Marine derived macrolide bryostatin 4 inhibits the TGF-ß signaling pathway against acute erythroleukemia.

PURPOSE: Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required. METHODS: Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-ß signaling in the progression of AEL. RESULTS: Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC50 values of 37 nM and 52 nM, respectively. B4 inhibited TGF-ß signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression. CONCLUSION: These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-ß signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.

Sponge-derived alkaloid AP-7 as a sensitizer to cisplatin in the treatment of multidrug-resistant NSCLC via Chk1-dependent mechanisms.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo. These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC.

Marine sponge-derived alkaloid inhibits the PI3K/AKT/mTOR signaling pathway against diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous non-Hodgkin lymphoma that is extremely aggressive and has an intermediate to high malignancy. Some patients still experience treatment failure, relapse, or resistance to rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) therapy. Therefore, there is an urgent need for further research on new agents for the treatment of DLBCL. AP-48 is an aaptamine alkaloid analog with potent anti-tumor effects that originates from marine natural products. In this study, we found that AP-48 exhibits dose-dependent cytotoxicity in DLBCL cell lines. Flow cytometry showed that AP-48 induced cell cycle arrest in the G0/G1 phase in SU-DHL-4 and Farage cells and in the S phase in WSU-DLCL-2 cells. AP-48 also accelerated apoptosis via the caspase-3-mediated intrinsic apoptotic pathway. Further experiments demonstrated that AP-48 exerted its anti-DLBCL effects through the PI3K/AKT/mTOR pathway, and that the PI3K agonist YS49 partially alleviated the inhibition of cell proliferation and apoptosis induced by AP-48. Finally, in a tumor xenograft model, AP-48 inhibited tumor growth and promoted apoptosis in tumor tissues, indicating its therapeutic potential in DLBCL.

A new simplified risk assessment model enhances postoperative prophylaxis of venous thromboembolism in Chinese adult patients with inguinal hernia (CHAT-3): A prospective, multicenter, randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) significantly affects the prognosis of surgical patients with inguinal hernia. The complex Caprini score, commonly used for postoperative VTE risk assessment, poses practical challenges for surgeons in clinical settings. METHODS: The CHAT-3 trial, a prospective, multicenter, randomized controlled trial, compared a simple three-factor model to assess VTE risk against routine practices in post-inguinal hernia surgery (IHS) patients. The patients were randomly assigned (1:1) to the intervention or control arm. The intervention group used the three-factor model to identify patients at moderate or high risk of VTE for subsequent prophylaxis according to clinical guidelines. Both groups were followed for four weeks, with randomization implemented using computer-generated sequences. The primary outcome measured was the rate of VTE prophylaxis. Secondary outcomes included time spent on VTE risk assessment (surgeon self-reported), postoperative D-dimer trends, perioperative VTE occurrence, bleeding events, and the net clinical benefit. RESULTS: Of the 1,109 participants, 508 in the experimental group and 601 in the control group completed follow-up. The three-factor model showed higher VTE prophylaxis rates in all patients (pharmacologic prophylaxis: 26.2% vs. 6.00%, P<0.001) and particularly in those at high risk (pharmacologic prophylaxis: 57.3% vs. 9.50%, P<0.001). The experimental group significantly reduced VTE risk assessment time compared to the Caprini score (1.39±0.55 min vs. 5.73±1.35 min, P<0.001). The experimental group had lower D-dimer levels (0.26±0.73 mg/L vs. 0.35±0.55 mg/L, P=0.028). In the experimental group, the patients did not experience an increased risk of VTE (0% vs. 1.66%, P=0.268) and bleeding (1.18% vs. 0.67%, P=0.558) compared to the controls. There was no significant difference in net clinical benefit, which combined VTE and bleeding events, between the experimental and control groups (1.18% vs. 0.83%, P=0.559). CONCLUSION: Applying the simple three-factor model in perioperative VTE management could quickly identify the patient with a high risk of VTE and improve the prophylaxis rate of perioperative VTE. TRIAL REGISTRATION: XXX. TRIAL REGISTRATION: ChiCTR2000033769.

Enhancing thromboprophylaxis after colorectal cancer surgery in China: Bridging the gap between evidence and implementation through pathway optimization.

BACKGROUND: The CRC-VTE trial conducted in China revealed a significant occurrence of venous thromboembolism (VTE) in patients following colorectal cancer (CRC) surgery, raising concerns about implementing thromboprophylaxis measures. The present study aimed to identify and analyze inappropriate aspects of current thromboprophylaxis practices. METHODS: This study performed an analysis of the CRC-VTE trial, a prospective multicenter study that enrolled 1836 patients who underwent CRC surgery. The primary objective was to identify independent risk factors for VTE after CRC surgery using multivariate logistic regression analysis. Furthermore, among the cases in which VTE occurred, the appropriateness of thromboprophylaxis was assessed based on several factors, including pharmacologic prophylaxis, time to initiate prophylaxis, drug selection, drug dosage, and duration of pharmacologic prophylaxis. Based on the analysis of the current state of thromboprophylaxis and relevant clinical guidelines, a modified Delphi method was used to develop a clinical pathway for VTE prophylaxis after CRC surgery. RESULTS: In this analysis of 1836 patients, 205 (11.2%) were diagnosed with VTE during follow-up. The multifactorial analysis identified several independent risk factors for VTE, including age (≥70 years), female sex, varicose veins in the lower extremities, intraoperative blood transfusion, and the duration of immobilization exceeding 24 h. None of the patients diagnosed with VTE in the CRC trial received adequate thromboprophylaxis. The main reasons for this inappropriate practice were the omission of thromboprophylaxis, delayed initiation, and insufficient duration of thromboprophylaxis. We developed a specialized clinical pathway for thromboprophylaxis after CRC surgery to address these issues. CONCLUSIONS: This study offers a comprehensive nationwide evaluation of existing thromboprophylaxis practices in patients after CRC surgery in China. A specialized clinical pathway was developed to address the identified gaps and improve the quality of care. This clinical pathway incorporates explicit, tailored, detailed recommendations for thromboprophylaxis after CRC surgery.

Marcytoglobosins A and B, Cytochalasans From a Marine Sponge Associated Chaetomium globosum 162105 Fungus.

Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25 µg/mL.

Mutagenetic analysis of the biosynthetic pathway of tetramate bripiodionen bearing 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton.

BACKGROUND: Natural tetramates are a family of hybrid polyketides bearing tetramic acid (pyrrolidine-2,4-dione) moiety exhibiting a broad range of bioactivities. Biosynthesis of tetramates in microorganisms is normally directed by hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machineries, which form the tetramic acid ring by recruiting trans- or cis-acting thioesterase-like Dieckmann cyclase in bacteria. There are a group of tetramates with unique skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, which remain to be investigated for their biosynthetic logics. RESULTS: Herein, the tetramate type compounds bripiodionen (BPD) and its new analog, featuring the rare skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, were discovered from the sponge symbiotic bacterial Streptomyces reniochalinae LHW50302. Gene deletion and mutant complementation revealed the production of BPDs being correlated with a PKS-NRPS biosynthetic gene cluster (BGC), in which a Dieckmann cyclase gene bpdE was identified by sit-directed mutations. According to bioinformatic analysis, the tetramic acid moiety of BPDs should be formed on an atypical NRPS module constituted by two discrete proteins, including the C (condensation)-A (adenylation)-T (thiolation) domains of BpdC and the A-T domains of BpdD. Further site-directed mutagenetic analysis confirmed the natural silence of the A domain in BpdC and the functional necessities of the two T domains, therefore suggesting that an unusual aminoacyl transthiolation should occur between the T domains of two NRPS subunits. Additionally, characterization of a LuxR type regulator gene led to seven- to eight-fold increasement of BPDs production. The study presents the first biosynthesis case of the natural molecule with 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton. Genomic mining using BpdD as probe reveals that the aminoacyl transthiolation between separate NRPS subunits should occur in a certain population of NRPSs in nature.

Deep Learning for Automated Detection and Localization of Traumatic Abdominal Solid Organ Injuries on CT Scans.

Computed tomography (CT) is the most commonly used diagnostic modality for blunt abdominal trauma (BAT), significantly influencing management approaches. Deep learning models (DLMs) have shown great promise in enhancing various aspects of clinical practice. There is limited literature available on the use of DLMs specifically for trauma image evaluation. In this study, we developed a DLM aimed at detecting solid organ injuries to assist medical professionals in rapidly identifying life-threatening injuries. The study enrolled patients from a single trauma center who received abdominal CT scans between 2008 and 2017. Patients with spleen, liver, or kidney injury were categorized as the solid organ injury group, while others were considered negative cases. Only images acquired from the trauma center were enrolled. A subset of images acquired in the last year was designated as the test set, and the remaining images were utilized to train and validate the detection models. The performance of each model was assessed using metrics such as the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value based on the best Youden index operating point. The study developed the models using 1302 (87%) scans for training and tested them on 194 (13%) scans. The spleen injury model demonstrated an accuracy of 0.938 and a specificity of 0.952. The accuracy and specificity of the liver injury model were reported as 0.820 and 0.847, respectively. The kidney injury model showed an accuracy of 0.959 and a specificity of 0.989. We developed a DLM that can automate the detection of solid organ injuries by abdominal CT scans with acceptable diagnostic accuracy. It cannot replace the role of clinicians, but we can expect it to be a potential tool to accelerate the process of therapeutic decisions for trauma care.

Marine sponge-derived alkaloid ameliorates DSS-induced IBD via inhibiting IL-6 expression through modulating JAK2-STAT3-SOCS3 pathway.

Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD.

Arenarialins A-F, Anti-inflammatory Meroterpenoids with Rearranged Skeletons from the Marine Sponge Dysidea arenaria.

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.

Isolation and absolute configuration of alkylpyridine alkaloids from the marine sponge Hippospongia lachne.

Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation.

A novel machine learning model to predict high on-treatment platelet reactivity on clopidogrel in Asian patients after percutaneous coronary intervention.

BACKGROUND: Various genetic and nongenetic variables influence the high on-treatment platelet reactivity (HTPR) in patients taking clopidogrel. AIM: This study aimed to develop a novel machine learning (ML) model to predict HTPR in Chinese patients after percutaneous coronary intervention (PCI). METHOD: This cohort study collected information on 507 patients taking clopidogrel. Data were randomly divided into a training set (90%) and a testing set (10%). Nine candidate Machine learning (ML) models and multiple logistic regression (LR) analysis were developed on the training set. Their performance was assessed according to the area under the receiver operating characteristic curve, precision, recall, F1 score, and accuracy on the test set. Model interpretations were generated using importance scores by transforming model variables into scaled features and representing in radar plots. Finally, we established a prediction platform for the prediction of HTPR. RESULTS: A total of 461 patients (HTPR rate: 19.52%) were enrolled in building the prediction model for HTPR. The XGBoost model had an optimized performance, with an AUC of 0.82, a precision of 0.80, a recall of 0.44, an F1 score of 0.57, and an accuracy of 0.87, which was superior to those of LR. Furthermore, the XGBoost method identified 7 main predictive variables. To facilitate the application of the model, we established an XGBoost prediction platform consisting of 7 variables and all variables for the HTPR prediction. CONCLUSION: A ML-based approach, such as XGBoost, showed optimum performance and might help predict HTPR on clopidogrel after PCI and guide clinical decision-making. Further validated studies will strengthen this finding.

Discovering the secondary metabolic potential of Saccharothrix.

Rare actinomycetes are highly valued as potential sources of novel bioactive secondary metabolites. Among these rare actinomycetes, the genus Saccharothrix is particularly noteworthy due to its ability to produce a diverse range of bioactive secondary metabolites. With the continuous sequencing of bacterial genomes and the rapid development of bioinformatics technologies, our knowledge of the secondary metabolic potential of Saccharothrix can become more comprehensive, but this space has not been reviewed or explored. This review presents a detailed overview of the chemical structures and bioactivities of 138 Saccharothrix-derived secondary metabolites, which are classified into five distinct groups based on their biosynthetic pathways. Furthermore, we delve into experimentally characterized biosynthetic pathways of nine bioactive metabolites. By utilizing a combination of cheminformatic and bioinformatic approaches, we attempted to establish connections between the metabolite families and the biosynthetic gene cluster families encoded by Saccharothrix strains. Our analysis provides a comprehensive perspective on the secondary metabolites that can be linked to corresponding BGCs and highlights the underexplored biosynthetic potential of Saccharothrix. This review also provides guidance for the targeted discovery and biosynthesis of novel natural products from Saccharothrix.

Global Research Hotspots in Venous Thromboembolism Anticoagulation: A Knowledge-Map Analysis from 2012 to 2021.

Background: Venous thromboembolism (VTE) is a common cardiovascular disease that seriously threatens human lives. Anticoagulant therapy is considered to be the cornerstone of VTE treatment. An increasing number of studies has been updated in the VTE anticoagulation field. However, no bibliometric analyses have assessed these publications comprehensively. Therefore, our study aimed to analyze the global status, hotspots, and trends of anticoagulant therapy for VTE. Methods: The relevant literature on VTE anticoagulation published between 2012 and 2021 was retrieved and collected from the Web of Science Core Collection database. VOSviewer, Cooccurrence Matrix Builder, gCLUTO, and some online visualization tools were adopted for bibliometric analysis. Results: A total of 15,152 related articles were retrieved. In recent years, the research output of VTE anticoagulation gradually increased. The United States was the most productive country. International cooperation is concentrated in North America and Europe; the most influential documents, journals, authors, and organizations were also from these two continents. Research hotspots mainly focus on clinical guidelines, VTE in special populations, non-vitamin K oral anticoagulants (NOACs), and parenteral anticoagulation. The research frontiers and trends include the assessment of NOACs and the antithrombotic management of VTE complicated with coronavirus disease 2019 (COVID-19). Conclusion: This bibliometric analysis provides a systematic overview of the VTE anticoagulation research, which will facilitate researchers to better understand the situation of VTE anticoagulation. Future studies should be dedicated to NOACs application and VTE-combined COVID-19 patients.

Phyllofenones F-M, Scalarane Sesterterpenes from the Marine Sponge Phyllospongia foliascens.

Eight new scalarane sesterterpenes, phyllofenones F-M (1-8), together with two known analogues, carteriofenones B and A (9-10), were isolated from the marine sponge Phyllospongia foliascens collected from the South China Sea. The structures of these compounds were determined based on extensive spectroscopic and quantum chemical calculation analysis. The antibacterial and cytotoxic activity of these compounds was evaluated. Among them, only compounds 4 and 6 displayed weak inhibitory activity against Staphylococcus aureus and Escherichia coli, with MIC values of 16 µg/mL and 8 µg/mL, respectively. Compounds 1-10 exhibited cytotoxic activity against the HeLa, HCT-116, H460, and SW1990 cancer cell lines, with IC50 values ranging from 3.4 to 19.8 µM.

A novel shared decision-making (SDM) tool for anticoagulation management in atrial fibrillation: protocol for a prospective, cluster randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia that requires anticoagulation therapy to prevent stroke. However, there is still a significant under-/over-treatment in stroke prevention for patients with AF. The adherence and the risk of bleeding associated with oral anticoagulation therapy (OACs) are major concerns. Shared decision-making (SDM) is an approach that involves patients and healthcare providers in making decisions about treatment options. This study aims to assess the effectiveness of a novel SDM tool for anticoagulation management in AF. METHODS: The study will be a prospective, cluster randomized controlled trial involving 440 patients with AF in 8 community health service centers (clusters) in Shanghai, China. The SDM group will receive anticoagulation management through the novel SDM tool, while the control group will receive standard care. The follow-up period will be at least 2 years. The primary outcome will be any bleeding event, while secondary outcomes include the accordance of stroke prophylaxis for AF according to the current guidelines, time in therapeutic range (TTR), the occurrences of major bleeding and thrombosis events, and patient knowledge, adherence, and satisfaction. DISCUSSION: This study will provide evidence of the effectiveness of shared decision-making in improving the appropriateness of OAC use in Chinese AF patients. The findings may inform the development of guidelines and policies for the management of AF and anticoagulation therapy in China and other countries. TRIAL REGISTRATION: ChiCTR ChiCTR2200062123. Registered on 23 July 2022.

Clinical comprehensive evaluation of direct oral anticoagulants for patients with atrial fibrillation in China.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly recommended over warfarin in stroke prevention for patients with non-valvular atrial fibrillation (AF). However, there is an important evidence gap in choosing the most appropriate DOAC for Chinese patients in clinical practice. METHODS: A multi-criteria decision analysis (MCDA) was adopted to build a scoring framework. Attributes and criteria were identified and determined by a scoping literature review, two rounds of Delphi surveys, and a consensus meeting. Weights of each attribute and criterion in the framework were determined using analytic hierarchy process (AHP). Evidence was collected based on the domestic or at least Asian data. Scoring methods for each criterion were developed depended on their characteristics and determined with an expert consensus meeting. Comprehensive scores of each DOAC were calculated based on the utility scores of each criterion and their corresponding weights. RESULTS: A total of 5 attributes, including safety, efficacy, costs/cost-effectiveness, suitability, and accessibility, were determined, and 16 criteria were under the 5 attributes. The safety and efficacy were ranked as the top two important attributes with the weights of 38.8% and 35.9%, respectively, while the suitability received the lowest weight of 7.9%. The comprehensive score for edoxaban was the highest (72.3), followed by dabigatran (49.7), rivaroxaban (37.9), and apixaban (35.8). CONCLUSIONS: This study provided a scoring framework developed for comprehensive evaluation of DOACs in China. The ranking of DOACs could help to support the decision-making in clinical practice. The framework could provide a reference for comprehensive evaluation of other drugs.

The Importance of Clinical Pharmacists in Improving Blood Glucose and Lipid Levels in Patients with Diabetes and Myocardial Infarction.

Purpose: The aim of this study was to evaluate whether intervention by clinical pharmacists can improve blood glucose and lipid levels in diabetic patients with complex medical conditions. Methods: The retrospective database included 138 patients with diabetes who had presented with acute myocardial infarction (AMI) between January 2019 and October 2021. Blood glucose and lipid levels were measured within 12 weeks and 78 weeks of follow-up. Propensity score matching (PSM) was used to balance the confounding effects of patients' characteristics. Results: A total of 138 eligible patients were assigned to either the intervention group (n = 47) or the usual care group (n = 91). After the intervention, there were significant improvements in blood glucose (glycosylated hemoglobin-HbA1C % from 9.0 to 8.3; fasting blood glucose-FBG mmol/L from 11.3 to 7.1; postprandial blood glucose-PBG mmol/L from 17.0 to 12.1; p < 0.001) and lipid levels (total cholesterol-TC from 4.9 to 3.5, low-density lipoprotein cholesterol-LDL-C from 3.0 to 1.8, p < 0.001, mmol/L) in both follow-up periods. The blood glucose effects were most pronounced in the PBG control rate (76.9% vs 54.0%) before PSM, while HbA1C% and PBG control rate after PSM were significantly higher in the intervention group (HbA1C% rate: 65.6% vs 38.5%; PBG rate: 79.2% vs 45.8%; p < 0.05, intervention vs non-intervention). Subgroup analysis further confirmed the improvement of blood glucose and lipid mainly in patients with higher baseline FBG (≧10mmol/L) and moderate follow-up duration (4-12 weeks). Conclusion: The intervention of clinical pharmacists in multidisciplinary team can significantly improve blood glucose and lipid levels in complex type 2 diabetic patients, especially those with high baseline FBG and moderate follow-up durations.

Dysambiol, an Anti-inflammatory Secomeroterpenoid from a Dysidea sp. Marine Sponge.

An unusual secomeroterpenoid, dysambiol (1), was isolated from a Dysidea sp. marine sponge collected from the South China Sea. Dysambiol features an unprecedented secomeroterpene scaffold with a rare lactone bridge. The structure of 1 was determined by extensive spectroscopic analysis, Mosher's method, and electronic circular dichroism calculation. Dysambiol displayed potent anti-inflammatory activity in LPS-induced Raw 264.7 macrophages by regulating the NF-κB/MPAK signaling pathway.

Biosynthesis of trialkyl-substituted aromatic polyketide NFAT-133 involves unusual P450 monooxygenase-mediating aromatization and a putative metallo-beta-lactamase fold hydrolase.

The bacterial trialkyl-substituted aromatic polyketides are structurally featured with the unusual aromatic core in the middle of polyketide chain such as TM-123 (1), veramycin A (2), NFAT-133 (3) and benwamycin I (4), which were discovered from Streptomyces species and demonstrated with antidiabetic and immunosuppressant activities. Though the biosynthetic pathway of 1-3 was reported as a type I polyketide synthase (PKS), the PKS assembly line was interpreted inconsistently, and it remains a mystery how the compound 3 was generated. Herein, the PKS assembly logic of 1-4 was revised by site-mutagenetic analysis of the PKS dehydratase domains. Based on gene deletion and complementation, the putative P450 monooxygenase nftE1 and metallo-beta-lactamase (MBL) fold hydrolase nftF1 were verified as essential genes for the biosynthesis of 1-4. The absence of nftE1 led to abolishment of 1-4 and accumulation of new products (5-8). Structural elucidation reveals 5-8 as the non-aromatic analogs of 1, suggesting the NftE1-catalyzed aromatic core formation. Deletion of nftF1 resulted in disappearance of 3 and 4 with the compounds 1 and 2 unaffected. As a rare MBL-fold hydrolase from type I PKSs, NftF1 potentially generates the compound 3 through two strategies: catalyze premature chain-offloading as a trans-acting thioesterase or hydrolyze the lactone-bond of compound 1 as an esterase.