Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties.

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation.

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

Resting-State EEG Reveals Abnormal Microstate Characteristics of Depression with Insomnia.

Previous research revealed various aspects of resting-state EEG for depression and insomnia. However, the EEG characteristics of depressed subjects with insomnia are rarely studied, especially EEG microstates that capture the dynamic activities of the large-scale brain network. To fill these research gaps, the present study collected resting-state EEG data from 32 subclinical depression subjects with insomnia (SDI), 31 subclinical depression subjects without insomnia (SD), and 32 healthy controls (HCs). Four topographic maps were generated from clean EEG data after clustering and rearrangement. Temporal characteristics were obtained for statistical analysis, including cross-group variance analysis (ANOVA) and intra-group correlation analysis. In our study, the global clustering of all individuals in the EEG microstate analysis revealed the four previously discovered categories of microstates (A, B, C, and D). The occurrence of microstate B was lower in SDI than in SD and HC subjects. The correlation analysis showed that the total Pittsburgh Sleep Quality Index (PSQI) score negatively correlated with the occurrence of microstate C in SDI (r = - 0.415, p < 0.05). Conversely, there was a positive correlation between Self-rating Depression Scale (SDS) scores and the duration of microstate C in SD (r = 0.359, p < 0.05). These results indicate that microstates reflect altered large-scale brain network dynamics in subclinical populations. Abnormalities in the visual network corresponding to microstate B are an electrophysiological characteristic of subclinical individuals with symptoms of depressive insomnia. Further investigation is needed for microstate changes related to high arousal and emotional problems in people suffering from depression and insomnia.

The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis.

BACKGROUND: With the increasing research on extracellular vesicles (EVs), EVs have received widespread attention as biodiagnostic markers and therapeutic agents for a variety of diseases. Stem cell-derived EVs have also been recognized as a new viable therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To assess their efficacy, we conducted a meta-analysis of existing preclinical experimental animal models of EVs for ALI treatment. METHODS: The database was systematically interrogated for pertinent data encompassing the period from January 2010 to April 2022 concerning interventions involving extracellular vesicles (EVs) in animal models of acute lung injury (ALI). The lung injury score was selected as the primary outcome measure for statistical analysis. Meta-analyses were executed utilizing RevMan 5.3 and State15.1 software tools. RESULTS: The meta-analyses comprised 31 studies, exclusively involving animal models of acute lung injury (ALI), categorized into two cohorts based on the presence or absence of extracellular vesicle (EV) intervention. The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05). EVs originating from stem and progenitor cells demonstrated mitigating effects on alveolar neutrophil infiltration, white blood cell counts, total cell counts in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight ratios (W/D), and total protein in BALF. Furthermore, pro-inflammatory mediators exhibited down-regulation, while anti-inflammatory mediators demonstrated up-regulation. Conversely, non-stem cell-derived EVs exacerbated lung injury. CONCLUSION: In preclinical animal models of acute lung injury (ALI), the administration of extracellular vesicles (EVs) originating from stem and progenitor cells demonstrably enhances pulmonary function. This ameliorative effect is attributed to the mitigation of pulmonary vascular permeability and the modulation of immune homeostasis, collectively impeding the progression of inflammation. In stark contrast, the utilization of EVs derived from non-stem progenitor cells exacerbates the extent of lung injury. These findings substantiate the potential utility of EVs as a novel therapeutic avenue for addressing acute lung injury.

Endothelial progenitor cells systemic administration alleviates multi-organ senescence by down-regulating USP7/p300 pathway in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has impacted approximately 390 million people worldwide and the morbidity is increasing every year. However, due to the poor treatment efficacy of COPD, exploring novel treatment has become the hotpot of study on COPD. Endothelial progenitor cells (EPCs) aging is a possible molecular way for COPD development. We aimed to explore the effector whether intravenous administration of EPCs has therapeutic effects in COPD mice. METHODS: COPD mice model was induced by cigarette smoke exposure and EPCs were injected intravenously to investigate their effects on COPD mice. At day 127, heart, liver, spleen, lung and kidney tissues of mice were harvested. The histological effects of EPCs intervention on multiple organs of COPD mice were detected by morphology assay. Quantitative real-time PCR and Western blotting were used to detect the effect of EPCs intervention on the expression of multi-organ senescence-related indicators. And we explored the effect of EPCs systematically intervening on senescence-related USP7/p300 pathway. RESULTS: Compared with COPD group, senescence-associated ß-galactosidase activity was decreased, protein and mRNA expression of p16 was down-regulated, while protein and mRNA expression of cyclin D1 and TERT were up-regulated of multiple organs, including lung, heart, liver, spleen and kidney in COPD mice after EPCs system intervention. But the morphological alterations of the tissues described above in COPD mice failed to be reversed. Mechanistically, EPCs systemic administration inhibited the expression of mRNA and protein of USP7 and p300 in multiple organs of COPD mice, exerting therapeutic effects. CONCLUSIONS: EPCs administration significantly inhibited the senescence of multiple organs in COPD mice via down-regulating USP7/p300 pathway, which presents a possibility of EPCs therapy for COPD.

Tetracyclic Steroids Bearing a Bicyclo[4.4.1] Ring System as Potent Antiosteoporosis Agents from the Deep-Sea-Derived Fungus Rhizopus sp. W23.

Chemical investigation of the deep-sea-derived fungus Rhizopus sp. W23 resulted in the identification of six new (1-3, 6, 8, 9) and 12 known (4, 5, 10-19) cyclocitrinol analogues, together with one handling artifact (7), all featuring an unusual 7/7/6/5-tetracyclic scaffold and bicyclo[4.4.1] A/B rings. Norcyclocitrinoic acids A and B (1, 2) represent the second occurrence of 24,25-bisnor cyclocitrinols. Structures were assigned to new steroids on the basis of extensive spectroscopic analysis and X-ray crystallography. Compound 13 significantly enhances osteoblastogenesis and inhibits adipogenesis in mature bone marrow stromal cells at 5 µM, indicating a potential to be an antiosteoporosis lead.

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.

[Research progress on the effects of childhood obstructive sleep apnea syndrome on cognition and brain functions].

Obstructive sleep apnea syndrome (OSAS), a prevalent sleep disorder in children, is characterized by recurring upper airway obstruction during sleep. OSAS in children can cause intermittent hypoxia and sleep fragmentation, ultimately affect brain development and further lead to cognitive impairment if lack of timely effective intervention. In recent years, magnetic resonance imaging (MRI) and electroencephalogram (EEG) have been employed to investigate brain structure and function abnormalities in children with OSAS. Previous studies have indicated that children with OSAS showed extensive gray and white matter damage, abnormal brain function in regions such as the frontal lobe and hippocampus, as well as a significant decline in general cognitive function and executive function. However, the existing studies mainly focused on the regional activity, and the mechanism of pediatric OSAS affecting brain networks remains unknown. Moreover, it's unclear whether the alterations in brain structure and function are associated with their cognitive impairment. In this review article, we proposed two future research directions: 1) future studies should utilize the multimodal neuroimaging techniques to reveal the alterations of brain networks organization underlying pediatric OSAS; 2) further investigation is necessary to explore the relationship between brain network alteration and cognitive dysfunction in children with OSAS. With these efforts, it will be promising to identify the neuroimaging biomarkers for monitoring the brain development of children with OSAS as well as aiding its clinical diagnosis, and ultimately develop more effective strategies for intervention, diagnosis, and treatment.

Computed Tomography-Guided Percutaneous Radiofrequency Ablation in Older Adults With Early-Stage Peripheral Lung Cancer: A Retrospective Cohort Study.

OBJECTIVES: To evaluate the feasibility, safety, and efficacy of computed tomography(CT)-guided percutaneous radiofrequency ablation (RFA) in medically inoperable older adults with clinical stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively reviewed the records of medically inoperable older adults (≥70 years) with clinical stage I NSCLC who underwent percutaneous multi-tined electrode RFA at our institution between January 2014 and December 2018. We analyzed the patients' characteristics, therapy response, survival, as well as the procedure-related complications. RESULTS: Eighteen patients (10 men and 8 women) with a mean age of 75.9 (71-85) years were treated in during the study period. The median tumor size was 25 mm (range, 19-43 mm); 10 and 8 cases involved stage T1 and T2a disease, respectively. The median follow-up duration was 25 (11-45) months. RFA was technically successful for all 18 lesions, with no treatment-related mortality. The disease control rate was 83.3% (15/18 lesions). There were 6 cases of pneumothorax: one symptomatic case requiring thoracic drainage, and five requiring no treatment. Minor complications, including pulmonary infection, chest pain, fever, and cough, were treated within 4 days (range, 1-4 days). The progression-free survival rates were 83.3%, 64.9%, and 51.9% 1, 2, and 3 years, respectively. The corresponding overall survival rates were 92.2%, 81.5%, and 54.3%, respectively. CONCLUSIONS: CT-guided percutaneous RFA is safe and effective in medically inoperable patients with stage I NSCLC and could be an alternative therapeutic strategy, particularly in older adults with early-stage peripheral lung cancer.

Methodology and experiences of rapid advice guideline development for children with COVID-19: responding to the COVID-19 outbreak quickly and efficiently.

BACKGROUND: Rapid Advice Guidelines (RAG) provide decision makers with guidance to respond to public health emergencies by developing evidence-based recommendations in a short period of time with a scientific and standardized approach. However, the experience from the development process of a RAG has so far not been systematically summarized. Therefore, our working group will take the experience of the development of the RAG for children with COVID-19 as an example to systematically explore the methodology, advantages, and challenges in the development of the RAG. We shall propose suggestions and reflections for future research, in order to provide a more detailed reference for future development of RAGs. RESULT: The development of the RAG by a group of 67 researchers from 11 countries took 50 days from the official commencement of the work (January 28, 2020) to submission (March 17, 2020). A total of 21 meetings were held with a total duration of 48 h (average 2.3 h per meeting) and an average of 16.5 participants attending. Only two of the ten recommendations were fully supported by direct evidence for COVID-19, three recommendations were supported by indirect evidence only, and the proportion of COVID-19 studies among the body of evidence in the remaining five recommendations ranged between 10 and 83%. Six of the ten recommendations used COVID-19 preprints as evidence support, and up to 50% of the studies with direct evidence on COVID-19 were preprints. CONCLUSIONS: In order to respond to public health emergencies, the development of RAG also requires a clear and transparent formulation process, usually using a large amount of indirect and non-peer-reviewed evidence to support the formation of recommendations. Strict following of the WHO RAG handbook does not only enhance the transparency and clarity of the guideline, but also can speed up the guideline development process, thereby saving time and labor costs.

Guidelines for the prevention and management of children and adolescents with COVID-19.

Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. CONCLUSION: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged. WHAT IS KNOWN: • Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. WHAT IS NEW: • The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

The identification of pregnant women with renal colic who may need surgical intervention.

BACKGROUND: Renal colic is a surgical emergency in pregnancy that is caused by a range of non-obstetric factors and known to occur more frequently during the second and third trimesters. Several studies have reported that up to 70-80% of stones pass spontaneously during pregnancy. There are some patients will not pass their stones and will ultimately require surgical intervention. Through retrospective analysis of the clinical data of 212 pregnant women with renal colic, the predictive factors of pregnant women with renal colic in need of surgical intervention were determined. METHODS: We conducted a retrospective review of 212 pregnant women presenting with renal colic between 1st January 2009 and 31st December 2020. Univariate and multivariate analyses identified a range of predictive variables for surgical intervention. In addition, we used receiver operating characteristic curve analysis to evaluate the predictive power of our model and created a nomogram for clinical application. RESULTS: Of the 212 patients presenting with acute renal colic in pregnancy, 100 patients (47.2%) underwent surgical intervention and 112 patients (52.8%) were treated conservatively. Univariate analysis identified significant differences between the two groups with regards to fever, the duration of pain, white blood cells, C-reactive protein, ureteral stone size, hydronephrosis, and stone location. Multivariate analysis further identified a number of independent predictors for surgical intervention, including fever, a duration of pain ≥ 4 days, a ureteral stone size ≥ 8 mm, and moderate or severe hydronephrosis. CONCLUSIONS: We identified several independent predictors for surgical intervention for renal colic in pregnancy. Fever, a duration of pain ≥ 4 days, a ureteral stone size ≥ 8 mm, and moderate/severe hydronephrosis, play significant roles in predicting surgical intervention. Our nomogram can help to calculate the probability of surgical intervention in a simple and efficient manner. Prospective studies are now required to validate our model.

Anti-HIV Compounds from the Deep-Sea-Derived Fungus Chaetomium globosum.

Chemical investigation on the deep-sea-derived fungus Chaetomium globosum led to the isolation of nine compounds. By extensive analyses of the 1D and 2D NMR as well as HR-ESI-MS spectra, their structures were elucidated as xylariol A (1), 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran (2), epicoccone B (3), epicoccolide B (4), chaetoglobosin G (5), chaetoglobosin Fex (6), cochliodone A (7), cochliodone B (8), and chaetoviridin A (9), assorting as four phenolics (1-4), two cytochalosans (5-6), and three azaplilones (7-9). Compounds 1-3 were firstly reported from C. globosum. Under the concentrations of 20 µg/mL, 1, 2, and 3 exhibited potent in vitro anti-HIV activity with the inhibition rates of 70 %, 75 %, and 88 %, respectively.

Nicorandil, an ATP-sensitive potassium channel activation, attenuates myocardial injury in rats with ischemic cardiomyopathy.

Ischemic cardiomyopathy is a common but underestimated cause of heart failure. This study investigated the myocardial-protective effects of nicorandil on rats with ischemic cardiomyopathy. In the present study, ischemic cardiomyopathy rats model were used to evaluate the effects of nicorandil. Cardiac ultrasonography was employed to examine the changes of heart structure and heart function. Electron microscopy was employed to observe the changes of pathological ultrastructure of the myocardium. Western blot and enzyme-linked immunosorbent assays were employed to detect protein levels and Mitochondrial Ca2+ concentration. The heart color ultrasound and myocardial pathology of the rats in the nicorandil group were improved significantly, the mitochondrial Ca2+ concentration was decreased, the expressions of MFN-1, OPA-1, and Bcl were increased, and the expressions of the mitochondrial mitotic proteins DRP-1, VDAC1, CytC, and Bax were decreased in ICM rats' heart treatment with nicorandil, compared with ICM rats. Nicorandil can reduce myocardial pathological damage in ICM rats, which may be caused by promoting the opening of mitochondrial ATP-sensitive potassium channel and inducing the changes of mitochondrial dynamics to induce the reduction of myocardial cell apoptosis.

A lightweight automatic sleep staging method for children using single-channel EEG based on edge artificial intelligence.

With the development of telemedicine and edge computing, edge artificial intelligence (AI) will become a new development trend for smart medicine. On the other hand, nearly one-third of children suffer from sleep disorders. However, all existing sleep staging methods are for adults. Therefore, we adapted edge AI to develop a lightweight automatic sleep staging method for children using single-channel EEG. The trained sleep staging model will be deployed to edge smart devices so that the sleep staging can be implemented on edge devices which will greatly save network resources and improving the performance and privacy of sleep staging application. Then the results and hypnogram will be uploaded to the cloud server for further analysis by the physicians to get sleep disease diagnosis reports and treatment opinions. We utilized 1D convolutional neural networks (1D-CNN) and long short term memory (LSTM) to build our sleep staging model, named CSleepNet. We tested the model on our childrens sleep (CS) dataset and sleep-EDFX dataset. For the CS dataset, we experimented with F4-M1 channel EEG using four different loss functions, and the logcosh performed best with overall accuracy of 83.06% and F1-score of 76.50%. We used Fpz-Cz and Pz-Oz channel EEG to train our model in Sleep-EDFX dataset, and achieved an accuracy of 86.41% without manual feature extraction. The experimental results show that our method has great potential. It not only plays an important role in sleep-related research, but also can be widely used in the classification of other time sequences physiological signals.

Polarization independent and non-reciprocal absorption in multi-layer anisotropic black phosphorus metamaterials.

The polarization independent and non-reciprocal absorption is particularly crucial for the realization of non-reciprocal absorption devices. Herein, we proposed and studied the absorption response of two- and three-layer anisotropic black phosphorus (BP) metamaterials by using the finite-difference time-domain (FDTD) simulation and radiation oscillator theory (ROT) analysis. It is shown that, due to unequal surface plasmon resonant modes excited in zigzag (ZZ) and armchair (AC) directions of the anisotropic BP layer, tunable polarization independent and dependent absorption can be achieved for the proposed multi-layer anisotropic BP metamaterials with AC-AC, AC-ZZ, ZZ-AC, AC-AC-φ, AC-ZZ-φ, and ZZ-AC-φ configurations. Especially, the polarization independent absorption also can be realized for odd-layer BP nanostructures. Unlike previous reports, polarization independence only can be achieved in the even-layer BP nanostructure. Moreover, tunable non-reciprocal absorption with the extremely large non-reciprocal degree (NRD) is also found in the case of AC-ZZ and ZZ-AC configurations and AC-ZZ-φ and ZZ-AC-φ configurations. These results may open up the possibility of realizing tunable polarization independent and non-reciprocal plasmonic devices based on 2D materials.

Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling.

The conversion of skeletal muscle fiber from fast twitch to slow-twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber-type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss-of-function models generated by phospholipase Cß antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations.

Solitumergosterol A, a unique 6/6/6/6/5 steroid from the deep-sea-derived Penicillium solitum MCCC 3A00215.

A unique C30 steroid, solitumergosterol A (1), was isolated from the deep-sea-derived fungus Penicillium solitum MCCC 3A00215. The planar structure and relative configuration of 1 were established mainly on the basis of extensive analysis of its 1D and 2D NMR as well as HRESIMS data, while its absolute configuration was clarified by comparison of the experimental and theoretical ECD spectra. Noteworthily, 1 is a Diels-Alder adduct of a heterogeneous steroid bearing a 6/6/6/6/5 pentacyclic carbon skeleton. Solitumergosterol A (1) exhibited weak in vitro anti-tumor activity against MB231 cells by a RXRα-dependent mechanism.

Discovery of andrastones from the deep-sea-derived Penicillium allii-sativi MCCC 3A00580 by OSMAC strategy.

Andrastones are unusual 6,6,6,5-tetracyclic meroterpenoids that are rarely found in nature. Previously, three andrastones were obtained from the rice static fermentation extract of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580. Inspired by one strain many compounds (OSMAC) approach, the oat static fermentation on P. allii-sativi was conducted. As a result, 14 andrastones were isolated by UV-guided isolation. The chemical structures of the nine new compounds (1-9) was established by comprehensive analysis of the NMR, MS, ECD, and X-ray crystallography and the five known ones (10-14) were assigned by comparing their NMR, MS, and OR data with those reported in literature. Compound 1 bears a novel hemiketal moiety while 2 is the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. All isolates were tested for anti-allergic bioactivity. Compound 10, 3-deacetylcitreohybridonol, significantly decreased degranulation with the IC50 value of 14.8 µM, compared to that of 92.5 µM for the positive control, loratadine. Mechanism study indicated 10 could decrease the generation of histamine and TNF-α by reducing the accumulation of Ca2+ in RBL-2H3 cells. These findings indicate andrastones could be potential to discover new anti-allergic candidate drugs.

p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). METHODS: Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and ß-galactosidase staining to count the proportion of senescent cells. RESULTS: The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. CONCLUSION: p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.