensing reactor along a microchannel, while disodium fluorescein (DSF) aqueous solution with a low RI is served as the cladding gain medium and fluorescent probes. The pump light is introduced along the fiber axis and guided by the total internal reflection at the fiber/cladding interface. The evanescent field of the pump light extends out of the fiber surface and efficiently excites the dye molecules residing in the evanescent field region of the Whispering Gallery Modes (WGMs) of the OFRRs to produce lasing emission. This pumping scheme provides a uniform excitation to the gain medium and significantly increases the signal-to-noise ratio, ensuring a low lasing threshold and highly sensitive sensing. The lasing threshold property under different pH conditions is experimentally and theoretically conducted to evaluate the sensing performance, which shows that the lasing threshold highly depends on the pH value of the cladding solution due to the increasing deprotonation process. We further verify that the intensity of the lasing emission and the pH value shows good linearity in the pH range 6.51-8.13, with a 2-order-of-magnitude sensitivity enhancement compared to fluorescence measurement. The proposed OFRR lasing platform shows excellent robustness and low sample consumption, providing a powerful sensing strategy in medicine, and hazardous/toxic/volatile sensing, which require label-free, real-time, and in situ detection.

Secondary Metabolites from the Fresh Leaves of Pinus yunnanensis Franch.

Fifteen metabolites, including two flavonols (1-2), three lignans (3-5), and ten diterpenoids (6-15), were isolated from the leaves of Pinus yunnanensis. Among them, flavanonol (1) were identified as undescribed flavonol derivative with natural rarely B-ring fission lactone. Massive spectroscopic methods, the DP4+ probabilities and CD/ECD calculations were applied to establish the structure of component 1. Among these compounds, taxifolin (2) showed potent cytotoxicity, having IC50 values from 21.33 to 45.48 µg/mL, it also showed broad antibacterial activity against human pathogens with MIC values from 32 to 64 µg/mL.

Prediction of clinical efficacy of subcutaneous immunotherapy for Artemisia sieversiana pollen allergic rhinitis by serum metabolomics.

BACKGROUND/PURPOSE: Specific immunotherapy is the only effective etiological treatment for allergic rhinitis, but subcutaneous immunotherapy has a slow onset and poor compliance. Predicting the clinical efficacy of subcutaneous immunotherapy in advance can reduce unnecessary medical costs and resource waste. This study aimed to identify metabolites that could predict the efficacy of subcutaneous immunotherapy on seasonal allergic rhinitis by serum metabolomics. METHODS: Patients (n = 43) with Artemisia sieversiana pollen allergic rhinitis were enrolled and treated with subcutaneous immunotherapy for one year. Patients were divided into the ineffective group (n = 10) and effective group (n = 33) according to the therapeutic index. Serum samples were collected before treatment. Metabolomics was determined by liquid chromatography-mass spectrometry combined with gas chromatography-mass spectrometry and analyzed differential compounds and related metabolic pathways. RESULTS: A total of 129 differential metabolites (P < 0.05) were identified and 4 metabolic pathways, namely taurine and hypotaurine metabolism, pentose and glucuronate interconversions, pentose phosphate pathway, and alanine, aspartate, and glutamate metabolism, were involved. CONCLUSION: Some metabolites, such as hypotaurine, taurine, and l-alanine, have the potential to become predictive biomarkers for effective subcutaneous immunotherapy.

High-powered optical superlattice with robust phase stability for quantum gas microscopy.

Optical superlattice has a wide range of applications in the study of ultracold atom physics. Especially, it can be used to trap and manipulate thousands of atom pairs in parallel which constitutes a promising system for quantum simulation and quantum computation. In the present work, we report on a high-power optical superlattice formed by a 532-nm and 1064-nm dual-wavelength interferometer with a short lattice spacing of 630 nm. The short-term fluctuation (in 10 seconds) of the relative phase between the short lattice and the long lattice is measured to be 0.003π, which satisfies the needs for performing two-qubit gates among neighboring lattice sites. We further implement this superlattice in a 87Rb experiment with a quantum gas microscope of single-site resolution, where the high-power 532-nm laser is necessary for pinning atoms in the short lattice during imaging, providing a unique platform for engineering quantum states.

Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa.

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a hereditary degenerative disorder in which mutations in the gene encoding RHO, the light-sensitive G protein-coupled receptor involved in phototransduction in rods, lead to progressive loss of rods and subsequently cones in the retina. Clinical phenotypes are diverse, ranging from mild night blindness to severe visual impairments. There is currently no cure for RHO-adRP. Although there have been significant advances in gene therapy for inherited retinal diseases, treating RHO-adRP presents a unique challenge since it is an autosomal dominant disease caused by more than 150 gain-of-function mutations in the RHO gene, rendering the established gene supplementation strategy inadequate. This review provides an update on RNA therapeutics and therapeutic editing genome surgery strategies and ongoing clinical trials for RHO-adRP, discussing mechanisms of action, preclinical data, current state of development, as well as risk and benefit considerations. Potential outcome measures useful for future clinical trials are also addressed.

Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress.

Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, we demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PaVN) in the adult rat is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in PaVN dopaminergic neurons that coexpress vesicular glutamate transporter 2 (VGLUT2), is accompanied by a loss of dopamine type 2 receptors (D2Rs) on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF. Suppressing activity of all PaVN glutamatergic neurons decreases the number of inhibitory PaVN dopaminergic neurons, indicating homeostatic regulation of transmitter expression in the PaVN.

A New Preoperative Upright Design for Dermatochalasis Correction.

BACKGROUND: Conventional assessment of the height of upper eyelid skin excision in dermatochalasis correction is performed with patient's eyes closed in supine position. It is not able to consider the effects of gravity on the upper eyelid, thus may lead to asymmetric postoperative appearance. The authors herein report a novel preoperative upright design (PUD) that can accurately determine the amount of skin excision with patients' eyes open in dermatochalasis correction. METHODS: Patients with dermatochalasis underwent PUD during blepharoplasty were enrolled and were followed-up for 9 to 15 months. RESULTS: A total of 116 patients (mean age 55.1 ±â€Š6.1 years, range 46-78 years) successfully underwent the surgery. Using the PUD, the vertical height of skin excision was 8.2 ±â€Š2.4 mm (6-19 mm), the preoperative margin fold distance was -0.5 ±â€Š1.0 mm (-4 - 1 mm), which improved to 2.1 ±â€Š0.6 mm (1-3 mm, P < 0.05) at the last follow-up visit. A total of 107 of 116 patients (92.2%) were judged as "good" (natural double eyelid folds with symmetric margin fold distance), 9 patients (7.8%) were judged as "fair" (natural double eyelid folds with the differences of margin fold distance between fellow eyelids within 2 mm), and no one was judged as "poor" (unsmooth double eyelid folds or the differences of margin fold distance between fellow eyelids is more than 2 mm). CONCLUSION: Preoperative upright design is a simple and effective method to accurately determine the amount of skin excision in blepharoplasty, and help to achieve symmetric double eyelids.

Rare benzonaphthoxanthenones from Chinese folk herbal medicine Polytrichum commune and their anti-neuroinflammatory activities in vitro.

Two new (1-2) as well as five known (3-7) compounds were isolated from Polytrichum commune, a folk herbal medicine in China, and three of them (2, 4, 5) belong to benzonaphthoxanthenones that are rarely found in nature. Their structures were elucidated by the approach to 1D and 2D NMR spectra. The absolute configuration of 2 was assigned by comparing its experimental and calculated ECD data. 1-5 were investigated for their anti-neuroinflammatory activity against LPS-induced BV-2 cells. 1 and 3 exhibited well protective effect at a concentration of 2.5 µmol/mL. Molecular docking studies were adopted to further investigate the possible mechanism, whose results suggested that 1 might exert anti-neuroinflammatory effect by inhibiting activity of p38α, JNK2 and TAK1 to reduce the liberation of pro-inflammatory cytokines.

Polyhydroxyl guaianolide terpenoids as potential NF-кB inhibitors induced cytotoxicity in human gastric adenocarcinoma cell line.

Six new guaiane-type sesquiterpenes (1-6), and one monoterpenoid (7) along with five known analogues (8-12), were isolated from the leaves of Artemisia argyi Lévl et Vant. The new compounds were characterized by the basic analysis of the spectroscopic data (HRMS, 1D and 2D NMR), and the absolute configurations were determined by both calculated electronic circular dichroism and DP4 calculations. The inhibitory effects of 1-12 against human gastric adenocarcinoma (AGS) cells were investigated in vitro, among which 1-3 and 8 showed remarkable cytotoxic activity with IC50 values in the range of 6.69-10.25 µM. The results suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on C-8. In order to rationalize the binding interactions of active compounds with the active site of NF-кB, in silico study was conducted and the results were in complete agreement with the experimental data for cytotoxicity evaluation.

Isoquinolines from national herb Corydalis tomentella and neuroprotective effect against lipopolysaccharide-induced BV2 microglia cells.

Five new isoquinolines (1-5) were isolated from national herb Corydalis tomentella. Their structures were elucidated by extensive analysis of the 1D and 2D NMR spectra and from the HRESIMS. Absolute configurations of 1-3 were determined by comparing their experimental and computed ECD data. Since plants from Corydalis have been reported to protect against Alzheimer's disease, all compounds were evaluated for their neuroprotective effect against lipopolysaccharide-induced BV2 microglia cells. Compound 2 and 3 showed well anti-neuroinflammatory activity at low concentration (25 µM).

Revealing synergistic mechanism of multiple components in Stauntonia brachyanthera Hand.-Mazz. for gout by virtual screening and system pharmacological approach.

Stauntonia brachyanthera Hand.-Mazz. (SB), reported as a traditional Chinese medicine, displays a wide spectrum of interesting bioactivities, such as anti-inflammatory and analgesia. It is noteworthy that anti-gout effects of the components in SB have been reported. Hence, this study contributes to the prediction of promising active compounds and mechanisms for the treatment of gout. The active compounds with better oral bioavailability, and drug-likeness of SB were selected for further investigation by the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, respectively. A total of 34 predicted targets and 98 compounds in SB were obtained. Sorted by structure types of compounds, phenylethanoid glycosides exhibited the best anti-gout activity, followed by phenolics and flavonoids. What's more, it was shown in the network analysis that Serine/threonine-protein kinase mTOR (mTOR), Mitogen-activated protein kinase 12 (MAPK12), tumor necrosis factor (TNF-α), Integrin alpha-4 (ITGA4) and Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the key targets with intensely interaction, which should be attached more attention for further study. The functional enrichment analysis indicated that SB probably produced the anti-gout effects by synergistically regulating many biological pathways, such as MAPK signaling pathway, PI3K-Akt signaling pathway, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway, etc. In addition, C61, C67, C68 and C81 might be promising leading compounds with good molecular docking score. As a consequence, the active constituents and mechanisms based on data analysis were holistically illuminated, which was of vital importance to the development of new drugs for gout.

Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology.

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.

lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.

Systems Pharmacological Approach to Investigate the Mechanism of Ohwia caudata for Application to Alzheimer's Disease.

Ohwia caudata (OC)-a traditional Chinese medicine (TCM)-has been reported to have large numbers of flavonoids, alkaloids, and triterpenoids. The previous studies on OC for treating Alzheimer's disease (AD) only focused on single targets and its mechanisms, while no report had shown about the synergistic mechanism of the constituents from OC related to their potential treatment on dementia in any database. This study aimed to predict the bioactive targets constituents and find potential compounds from OC with better oral bioavailability and blood-brain barrier permeability against AD, by using a system network level-based in silico approach. The results revealed that two new flavonoids, and another 26 compounds isolated from OC in our lab, were highly connected to AD-related signaling pathways and biological processes, which were confirmed by compound-target network, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, respectively. Predicted by the virtual screening and various network pharmacology methods, we found the multiple mechanisms of OC, which are effective for alleviating AD symptoms through multiple targets in a synergetic way.

The ability of anterior thalamic signals to predict seizures in temporal lobe epilepsy in kainate-treated rats.

OBJECTIVE: To analyze the local field potential (LFP) of the anterior nucleus of the thalamus (ANT) of epileptic rats using the Generic Osorio-Frei algorithm (GOFA), and to determine the ability of the ANT LFP to predict clinical seizures in temporal lobe epilepsy. METHODS: GOFA is an advanced real-time technique used to detect and predict seizures. In this article, GOFA was utilized to process the electrical signals of ANT and the motor cortex recorded in 12 rat models of temporal lobe epilepsy (TLE) induced via the injection of kainic acid into the unilateral hippocampus. The electroencephalography (EEG) data included (1) 161 clinical seizures (each contained a 10-min segment) involving the ANT and cortical regions and (2) one hundred three 10-min segments of randomly selected interictal (no seizure) data. RESULTS: Minimal false-positives (0.51 ± 0.36/h) and no false-negatives were detected based on the ANT LFP data processed using GOFA. In ANT LFP, the delay from electrographic onset (EO) to automated onset (AO) was 1.24 ± 0.47 s, and the delay from AO to clinical onset (CO) was 7.73 ± 3.23 s. The AO time occurred significantly earlier in the ANT than in the cortex (p = 0.001). In 75.2% of the clinical onsets predicted by ANT LFP, it was 1.37 ± 0.82 s ahead of the prediction of cortical potentials (CPs), and the remainder were 0.84 ± 0.31 s slower than the prediction of CPs. SIGNIFICANCE: ANT LFP appears to be an optimal option for the prediction of seizures in temporal lobe epilepsy. It was possible to upgrade the responsive neurostimulation system to emit electrical stimulation in response to the prediction of epileptic seizures based on the changes in the ANT LFP.

Anti-gout nor-oleanane triterpenoids from the leaves of Stauntonia brachyanthera.

With the aim of finding more potential anti-gout compounds from natural resources, a phytochemical study on the leaves of Stauntonia brachyanthera was carried out, which led to the isolation of 11 nor-oleanane triterpenoids, including 4 new ones. Their structures were determined by the comprehensive 1D, 2D NMR, HRMS, and HPLC analysis after acid hydrolysis. Brachyantheraoside B4 (3) and 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranosyl-30-norolean-12,20(29)-dien-28-oic acid (8) exhibited significant inhibitory activities on xanthine oxidase with IC50 values of 0.20 and 18.5µM, respectively. Brachyantheraoside C2 (2) also showed moderate effects on XO. A primary structure-activity relationship was also summarized, which revealed the anti-gout abilities of three nor-oleanane triterpenoids and their potential possibilities as the candidate compounds for the treatment of gout. The discovery of nor-oleanane triterpenoids also widens people's idea for the study of anti-gout agents and promotes the comprehensive development of S. brachyanthera.