A new resorcylic acid lactone from the endophytic fungus Chaetosphaeronema sp.

A new 14-membered resorcylic acid lactone (RAL14), chaetolactone A (1), along with three known ones (2-4), was obtained from the fermentation of the soil-derived fungus Chaetosphaeronema sp. SSJZ001. Their structures were established based on extensive spectroscopic data analyses (UV, IR, HRESIMS, 1D, and 2D NMR),13C NMR chemical shifts calculations coupled with the DP4+ probability method, theoretical calculations of ECD spectra, as well as X-ray diffraction analysis. All compounds were evaluated for their cytotoxic effects against A549, HO-8910, and MCF-7 cell lines.

Oleanane and 30-noroleanane triterpenoids from the roots of Paeonia lactiflora.

An investigation of EtOAc extract from the roots of Paeonia lactiflora yielded three new 30-noroleanane triterpenoids paeonenoides L-N (1-3) and one new oleanane triterpenoid paeonenoide O (4) together with 7 known compounds (5-11). Extensive spectrographic experiments were applied to identify the structures of 1-4, and their absolute configurations were unambiguously determined by theoretical calculations of ECD spectra, as well as the single-crystal X-ray diffraction analysis. Compounds 8, 9 and 10 were isolated from the Paeonia genus for the first time. Moreover, compounds 8, 9 and 11 showed inhibitory activities against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages with the IC50 values of 72. 17 ± 4.74, 30.02 ± 2.03 and 28.34 ± 1.85 µM, respectively.

Ketogenic diet-produced ß-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Effectiveness of opportunistic osteoporosis screening on chest CT using the DCNN model.

OBJECTIVE: To develop and evaluate a deep learning model based on chest CT that achieves favorable performance on opportunistic osteoporosis screening using the lumbar 1 + lumbar 2 vertebral bodies fusion feature images, and explore the feasibility and effectiveness of the model based on the lumbar 1 vertebral body alone. MATERIALS AND METHODS: The chest CT images of 1048 health check subjects from January 2021 to June were retrospectively collected as the internal dataset (the segmentation model: 548 for training, 100 for tuning and 400 for test. The classification model: 530 for training, 100 for validation and 418 for test set). The subjects were divided into three categories according to the quantitative CT measurements, namely, normal, osteopenia and osteoporosis. First, a deep learning-based segmentation model was constructed, and the dice similarity coefficient(DSC) was used to compare the consistency between the model and manual labelling. Then, two classification models were established, namely, (i) model 1 (fusion feature construction of lumbar vertebral bodies 1 and 2) and (ii) model 2 (feature construction of lumbar 1 alone). Receiver operating characteristic curves were used to evaluate the diagnostic efficacy of the models, and the Delong test was used to compare the areas under the curve. RESULTS: When the number of images in the training set was 300, the DSC value was 0.951 ± 0.030 in the test set. The results showed that the model 1 diagnosing normal, osteopenia and osteoporosis achieved an AUC of 0.990, 0.952 and 0.980; the model 2 diagnosing normal, osteopenia and osteoporosis achieved an AUC of 0.983, 0.940 and 0.978. The Delong test showed that there was no significant difference in area under the curve (AUC) values between the osteopenia group and osteoporosis group (P = 0.210, 0.546), while the AUC value of normal model 2 was higher than that of model 1 (0.990 vs. 0.983, P = 0.033). CONCLUSION: This study proposed a chest CT deep learning model that achieves favorable performance on opportunistic osteoporosis screening using the lumbar 1 + lumbar 2 vertebral bodies fusion feature images. We further constructed the comparable model based on the lumbar 1 vertebra alone which can shorten the scan length, reduce the radiation dose received by patients, and reduce the training cost of technologists.

Risk factors and predicting nomogram for the clinical deterioration of non-severe community-acquired pneumonia.

BACKGROUND: Currently, there remains insufficient focus on non-severe community-acquired pneumonia (CAP) patients who are at risk of clinical deterioration, and there is also a dearth of research on the related risk factors. Early recognition of hospitalized patients at risk of clinical deterioration will be beneficial for their clinical management. METHOD: A retrospective study was conducted in The First Affiliated Hospital of Wenzhou Medical University, China, spanning from January 1, 2018 to April 30, 2022, and involving a total of 1,632 non-severe CAP patients. Based on whether their condition worsened within 72 h of admission, patients were divided into a clinical deterioration group and a non-clinical deterioration group. Additionally, all patients were randomly assigned to a training set containing 75% of patients and a validation set containing 25% of patients. In the training set, risk factors for clinical deterioration in patients with non-severe CAP were identified by using LASSO regression analysis and multivariate logistic regression analysis. A nomogram was developed based on identified risk factors. The effectiveness of the nomogram in both the training and validation sets was assessed using Receiver Operating Characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: Age, body mass index (BMI), body temperature, cardiovascular comorbidity, respiratory rate, LDH level, lymphocyte count and D-dimer level were identified as risk factors associated with the clinical deterioration of non-severe CAP within 72 h of admission. The area under curve (AUC) value of the nomogram was 0.78 (95% CI: 0.74-0.82) in the training set and 0.75 (95% CI: 0.67-0.83) in the validation set. Furthermore, the calibration curves for both the training and validation sets indicated that the predicted probability of clinical deterioration aligned with the actual probability. Additionally, DCA revealed clinical utility for the nomogram at a specific threshold probability. CONCLUSION: The study successfully identified the risk factors linked to the clinical deterioration of non-severe CAP and constructed a nomogram for predicting the probability of deterioration. The nomogram demonstrated favorable predictive performance and has the potential to aid in the early identification and management of non-severe CAP patients at elevated risk of deterioration.

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH and ASK1-JNK pathway are targetable to alleviate PCOS.

DeepmdQCT: A multitask network with domain invariant features and comprehensive attention mechanism for quantitative computer tomography diagnosis of osteoporosis.

In the medical field, the application of machine learning technology in the automatic diagnosis and monitoring of osteoporosis often faces challenges related to domain adaptation in drug therapy research. The existing neural networks used for the diagnosis of osteoporosis may experience a decrease in model performance when applied to new data domains due to changes in radiation dose and equipment. To address this issue, in this study, we propose a new method for multi domain diagnostic and quantitative computed tomography (QCT) images, called DeepmdQCT. This method adopts a domain invariant feature strategy and integrates a comprehensive attention mechanism to guide the fusion of global and local features, effectively improving the diagnostic performance of multi domain CT images. We conducted experimental evaluations on a self-created OQCT dataset, and the results showed that for dose domain images, the average accuracy reached 91%, while for device domain images, the accuracy reached 90.5%. our method successfully estimated bone density values, with a fit of 0.95 to the gold standard. Our method not only achieved high accuracy in CT images in the dose and equipment fields, but also successfully estimated key bone density values, which is crucial for evaluating the effectiveness of osteoporosis drug treatment. In addition, we validated the effectiveness of our architecture in feature extraction using three publicly available datasets. We also encourage the application of the DeepmdQCT method to a wider range of medical image analysis fields to improve the performance of multi-domain images.

[Mn/Al-layered Double Oxide-loaded Biochar Reduced the Toxic Effects of Heavy Metals on Ryegrass in Soil].

The combined pollution of heavy metal Cu and Cd in soil induced by the e-waste dismantling process has become a severe problem. To deal with this issue, crab shell biochar (BC) and Mn/Al-layered double oxide-loaded crab shell biochar (LDO/BC) were prepared using coprecipitation and co-pyrolysis of discarded crab shells and manganese aluminum salt. The experimental results showed that not only were the soil pH, available phosphorus, available potassium, and soil enzymatic activity enhanced, but the contents of DTPA-Cu and DTPA-Cd in the soil were also reduced after remediation by BC and LDO/BC. Microbial community analysis indicated that BC-1% could promote the relative abundance of Gemmatimonadota and Acidobacteriota; meanwhile, LDO/BC-1% could promote the relative abundance of Proteobacteria, which could reduce the accumulation of Cd in plants. Ryegrass was planted for further investigating the toxic effect of heavy metals in soil after remediation. The results demonstrated that after remediating with BC-5% and LDO/BC-1%, ryegrass grew more vigorously and with a lower content of the heavy metals Cu and Cd in the plants than that of CK, and the germination rate increased by 29% and 60%, respectively. Further, LDO/BC-1% had a more excellent remediation performance than that of the other groups, and the Mn in LDO/BC could reduce the content of heavy metal Cd adsorbed by ryegrass in soil.

Gymnadenia conopsea (L.) R. Br.: Comprehensive review of propagation and breeding, traditional uses, chemical composition, pharmacology, quality control, and processing.

ETHNOPHARMACOLOGICAL RELEVANCE: Gymnadenia conopsea, a perennial herbaceous flowering plant that belongs to the family of Orchidaceae, sporadic distributed in the altitudes of 200-4700 m across northern Europe and, temperate and subtropical Asia region. The dried tubers of G. conopsea have been used to treat cough, asthma, and their syndromes, and also as a tonic in China and surrounding countries for a long history. G. conopsea is often processed deeply processed before use to enhance its efficacy. In recent years, because of its remarkable pharmacological activity and health care function, G. conopsea has been used more and more widely. Due to its extensive application and bad growth environment, the wild distribution of G. conopsea is decreasing and it has been listed as an endangered plant. AIM OF THE REVIEW: This review aims to summarize the propagation and breeding, traditional uses, chemical composition, pharmacology, quality control, and processing of G. conopsea. Moreover, it also provides suggestions for the future high-value utilization of G. conopsea. MATERIALS AND METHODS: A literature search on Gymnadenia genus and G. conopsea was performed using scientific databases including SciFinder, ACS, Web of Science, Springer, ScienceDirect, PubMed, and CNKI. Information was also collected from classic books of Chinese herbal medicine, official websites, Ph.D. and M.Sc. Dissertations, and so on. Structures of chemical compounds were drawn by ChemDraw software. RESULTS: As of submission date of this manuscript, total 170 natural compounds have been isolated and characterized from G. conopsea, and all of the compounds were isolated from the tubers. The isolated compounds including benzylester glucosides, dihydrostilbenes, phenanthrenes, phenolic compounds, alkaloids, polysaccharide, lignans, flavones, triterpenoids, steroids, and other compounds. Some of these compounds and active extracts exhibited a wide range of pharmacological activities, in which, the tonifying, anti-fatigue, anti-oxidant, anti-viral, sedative and hypnotic activities are consistent with the traditional uses for the treatment of diseases. In addition, a variety of new pharmacological activities, such as preventing and treating gastric ulcers, immunoregulatory, anti-hyperlipidemia, anti-anaphylaxis, anti-silicosis, anti-cancer and neuroprotective activities have also been reported. However, the bioactive compounds responsible for most of the above pharmacological effects have not been well summarised till now. In this manuscript, analysis, speculation and summary of compounds that responsible for pharmacological effects were conducted. CONCLUSIONS: The chemical constituents and pharmacological activities studies of G. conopsea extract have been summarised in this context, the isolated compounds responsible for the pharmacological activities were also analyzed and deduced according to the publications, all above led to suggestions for the future high-value utilization of G. conopsea.

Two unusual novel iridoid glycosides from Cornus officinalis fruit and their biological activities.

Two unusual novel iridoid glycosides, cornsecoside A (1) and cornsecoside B (2), were isolated from a 40% ethanol elution fraction of a 50% ethanol extract of Cornus officinalis fruit. Their structures were determined by spectroscopic data analysis combined with hydrolysis and ECD spectroscopy. In addition, compounds 1 and 2 exhibited cytotoxic activity against Bel-7402 cells with IC50 values of 8.12 and 9.31 µM, and were neuroprotective against H2O2-induced SH-SY5Y cell injure at a concentration of 10 µM.

Phenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRß.

Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRß) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) develop insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylate lysine 1057/1079 of IRß (F-K1057/1079), inactivating IRß and preventing insulin from promoting glucose uptake by cells. SIRT1 reverse F-K1057/1079 and counteract the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients are positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizes insulin signaling and relieves T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation.

Two New Nor-seco-Isodhilarane-Type Meroterpenoids from the Endophytic Fungus Penicillium purpurogenum.

Two new nor-seco isodhilarane meroterpenoids (NSIMs), purpurogenolides F (1) and G (2), along with three known meroterpenoid analogs (3-5), were isolated from the cultures of an endophytic fungus, Penicillium purpurogenum. Structures and absolute configurations of the new NSIMs were determined based on extensive spectroscopic data analyses, including HR-ESI-MS, UV, IR, NMR chemical shift calculations together with DP4+ probability analysis, as well as ECD calculations. All the isolated meroterpenoids were assessed for their anti-inflammatory activities, and compound 4 exhibited moderate inhibitory activity against the nitric oxide (NO) production in lipopolysaccharide (LPS) induced RAW 264.7 cells with an IC50 value of 20.85±2.31 µM.

Bioactive neolignans and lignans from the roots of Paeonia lactiflora.

Two new neolignans and one new lignan (1-3) were obtained from the roots of Paeonia lactiflora. Their structures were unambiguously elucidated based on extensive spectroscopic analysis, single-crystal X-ray crystallography, and the calculated and experimental electronic circular dichroism (ECD) spectra. Compound 1 was a racemic mixture and successfully resolved into the anticipated enantiomers via chiral-phase HPLC. Compound 3 demonstrated moderate inhibitory activity against human carboxylesterase 2A1 (hCES2A1) with an IC50 value of 7.28 ± 0.94 µmol·-1.

Diagnostic performance of the metagenomic next-generation sequencing in lung biopsy tissues in patients suspected of having a local pulmonary infection.

PURPOSE: This study aims to evaluate the diagnostic application and performance of the metagenomic next-generation sequencing (mNGS) in patients suspected of local pulmonary infection by comparing it to the traditional pathogen detection methods in lung tissue specimens obtained by a computerized tomography-guided biopsy (CT-guided biopsy). METHODS: We retrospectively reviewed patients, admitted to the First Affiliated Hospital of Wenzhou Medical University, China from May 2018 to December 2020, who were suspected of local pulmonary infection. All cases received a CT-guided lung biopsy, tissue samples were sent both for conventional examinations (CE) and mNGS tests. The sensitivity and specificity of the two diagnostic approaches were compared. RESULTS: 106 patients enrolled, 76 patients were diagnosed with a pulmonary infection. Among 49 patients with identified pathogens, CE confirmed pathogenic infections in 32 cases. Mycobacterium spp. and fungi accounted for 37.5% (12/32) and 28.1% (9/32), respectively, with bacteria 34.4% (11/32). The mNGS examination detected extra pathogenic microorganisms in 22 patients that were consistent with the patients' clinical and radiographic pictures. The sensitivity of mNGS was 53.9% vs. 42.1% for the CE, while the specificity was 56.7% versus 96.7%. For detection rate, mNGS was significantly superior to CE in bacterial (96.3% vs. 40.7%, p < 0.05), and mixed infections (100% vs. 50%, p < 0.05), but inferior to CE in fungal (60% vs. 90%, p > 0.05) and Mycobacterium spp. infections (66.7% vs. 100%, p > 0.05) with no significant difference. Among 31 cases diagnosed with lung abscess, the diagnostic performance of the detection rate was 67.7% (21/31) in favour of mNGS compared to 29.0% (9/31) for CE (p < 0.05). Most polymicrobial infections were induced by anaerobic species that coexisted with Streptococcus constellatus. And Klebsiella pneumoniae was the most common isolated monomicrobial infection. CONCLUSIONS: The most commonly detected causative pathogens for local pulmonary infections were bacteria, Mycobacterium spp. and fungi. Compared with the CE, the advantages of mNGS in the pathogens detection lie in the discovery of bacterial and mixed infections, as well as in the detection of lung abscess. Conversely, mNGS is not good enough to be recommendable for the detection of Mycobacterium spp. and fungi.

Three new ursane-type triterpenoids from Rosmarinus officinalis and their biological activities.

Three new ursane-type triterpenoids, 3-oxours-12-en-20, 28-olide (1), 3ß-hydroxyurs-12-en-20, 28-olide (2) and 3ß-hydroxyurs-11, 13(18)-dien-20, 28-olide (3), were isolated from a potent anti-inflammatory and antibacterial fraction of the ethanolic extract of Rosmarinus officinalis. Their structures were elucidated by a combination of extensive 1D- and 2D-NMR experiments, MS data and comparisons with literature reports. Compounds 1-3 exhibited significantly inhibitory effects on nitric oxide production in lipopolysaccharide-activated mouse RAW264.7 macrophages, but no antibacterial activity was found at a concentration of 128 µg·mL-1.

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake.

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Secoiridoid glycosides from the fruits of Cornus officinalis.

Five new secoiridoid glycosides, cornusphenosides E-I (1-5), were isolated and characterized from an active fraction of ethanol extract of the fruits of Cornus officinalis. Their structures were determined by extensive spectroscopic data analysis, including 2 D NMR and HRESIMS experiments. In the preliminary assay, compound 5 (when evaluated at 10 µM) showed the neuroprotective effect against H2O2-induced SH-SY5Y cell damage.

Bioactive sesquineolignans from the twigs of Litsea cubeba.

In a continuing search for biological natural products with structure diversity from traditional Chinese herbs, five new sesquineolignans (1-5) were isolated from an ethyl acetate extract of the twigs of Litsea cubeba. Their structures were elucidated based on MS, 1D and 2D NMR spectroscopic data, as well as experimental electronic circular dichroism (ECD) spectra. Compounds 1-5 showed moderate inhibitory effects against LPS-induced NO production in RAW264.7 macrophages, with IC50 values of 16.2, 20.2, 22.1, 15.1, and 16.6 µmol·L-1, respectively.

[Research progress on chemical constituents and pharmacological activities of Trigonella foenum-graecum].

Trigonella foenum-graecum is an annual plant of the genus Trigonella in the Leguminosae family. It is widely distributed in China and has a long history of application. According to phytochemistry research, the seeds, stem, and leaves of this herb contain not only a variety of bioactive ingredients, including alkaloids, saponins, polysaccharides, flavonoids, and phenols, but also abundant nutrients such as unsaturated fatty acids and amino acids and various trace elements. Pharmacological studies have shown that both the extract of T. foenum-graecum and its chemical constituents exhibit hypoglycemic, hypolipidemic, antitumor, antioxidative, antimicro-bial, and hepatoprotective activities. This paper reviews the research progress on the chemical constituents and pharmacological effects of T. foenum-graecum, which may contribute to further development, application, and clinical research of this herb.