Lycocasine A, a Lycopodium Alkaloid from Lycopodiastrum casuarinoides and Its Acid-Sensing Ion Channel 1a Inhibitory Activity.

A novel Lycopodium alkaloid, lycocasine A (1), and seven known Lycopodium alkaloids (2-8), were isolated from Lycopodiastrum casuarinoides. Their structures were determined through NMR, HRESIMS, and X-ray diffraction analysis. Compound 1 features an unprecedented 5/6/6 tricyclic skeleton, highlighted by a 5-aza-tricyclic[6,3,1,02,6]dodecane motif. In bioactivity assays, compound 1 demonstrated weak inhibitory activity against acid-sensing ion channel 1a.

Lycopodium Alkaloids from Huperzia goebelii.

One new fawcettimine-type Lycopodium alkaloid, hupertimine F (1), together with five known (2-6) Lycopodium alkaloids were isolated from Huperzia goebelii. The structure of 1 was elucidated by 1D and 2D NMR spectra, HRESIMS, and X-ray diffraction. Structurally, 1 represents the fourth example of Lycopodium alkaloids characterized by a 5/5/5/5/6 pentacyclic ring system with a 1-aza-7-oxabicyclo[2.2.1]heptane moiety. These known compounds 2, 3, 5, and 6 were isolated from H. goebelii for the first time. Compounds 1-6 were evaluated for acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B inhibitory activities in vitro.

Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells.

Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non-small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34- cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia. SIGNIFICANCE: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.

Casuattimines A-N, fourteen new Lycopodium alkaloids from Lycopodiastrum casuarinoides with Cav3.1 channel inhibitory activity.

Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Cav3.1 channel inhibitory activities presenting IC50 values of 10.75 ± 1.02 µM, 9.33 ± 0.79 µM, and 7.14 ± 0.86 µM, respectively. The dynamics of compound 4 against the Cav3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.

Corrigendum: Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.

[This corrects the article DOI: 10.3389/fphar.2022.972397.].

Adult Laryngeal Pleomorphic Rhabdomyosarcoma: A Rare Entity.

Rhabdomyosarcoma (RMS) is a rare and aggressive cancerous tumor that arises from embryonal mesenchymal cells with skeletal muscle differentiation, and it is exceedingly rare that occurs specifically in the larynx. To date, only 22 instances of laryngeal pleomorphic RMSs have been documented in adults. Consequently, there is limited information available to assist healthcare professionals in effectively handling RMS in the larynx of adult patients. Here, we present an uncommon occurrence involving a 45-year-old man who experienced progressive hoarseness and received a diagnosis of pleomorphic RMS affecting the larynx. Pleomorphic RMS had been pathologically diagnosed after a vertical hemilaryngectomy. Following the surgical intervention, the patient underwent chemotherapy and radiation therapy. As of now, there have been no indications of tumor recurrence.

Colchicine efficacy comparison at varying time points in the peri-operative period for coronary artery disease: a systematic review and meta-analysis of randomized controlled trials.

Objectives: Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD. Methods: Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software. Results: We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) (p < 0.00001), but it also raised the rate of adverse events (p = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients (p = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective (p = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels (p = 0.02). Conclusion: Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=316751, identifier CRD42022316751.

Three New Selaginellin Derivatives from Selaginella pulvinata and Their α-Glucosidase Inhibitory Activity.

Three new selaginellin derivatives, selaginpulvilins V-X (1-3), together with seven known analogs (4-10) were isolated from whole plants of Selaginella pulvinata. Their structures were determined by extensive spectroscopic methods including 1D and 2D NMR, HR-ESI-MS and chemical derivatization method. Compound 1 represents a rare example of naturally occurring selaginellin with an alkynylphenol-trimmed skeleton. Biological evaluation showed that compounds 2, 6 and 8 displayed moderate inhibition against α-glucosidase with IC50 values of 3.71, 2.04 and 4.00 µM, respectively.

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.

Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-ß1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

Clerodane-type Diterpene Glycosides from Dicranopteris pedata.

Three new clerodane-type diterpene glycosides, (5R,6S,8R,9S,10R)-6-O-[ß-D-glucopyranosyl-(1 → 4)-α-L-rhamnopyranosyl]cleroda-3,13(16),14-diene (1), (5R,6S,8R,9S,10R,13S)-6-O-[ß-D-glucopyranosyl-(1 → 4)-α-L-rhamnopyranosyl]-2-ox-oneocleroda-3,13-dien-15-ol (2), (5R,6S,8R,9S,10R)-6-O-[ß-D-glucopyranosyl-(1 → 4)-α-L-rhamnopyranosyl]-(13E)-2-oxoneocleroda-3,14-dien-13-ol (3), together with two known compounds 4 and 5 were isolated from Dicranopteris pedata. The structures of these compounds were elucidated by detailed spectroscopic analysis, and the absolute configuration of compound 2 was determined by ECD calculations. In addition, compound 1 exhibited weak inhibitory activities against SMMC-7721, MCF-7 and SW480.

Shexiang Tongxin Dropping Pill () Reduces Coronary Microembolization in Rats via Regulation of Mitochondrial Permeability Transition Pore Opening and AKT-GSK3ß Phosphorylation.

OBJECTIVE: To investigate the protective effects of Shexiang Tongxin Dropping Pill (, STDP) following sodium laurate-induced coronary microembolization (CME) in rats. METHODS: Forty rats were divided into 4 groups: the control (sham) group, CME group, low-dose STDP pretreatment group (20 mg·kg-1·d-1), and high-dose STDP pretreatment group (40 mg·kg-1·d-1). The rats were intragastric administrated with STDP 2 weeks before operation. Moreover, the histopathological alterations were observed using optical microscopy and transmission electron microscopy. Antioxidant biomarkers were analyzed by enzyme-linked immunosorbent assay. Mitochondrial functions including the mitochondrial permeability transition pore (mPTP) mtDNA copy number were determined and proteins of AKT/GSK3ß were analyzed by Western blot. RESULTS: The rats in the CME group showed a significant increase in the fibrinogen-like protein 2 expression level and mitochondrial dysfunction and a decrease in the expression level of antioxidant biomarkers (superoxide dismutase and catalase, P<0.01 for all). In contrast, the rats in the low- and high-dose STDP pretreatment groups showed a significant decrease in coronary microthrombi (P<0.05); moreover, STDP restored the antioxidant-related protein activities and mitochondrial function, inhibited mPTP opening, decreased AKT-Ser473 phosphorylation, and increased GSK3ß-Ser9 phosphorylation (P<0.05 or P<0.01). CONCLUSION: STDP may be useful for treatment of CME, possibly via regulation of mPTP opening and AKT/GSK3ß phosphorylation.

Prevalence of depressive symptoms in patients with Heart Failure in China: a meta-analysis of comparative studies and epidemiological surveys.

BACKGROUND: Although depressive symptoms is a frequent psychiatric comorbidity in people with Heart Failure (HF) in China, its prevalence was not estimated. This is a meta-analysis of studies examining depressive symptoms in HF patients in China. METHODS: The following databases including PubMed, the Cochrace Library, Embase, China National Knowledge Infrastructure (CNKI), WanFang and VIP were independently and systematically searched from inception until March 31, 2019. Statistical analyses were performed using the Stata 13.0 software. The pooled prevalence of depressive symptoms was performed using a random-effects model. In addition, subgroup analysis was conducted based on the New York Heart Association (NYHA) functional class, the assessment tools of depression and gender. RESULTS: Altogether 53 studies (10649 participants) met the inclusion criteria for the analysis. The point prevalence of depressive symptoms in HF was 43%. In subgroup analyses, the prevalence of depressive symptoms was higher in females than in males (46% vs 34%, respectively), and the prevalence of depressive symptoms positively correlated with New York Heart Association functional classes (II 28%, III 46%, IV 52%) . Rates of depression were highest when measured using BDI scale (62%), and lowest when measured using the CES-D (31%). CONCLUSIONS: This meta-analysis confirmed that the prevalence of depressive symptoms was common in HF patients in China and it is related to the severity of heart failure, gender and the diversity of assessment tools. Appropriate strategies for prevention and treatment of depressive symptoms in this population need greater attention.

[Changes of pigment components in Dendrobium catenatum flower under different storage conditions].

The flower color of Dendrobium catenatum(D. officinale) tends to fade during storage. In order to clarify the influence of storage conditions on the pigment components in flowers, two conditions were applied:temperature and illumination. The contents of pigments in the D. catenatum flower were determined by UV-Vis spectrophotometry and HPLC, and the changes of them during storage were analyzed. The results showed that illumination and temperature had an effect on the pigments of D. catenatum flower during sto-rage. Illumination significantly promoted the degradation of pigments. The contents of total chlorophyll, carotenoids and anthocyanins in the light samples were significantly lower than those in the dark. The total chlorophyll, carotenoids and anthocyanins in the light samples were decreased by 46.5%, 63.4%, and 69.2% respectively. Illumination had a greater effect on fat-soluble pigments than water-soluble pigments. Among the three temperature treatments, the contents of chlorophyll, carotenoid and anthocyanin were as follows:-20 ℃>4 ℃>room temperature, it is indicated that-20 ℃ was the best temperature to maintain the stability of pigment composition. The contents of chlorophyll a, chlorophyll b, ß-carotene, lutein and zeaxanthin in the light samples decreased by 34.8%, 69.0%, 72.5%, 61.6%, 36.1%, respectively. After storage for 5 months, the contents of chlorophyll, carotenoid and anthocyanin constituent at-20 ℃ was significantly higher than those at 4 ℃ and room temperature. The results show that light avoiding and low-temperature can effectively slow down the degradation of pigment components. Therefore, it is suggested that D. catenatum flower should be stored in light avoiding and low-temperature conditions in actual production and processing, which can prolong the usable time.

Clinical implications of plasma Nogo-A levels in patients with coronary heart disease.

INTRODUCTION: Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Recently, increasing evidence has shown that Nogo-A plays important roles in cardiac development and may act as a potential indicator for heart failure. In addition, increased oxidative stress has been found in individuals with cardiovascular diseases. However, not much is known regarding the expression levels of Nogo-A and reactive oxygen species (ROS) in patients with coronary heart disease (CHD). Therefore, we sought to investigate the relationship between Nogo-A, ROS levels and CHD. MATERIAL AND METHODS: The plasma Nogo-A and ROS concentrations of 122 acute coronary syndrome (ACS), 101 unstable angina pectoris (UAP), and 21 acute myocardial infarction (AMI) patients and 56 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). We further generated a receiver operating characteristic (ROC) curve to assess the diagnostic accuracy of Nogo-A and ROS in CHD. RESULTS: The Nogo-A and ROS levels were significantly higher in patients with CHD than those in healthy controls. In addition, multivariate logistic regression analysis revealed that the level of Nogo-A (odds ratio (OR) = 1.624, 95% confidence interval: 1.125-2.293, p = 0.009) is a risk factor for prediction of CHD. Nogo-A has diagnostic value, with an optimal threshold of 5.466 ng/ml for maximized diagnostic performance (59% sensitivity and 78.6% specificity, area under curve, p < 0.05). However, ROS concentration is not a risk factor for prediction of CHD (OR = 0.999, 95% confidence interval: 0.997-1.001, p = 0.320). CONCLUSIONS: Increased plasma Nogo-A level may be associated with CHD.

[Auto-shutter of CR/DR images and applications in the post-image processing of PACS].

A method for automatic background recognition and removal in CR/DR images is presented in the paper. It is applied to PACS environment, significantly improving and increasing various features such as image display, image printing, image transporting and image compression.