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.

Chemical Constituents from the deep-sea-derived Fungus Aureobasidium melanogenum LUO5.

Three new C10 and C12 aliphatic δ-lactones (1-3), three new fatty acid methyl esters (4-6), and eight known compounds (7-14) were isolated from the marine Aureobasidium sp. LUO5. Their structures were established by detailed analyses of the NMR, HRESIMS, optical rotation, and ECD data. All isolates were tested for their inhibitory effects on nitric oxide production in LPS-induced BV-2 cells. Notably, compound 4 displayed the strongest inhibitory effect with the IC50 value of 120.3 nM.

Long non-coding RNA MIR17HG impedes FOSL2-mediated transcription activation of HIC1 to maintain a pro-inflammatory phenotype of microglia during intracerebral haemorrhage.

Activation and polarization of microglia play decisive roles in the progression of intracerebral haemorrhage (ICH), and lactate exposure correlates with microglia polarization. This study explores molecules influencing lactate production and microglia phenotype alteration following ICH. A murine model of ICH was induced by intracerebral injection of collagenase. The mice experienced autonomous neurological function recovery, haematoma resolution and rapid lactate production, along with a gradual increase in angiogenesis activity, neuronal recovery and an M1-to-M2 phenotype change of microglia. Galloflavin, a lactate dehydrogenase antagonist, suppressed this phenotype change and the functional recovery in mice. FOS like 2 (FOSL2) was significantly upregulated in the brain tissues from day 7 post-ICH. Overexpression of FOSL2 induced an M1-to-M2 phenotype shift in microglia and accelerated lactate production in vivo and in haemoglobin-treated microglia in vitro. Long non-coding RNA MIR17HG impeded FOSL2-mediated transcription activation of hypermethylated in cancer 1 (HIC1). MIR17HG overexpression induced pro-inflammatory activation of microglia in mice, which was blocked by further HIC1 overexpression. Overall, this study demonstrates that MIR17HG maintains a pro-inflammatory phenotype of microglia during ICH progression by negating FOSL2-mediated transcription activation of HIC1. Specific inhibition of MIR17HG or upregulation of FOSL2 or HIC1 may favour inflammation inhibition and haematoma resolution in ICH.

Chalcogen bond-assisted syn-locked scaffolds: DFT analysis and biological implications of novel tubulin inhibitors.

A series of new tubulin inhibitors containing chalcogen bonds have been discovered. Density functional theory (DFT) analysis of the O-C-C-S torsion profile shows a preference of 0.8 kcal/mol for the syn-conformer over the anti-conformer. Besides, the O-S natural bond orbital (NBO) analysis reveals that the OLP âˆ¼ C-SBD∗ energy potential is 0.62 kcal/mol. Further pharmacochemical screening of several series of (4-arylthiophen-2-yl)(3,4,5-trimethoxyphenyl)methanones identified IPO-10 as a highly effective tubulin inhibitor with an IC50 of 23 nm for MCF-7.

Neotricitrinols A-C, unprecedented citrinin trimers with anti-osteoporosis activity from the deep-sea-derived Penicillium citrinum W23.

Marine fungi are prolific source for the discovery of structurally diverse and bioactive molecules. In our search for new anti-osteoporosis compounds from deep-sea-derived fungi, we prioritized a fungus whose extract exhibited moderate activity and rich chemical diversity. The investigation of this strain afforded a class of citrinins, including three new citrinin trimers, neotricitrinols A-C (1-3), and three known dimeric/monomeric precursors (4-6). Neotricitrinols A-C (1-3) feature a unique octacyclic carbon scaffold among the few reported citrinin trimers with their absolute configurations established by spectroscopic analysis, theoretical-statistical approaches (GIAO-NMR, TDDFT-ECD/ORD calculations), DP4+ probability analysis as well as biogenetic consideration. A plausible biosynthetic pathway linking 1-3 from the common intermediate metabolite penicitrinol A (4) was proposed. Biologically, neotricitrinol B (2) showed potential anti-osteoporosis activity by promoting osteoblastogenesis and inhibiting adipogenic differentiation on primary bone mesenchymal stem cells, while displaying no cytotoxicity.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

Ferroptosis Inhibitory Compounds from the Deep-Sea-Derived Fungus Penicillium sp. MCCC 3A00126.

Two new xanthones (1 and 2) were isolated from the deep-sea-derived fungus Penicillium sp. MCCC 3A00126 along with 34 known compounds (3-36). The structures of the new compounds were established by spectroscopic data. The absolute configuration of 1 was validated by comparison of experimental and calculated ECD spectra. All isolated compounds were evaluated for cytotoxicity and ferroptosis inhibitory activities. Compounds 14 and 15 exerted potent cytotoxicity against CCRF-CEM cells, with IC50 values of 5.5 and 3.5 µM, respectively, whereas 26, 28, 33, and 34 significantly inhibited RSL3-induced ferroptosis, with EC50 values of 11.6, 7.2, 11.8, and 2.2 µM, respectively.

Penidihydrocitrinins A-C: New Polyketides from the Deep-Sea-Derived Penicillium citrinum W17 and Their Anti-Inflammatory and Anti-Osteoporotic Bioactivities.

Three new polyketides (penidihydrocitrinins A-C, 1-3) and fourteen known compounds (4-17) were isolated from the deep-sea-derived Penicillium citrinum W17. Their structures were elucidated by comprehensive analyses of 1D and 2D NMR, HRESIMS, and ECD calculations. Compounds 1-17 were evaluated for their anti-inflammatory and anti-osteoporotic bioactivities. All isolates exhibited significant inhibitory effects on LPS-stimulated nitric oxide production in murine brain microglial BV-2 cells in a dose-response manner. Notably, compound 14 displayed the strongest effect with the IC50 value of 4.7 µM. Additionally, compounds 6, 7, and 8 significantly enhanced osteoblast mineralization, which was comparable to that of the positive control, purmorphamine. Furthermore, these three compounds also suppressed osteoclastogenesis in a dose-dependent manner under the concentrations of 2.5 µM, 5.0 µM, and 10 µM.

Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Citriquinolinones A and B: Rare Isoquinolinone-Embedded Citrinin Analogues and Related Metabolites from the Deep-Sea-Derived Aspergillus versicolor 170217.

A systematic chemical investigation of the deep-sea-derived fungus Aspergillus versicolor 170217 resulted in the isolation of six new (1-6) and 45 known (7-51) compounds. The structures of the new compounds were established on the basis of exhaustive analysis of their spectroscopic data and theoretical-statistical approaches including GIAO-NMR, TDDFT-ECD/ORD calculations, DP4+ probability analysis, and biogenetic consideration. Citriquinolinones A (1) and B (2) feature a unique isoquinolinone-embedded citrinin scaffold, representing the first exemplars of a citrinin-isoquinolinone hybrid. Dicitrinones K-L (3-4) are two new dimeric citrinin analogues with a rare CH-CH3 bridge. Biologically, frangula-emodin (32) and diorcinol (17) displayed remarkable anti-food allergic activity with IC50 values of 7.9 ± 3.0 µM and 13.4 ± 1.2 µM, respectively, while diorcinol (17) and penicitrinol A (20) exhibited weak inhibitory activity against Vibrio parahemolyticus, with MIC values ranging from 128 to 256 µM.

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 %.

Development and validation of a novel model to predict liver-related mortality in patients with idiosyncratic drug-induced liver injury.

BACKGROUND: Early identification of patients with high mortality risk is critical for optimizing the clinical management of drug-induced liver injury (DILI). We aimed to develop and validate a new prognostic model to predict death within 6 months in DILI patients. METHODS: This multicenter study retrospectively reviewed the medical records of DILI patients admitted to three hospitals. A DILI mortality predictive score was developed using multivariate logistic regression and was validated with area under the receiver operating characteristic curve (AUC). A high-mortality-risk subgroup was identified according to the score. RESULTS: Three independent DILI cohorts, including one derivation cohort (n = 741) and two validation cohorts (n = 650, n = 617) were recruited. The DILI mortality predictive (DMP) score was calculated using parameters at disease onset as follows: 1.913 × international normalized ratio + 0.060 × total bilirubin (mg/dL) + 0.439 × aspartate aminotransferase/alanine aminotransferase - 1.579 × albumin (g/dL) - 0.006 × platelet count (109/L) + 9.662. The predictive performance for 6-month mortality of DMP score was desirable, with an AUC of 0.941 (95% CI: 0.922-0.957), 0.931 (0.908-0.949) and 0.960 (0.942-0.974) in the derivation, validation cohorts 1 and 2, respectively. DILI patients with a DMP score ≥ 8.5 were stratified into high-risk group, whose mortality rates were 23-, 36-, and 45-fold higher than those of other patients in the three cohorts. CONCLUSIONS: The novel model based on common laboratory findings can accurately predict mortality within 6 months in DILI patients, which should serve as an effective guidance for management of DILI in clinical practice.

Contribution identification of hydrolyzed products of potassium ferrate on promoting short-chain fatty acids production from waste activated sludge.

Potassium ferrate (K2FeO4) has been extensively employed to promote short-chain fatty acids (SCFAs) production from anaerobic fermentation of waste activated sludge (WAS) because of its potent oxidizing property and formation of alkaline hydrolyzed products (potassium hydroxide, KOH and ferric hydroxide, Fe(OH)3). However, whether K2FeO4 actually works as dual functions of both an oxidizing agent and an alkalinity enhancer during the anaerobic fermentation process remains uncertain. This study aims to identify the contributions of hydrolyzed products of K2FeO4 on SCFAs production. The results showed that K2FeO4 did not execute dual functions of oxidization and alkalinity in promoting SCFAs production. The accumulation of SCFAs using K2FeO4 treatment (183 mg COD/g volatile suspended solids, VSS) was less than that using either KOH (192 mg COD/g VSS) or KOH & Fe(OH)3 (210 mg COD/g VSS). The mechanism analysis indicated that the synergistic effects caused by oxidization and alkalinity properties of K2FeO4 did not happen on solubilization, hydrolysis, and acidogenesis stages, and the inhibition effect caused by K2FeO4 on methanogenesis stage at the initial phase was more severe than that of its hydrolyzed products. It was also noted that the inhibition effects of K2FeO4 and its hydrolyzed products on the methanogenesis stage could be relieved during a longer sludge retention time, and the final methane yields using KOH or KOH & Fe(OH)3 treatment were higher than that using K2FeO4, further confirming that dual functions of K2FeO4 were not obtained. Therefore, K2FeO4 may not be an alternative strategy for enhancing the production of SCFAs from WAS compared to its alkaline hydrolyzed products. Regarding the strong oxidization property of K2FeO4, more attention could be turned to the fates of refractory organics in the anaerobic fermentation of WAS.

Set of Cytochrome P450s Cooperatively Catalyzes the Synthesis of a Highly Oxidized and Rearranged Diterpene-Class Sordarinane Architecture.

Cytochrome P450s are one of the most versatile oxidases that catalyze significant and unique chemical transformations for the construction of complex structural frameworks during natural product biosynthesis. Here, we discovered a set of P450s, including SdnB, SdnH, SdnF, and SdnE, that cooperatively catalyzes the reshaping of the inert cycloaraneosene framework to form a highly oxidized and rearranged sordarinane architecture. Among them, SdnB is confirmed to be the first P450 (or oxidase) that cleaves the C-C bond of the epoxy residue to yield formyl groups in pairs. SdnF selectively oxidizes one generated formyl group to a carboxyl group and accelerates the final Diels-Alder cyclization to furnish the sordarinane architecture. Our work greatly enriches the enzyme functions of the P450 superfamily, supplies the missing skills of the P450 synthetic toolbox, and supports them as biocatalysts in further applications toward the synthesis of new chemical entities.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Cladosporioles A and B, Two New Indole Derivatives from the Deep-Sea-Derived Fungus Cladosporium cladosporioides 170056.

Two new (cladosporioles A and B, 1 and 2) and fourteen known (3-16) compounds were isolated from the deep-sea-derived fungus Cladosporium cladosporioides 170056. The relative structures of the new compounds were elucidated mainly by detailed analysis of their NMR and HR-ESI-MS spectroscopic data. Their absolute configurations were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were tested for antimicrobial activity against Vibrio parahaemolyticus. Compound 15 exhibited weak effect with the MIC value of 156.25 µg/mL.

Chemical Constituents of the Deep-Sea-Derived Fungus Cladosporium oxysporum 170103 and Their Antibacterial Effects.

The Cladosporium fungi, one of the largest genera of dematiaceous hyphomycetes, could produce various bioactive secondary metabolites. From the AcOEt-soluble extract of Cladosporium oxysporum 170103, three new secopatulolides (1-3) and thirteen known compounds (4-16) were obtained. Their structures were established by detailed analysis of the NMR and HR-ESI-MS data. All sixteen compounds were tested for antibacterial activity against Vibrio parahemolyticus, ergosterol (10) presented moderate effect with the minimum inhibitory concentration (MIC) of 32 µM. It can destruct the membrane integrity of Vibrio parahemolyticus to change the cell shape.

Improved LDTW Algorithm Based on the Alternating Matrix and the Evolutionary Chain Tree.

Dynamic time warping under limited warping path length (LDTW) is a state-of-the-art time series similarity evaluation method. However, it suffers from high space-time complexity, which makes some large-scale series evaluations impossible. In this paper, an alternating matrix with a concise structure is proposed to replace the complex three-dimensional matrix in LDTW and reduce the high complexity. Furthermore, an evolutionary chain tree is proposed to represent the warping paths and ensure an effective retrieval of the optimal one. Experiments using the benchmark platform offered by the University of California-Riverside show that our method uses 1.33% of the space, 82.7% of the time used by LDTW on average, which proves the efficiency of the proposed method.

SRY-related high-mobility-group box 4: Crucial regulators of the EMT in cancer.

The epithelial-mesenchymal transition (EMT) is a process of cell transformation under certain physiological and pathological states in which epithelial cells are transformed into mesenchymal cells with fibroblast-like properties, which confers upon them the increased invasion and migration capabilities of cancer cells. Previous studies have demonstrated that SRY-related high-mobility-group box 4 (Sox4) protein coordinates EMT-related pathways and EMT-related transcription factors, thereby regulating the EMT process. The focus of this review is to evaluate recent advances regarding the role of Sox4 protein in the cancer EMT. First, we provide an overview of the general background of Sox4 (structure and function) and the EMT in cancer. Next, we introduce the interactions between Sox4 protein and various factors during cancer EMT. Finally, we suggest directions for future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information on the subject matter and contribute to the design of other research and future efforts to develop therapeutic strategies that target the Sox4 protein.

Crystal Structure and Ferroelectric Evidence of BaZnSi3 O8 , a Low-Permittivity Microwave Dielectric Ceramic.

BaZnSi3 O8 ceramic was prepared by the conventional solid-state method and sintered at 1100 °C. XRD and synchrotron Rietveld refinement analyses revealed the BaZnSi3 O8 ceramic presented a monoclinic structure with a space group of P21 /a (No.14), which is reported for the first time. The BaZnSi3 O8 ceramic presented a weak ferroelectricity, which was confirmed by the P-E loop and the 90° nanoscale ferroelectric domain. Although ϵr -T displayed two ϵr abnormal peaks at 400 °C and 460 °C, the Curie temperature (Tc ) was located at 460 °C according to the dielectric loss and Curie-Weiss law. Moreover, the BaZnSi3 O8 ceramic exhibited optimized microwave dielectric properties with ϵr =6.55, Q×f=52400 GHz, and τf =-24.5 ppm/°C. Hence, the BaZnSi3 O8 ceramic in the ternary BaO-ZnO-SiO2 system possessed both weak ferroelectricity and microwave dielectric properties. These results are expected to break the technical barrier of ferroelectric phase shifter applications in microwave and even millimeter-wave frequency bands.