Integrated bioinformatic analysis reveals NOS2 as a novel ferroptosis-related biomarker for pre-eclampsia.

BACKGROUND: Pre-eclampsia (PE) is a common condition in pregnancy; however, methods for early diagnosis and effective treatment options are lacking. Ferroptosis is a newly identified iron-dependent cell death pathway. The aim of this study was to investigate the role of ferroptosis-related genes in PE, the underlying mechanism, and their potential diagnostic value using a bioinformatics approach. METHODS: We downloaded the GSE48424 and GSE98224 datasets from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between PE and healthy pregnancy samples were identified in the GSE48424 dataset and subjected to weighted gene co-expression network analysis; the most relevant modules were intersected with known ferroptosis-related genes to distinctly identify the role of ferroptosis in PE. We further searched transcription factors and microRNAs that are predicted to regulate these ferroptosis-related genes, and patients in the GSE48424 dataset were divided into two groups according to high or low expression of the key ferroptosis-related genes associated with PE. To obtain robust key ferroptosis-related genes in PE, we validated their expression levels in the external dataset GSE98224. Finally, the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay was utilized to access the expression of these genes in the PE and normal blood samples. RESULTS: Six ferroptosis-related genes involved in PE were obtained by overlapping 3661 genes most associated with PE, 565 DEGs between PE and normal samples, and 259 known ferroptosis-related genes. Among these genes, patients with PE displaying lower expression levels of NOS2 and higher expression levels of PTGS2 had a higher ferroptosis potential index. The expression pattern of NOS2 was consistent in the GSE48424 and GSE98224 datasets. RT-qPCR data confirmed that NOS2 expression was more significantly elevated in patients with PE than in those with a normal pregnancy. CONCLUSIONS: Our study explored the diagnostic value of ferroptosis-related genes in PE, and identified NOS2 as the key gene linking ferroptosis and PE, suggesting a new candidate biomarker for early PE diagnosis.

Loss of microRNA-147 function alleviates synovial inflammation through ZNF148 in rheumatoid and experimental arthritis.

MicroRNA-147 (miR-147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno-miR-147 antagomir was locally administrated into individual ankle compared with negative control or rno-miR-155-5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa-miR-147b-3p/hsa-miR-155-5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT-quantitative PCR, and protein expression was detected by using Western blotting. Anti-miR-147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa-miR-147b-3p/hsa-miR-155-5p function in TNF-α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa-miR-147b-3p/hsa-miR-155-5p function could downregulate the gene expression of TNF-α, IL-6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR-147's target, increased gene expression of TNF-α, IL-6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa-miR-147b-3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation-related pathways. Taken together, miR-147b-3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis.

Upregulated PKM2 in Macrophages Exacerbates Experimental Arthritis via STAT1 Signaling.

Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis. We hypothesize that Pkm2, as a key regulatory enzyme of glycolysis pathway, triggers the activation of macrophages (Mφ), which results in proinflammatory cytokine production during the arthritis progress. In this study, Pkm2 was found to be overexpressed in ED1-positive Mφ in spleens and synovial tissues from arthritic rats via immunofluorescence, Western blotting, and quantitative RT-PCR. To reveal the role of Pkm2, Dark Agouti rats were treated with either Pkm2 enzyme inhibitor shikonin or the RNA interference plasmids of Pkm2 and negative control plasmids, respectively, via i.p. injection. Pkm2 intervention could alleviate the severity of pristane-induced arthritis in aspects of the macroscopic arthritis score, perimeter changes of midpaw, and the synovitis and destruction of the bone and cartilage as well as reduce the ED1 and p-Stat1-positive cell population in rat synovial tissues. Silencing Pkm2 by RNA interference in classical activated rat and mouse Mφ resulted in less Tnf-α, Il-1ß production via Stat1 signaling. Collectively, Pkm2 is highly expressed in ED1-positive Mφ of spleens and synovial tissues from arthritic rats and promotes Mφ activation via Stat1 signaling. Pkm2 might be a promising selective metabolic target molecule for rheumatoid arthritis treatment.

Determination of risk factors for predicting the onset of symptoms in asymptomatic COVID-19 infected patients.

Background: The number of asymptomatic infected patients with coronavirus disease 2019 (COVID-2019) is rampaging around the world but limited information aimed on risk factors of asymptomatic infections. The purpose of this study is to investigate the risk factors of symptoms onset and clinical features in asymptomatic COVID-19 infected patients. Methods: A retrospective study was performed in 70 asymptomatic COVID-2019 infected patients confirmed by nucleic acid tests in Hunan province, China between 28 January 2020 and 18 February, 2020. The epidemiological, clinical features and laboratory data were reviewed and analyzed. Presence or absence at the onset of symptoms was taken as the outcome. A Cox regression model was performed to evaluate the potential predictors of the onset of symptoms. Results: The study included 36 males and 34 females with a mean age of 33.24±20.40 years (range, 0.5-84 years). There were 22 asymptomatic carriers developed symptoms during hospitalization isolated observation, and diagnosed as confirmed cases, while 48 cases remained asymptomatic throughout the course of disease. Of 70 asymptomatic patients, 14 (14/70, 20%) had underlying diseases, 3 (3/70, 4.3%) had drinking history, and 11 (11/70, 15.7%) had smoking history. 22 patients developed symptoms onset of fever (4/22, 18.2%), cough (13/22, 59.1%), chest discomfort (2/22, 9.1%), fatigue (1/22, 4.5%), pharyngalgia (1/22, 4.5%) during hospitalization; only one (1/22, 4.5%) patient developed signs of both cough and pharyngalgia. Abnormalities on chest CT were detected among 35 of the 69 patients (50.7%) after admission, except for one pregnant woman had not been examined. 4 (4/70, 5.7%) and 8 (8/70, 11.4%) cases showed leucopenia and lymphopenia. With the effective antiviral treatment, all the 70 asymptomatic infections had been discharged, none cases developed severe pneumonia, admission to intensive care unit, or died. The mean time from nucleic acid positive to negative was 13.2±6.84 days. Cox regression analysis showed that smoking history (P=0.028, hazard ratio=4.49, 95% CI 1.18-17.08) and existence of pulmonary disease (P=0.038, hazard ratio=7.09, 95% CI 1.12-44.90) were risk factors of the onset of symptoms in asymptomatic carries. Conclusion: The initially asymptomatic patients can develop mild symptoms and have a good prognosis. History of smoking and pulmonary disease was prone to illness onset in asymptomatic patients, and it is necessary to be highly vigilant to those patients.

Management of an Adult with Goodpasture's Syndrome Following Brain Trauma with Extracorporeal Membrane Oxygenation: A Case Report.

A 22-year-old man suffered from acute pulmonary hemorrhage and deteriorated renal function occurred within 3 days after traumatic brain injury. Mechanical ventilation cannot correct his severe hypoxemia, therefore, venoarterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated and finally resolved his hypoxemia. Concomitantly, continuous renal replacement therapy was performed to improve his kidney function. Although no anti-glomerular basement membrane (anti-GBM) antibody was detected in serum, Goodpasture's syndrome was considered. After treated with methylprednisolone pulse therapy and plasmapheresis, his renal function was significantly improved. ECMO was eventually discontinued after 60 hours of treatment and extubated on day 10. He was discharged home with normal pulmonary and renal functions.

Association of frailty and serum neurofilament light chain levels: the mediating role of estimated glomerular filtration rate.

Background: Both frailty and elevated serum neurofilament light chain (sNfL) levels are linked to cognitive impairment. However, evidence of their relationship is lacking, and whether it was mediated by renal function was unknown. This study aimed to investigate the association between frailty and sNfL levels in a representative U.S. population, and to explore the potential mediating role of estimated glomerular filtration rate (eGFR) in this relationship. Methods: Data from 1,782 participants aged 20-75 years in the 2013-2014 National Health and Nutrition Examination Survey (NHANES) were analyzed. Frailty was assessed using a 49-item frailty index, and participants were categorized as non-frail, pre-frail, or frail. sNfL levels were measured using acoustic emission technology. Multivariable linear regression models and restricted cubic spline analyses were employed to examine the associations between frailty, eGFR, and sNfL levels. Mediation analysis was conducted to evaluate the role of eGFR in the frailty-sNfL relationship. Results: The prevalence of pre-frailty and frailty was 45.39 and 11.60%, respectively. A significant positive association was observed between frailty score and sNfL levels (adjusted ß: 39.97, SE: 11.07, p = 0.003), with a linear relationship confirmed by restricted cubic spline analysis. Frail individuals had significantly higher sNfL levels compared to non-frail participants (adjusted ß: 11.86, SE: 5.42, p = 0.04). eGFR was negatively associated with sNfL levels (adjusted ß: -0.23, SE: 0.05, p < 0.001). Mediation analysis revealed that eGFR accounted for 12.52% of the total effect of frailty on sNfL levels (p < 0.0001). Conclusion: This study demonstrates a significant association between frailty and elevated sNfL levels in a representative U.S. population, with eGFR partially mediating this relationship. These findings suggest that sNfL may serve as a potential biomarker for frailty-related neuronal damage and highlight the importance of kidney function in this association. Further research is warranted to explore the clinical implications of these findings in frailty assessment and management strategies.

Oxygen-bridged Schottky junction in ZnO-Ni3ZnC0.7 promotes photocatalytic reduction of CO2 to CO: Steering charge flow and modulating electron density of active sites.

Developing carbon dioxide (CO2) photocatalysts from transition metal carbides (TMCs) with abundant active sites, modulable electron cloud density, as well as low cost and high stability is of great significance for artificial photosynthesis. Building an efficient electron transfer channel between the photo-excitation site and the reaction-active site to extract and steer photo-induced electron flow is necessary but challenging for the highly selective conversion of CO2. In this study, we achieved an oxygen-bridged Schottky junction between ZnO and Ni3ZnC0.7 (denoted as Znoxide-O-ZnTMC) through a ligand-vacancy strategy of MOF. The ZnO-Ni3ZnC0.7 heterostructure integrates the photo-exciter (ZnO), high-speed electron transport channel (Znoxide-O-ZnTMC), and reaction-active species (Ni3ZnC0.7), where Znoxide-O-ZnTMC facilitates the transfer of excited electrons in ZnO to Ni3ZnC0.7. The Zn atoms in Ni3ZnC0.7 serve as electron-rich active sites, regulating the CO2 adsorption energy, promoting the transformation of *COOH to CO, and inhibiting H2 production. The ZnO-Ni3ZnC0.7 shows a high CO yield of 2674.80 µmol g-1h-1 with a selectivity of 93.40 % and an apparent quantum yield of 18.30 % (λ = 420 nm) with triethanolamine as a sacrificial agent. The CO production rate remains at 96.40 % after 18 h. Notably, ZnO-Ni3ZnC0.7 exhibits a high CO yield of 873.60 µmol g-1h-1 with a selectivity of 90.20 % in seawater.

Combining experiments and bioinformatics to identify transforming growth factor-ß1 as a key regulator in angiotensin II-induced trophoblast senescence.

INTRODUCTION: Accelerated senescence of trophoblast may cause several diverse pregnancy outcomes; however, the cause of accelerated trophoblast senescence remains unclear. The renin-angiotensin system (RAS) is closely related to organ senescence. Therefore, in the present study, we hypothesized that angiotensin (Ang)II, one of the most important RAS family members, accelerates trophoblast senescence through the transforming growth factor ß-1 (TGF-ß1) pathway. METHODS: AngII and Ang1-7 were used to stimulate pregnant rats. AngII and its inhibitor olmesartan were used to stimulate trophoblast. Thereafter, senescence levels were measured. Furthermore, we used AngII to stimulate trophoblast and utilized RNA-sequencing (RNAseq) to analyze the expression of differentially expressed genes (DEGs). After identifying the overlapping genes by comparing the DEGs and senescence-related genes, we employed CytoHubba software to calculate the top five hub genes and selected TGF-ß1 as the target gene. We transfected the AngII-stimulated trophoblast with TGF-ß1 small interfering RNA (siRNA) and measured the senescence levels. RESULTS: Senescence markers were upregulated in the AngII group compared with that in the control group. Furthermore, following AngII stimulation and RNAseq measurement, we identified 607 DEGs and 13 overlapping genes. The top five hub genes were as follows: PLAU, PTGS2, PDGF-ß, TGF-ß1, and FOXO3. Upon knockdown of TGF-ß1 expression in AngII-stimulated trophoblast using TGF-ß1 siRNA, we observed a downregulation of p53 and p62 mRNA expression. DISCUSSION: AngII accelerates trophoblast senescence through the TGF-ß1 pathway.

Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine.

OBJECTIVE: The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products. METHODS: The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products. RESULTS: Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity. CONCLUSION: Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.

MetaboliteCOVID: A manually curated database of metabolite markers for COVID-19.

In the realm of unraveling COVID-19's intricacies, numerous metabolomic investigations have been conducted to discern the unique metabolic traits exhibited within infected patients. These endeavors have yielded a substantial reservoir of potential data pertaining to metabolic biomarkers linked to the virus. Despite these strides, a comprehensive and meticulously structured database housing these crucial biomarkers remains absent. In this study, we developed MetaboliteCOVID, a manually curated database of COVID-19-related metabolite markers. The database currently comprises 665 manually selected entries of significantly altered metabolites associated with early diagnosis, disease severity, prognosis, and drug response in COVID-19, encompassing 337 metabolites. Additionally, the database offers a user-friendly interface, containing abundant information for querying, browsing, and analyzing COVID-19-related abnormal metabolites in different body fluids. In summary, we believe that this database will effectively facilitate research on the functions and mechanisms of COVID-19-related metabolic biomarkers, thereby advancing both basic and clinical research on COVID-19. MetaboliteCOVID is free available at: https://cellknowledge.com.cn/MetaboliteCOVID.

Investigating the molecular mechanism of traditional Chinese medicine for the treatment of placental syndromes by influencing inflammatory cytokines using the Mendelian randomization and molecular docking technology.

Introduction: Placental syndromes, which include pregnancy loss, preterm birth, gestational diabetes mellitus (GDM), and hypertensive disorders in pregnancy (HDP), have a strong association with disorder inflammatory reactions. Nonetheless, the exact causal relationship has not been established. This study aims to investigate the causal relationship between placental syndromes and inflammatory cytokines utilizing Mendelian randomization (MR). Additionally, we examined the interaction between small molecular compounds derived from traditional Chinese medicine and inflammatory cytokines using molecular docking method. Methods: After obtaining the data of inflammatory cytokines and placental syndromes, as well as establishing single nucleotide polymorphisms (SNPs), we employed the inverse variance weighted (IVW) method to assess the causal relationship. We also accessed the heterogeneity and the horizontal pleiotropy of these data. The "ClusterProfiler" R package was utilized for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term analyses. The protein-protein interaction (PPI) network was constructed using STRING database. AutoDock Vina software was used for molecular docking, and Discovery Studio 2019 was used for visualization purposes. Results: We found that the growth regulated oncogene A (GROA) and interleukin-9 (IL-9) were associated with the development of pregnancy hypertension, whereas interleukin-10 (IL-10) and hepatocyte growth factor (HGF) were linked to the occurrence of preeclampsia. Moreover, there were correlations observed between interleukin-18 (IL-18), IL-10, macrophage colony-stimulating factor (MCSF), and platelet-derived growth factor BB (PDGFbb) in cases of chronic hypertension combined with pregnancy (CHP). Additionally, macrophage migration inhibitory factor (MIF) exhibited a connection with GDM, and TNF related apoptosis inducing ligand (TRAIL) demonstrated a causal relationship with preterm birth. It is plausible to suggest that interleukin-1ß (IL-1ß) might contribute to the promotion of pregnancy loss. All of the binding free energy values of small molecular compounds with inflammatory cytokines were below -5.0 kcal/mol. Furthermore, all of the RMSD values were less than 2. Conclusions: GROA, IL-1ß, IL-9, IL-10, IL-18, MIF, MCSF, HGF, PDGFbb and TRAIL were found to be causally associated with placental syndromes. Molecular docking analysis revealed that small molecular compounds, such as puerarin, magnolol, atractylenolide I, paeoniflorin, tumulosic acid and wogonin, are closely bound to these inflammatory cytokines.

Attenuated Structural Transformation of Indaconitine during Sand Frying Process and Anti-Arrhythmic Effects of Its Transformed Products.

The transformation pathways of diterpenoid alkaloids have been clarified clearly in the boiling and steaming process, but remain to be determined in the sand frying process. The aims of the study were to investigate the transformation pathways of indaconitine in the sand frying process, as well as examine the cardiotoxicity and anti-arrhythmic activity of indaconitine and its transformed products. The transformed product was separated by column chromatography, and the structure was identified by 1H NMR, 13C NMR, and HR-ESI-MS. The cardiotoxicity of indaconitine and its transformed products was clarified by observing the electrocardiogram (ECG) changes at the same dose. Furthermore, the anti-arrhythmic activity of the transformed products was investigated using an aconitine-induced rat arrhythmia model. Consequently, Δ15(16)-16-demethoxyindaconitine, a new diterpenoid alkaloid, was isolated from processed indaconitine. Intravenous injection of 0.06 mg/kg indaconitine induced arrhythmias in SD rats, while Δ15(16)-16-demethoxyindaconitine did not exhibit arrhythmias at the same dose. In the anti-arrhythmic assay, mithaconitine, obtained in the previous research, together with Δ15(16)-16-demethoxyindaconitine, could dose-dependently delay the onset time of ventricular premature beat (VPB) and reduce the incidence of ventricular tachycardia (VT), combined with the increasing arrhythmia inhibition rate, exhibiting strong anti-arrhythmic activities. These results indicated that two or more pathways exist in the sand frying process, and the transformed products exhibited lower cardiotoxicity and strong anti-arrhythmic activities, which had the possibility of being developed into anti-arrhythmic drugs.

Investigating the Intercellular Communication Network of Immune Cell in Acute Respiratory Distress Syndrome with Sepsis.

Acute respiratory distress syndrome (ARDS) is recognized as a serious public health issue that results in respiratory failure and high mortality rates. The syndrome is characterized by immune cell aggregation, communication, activation, and alveolar epithelial damage. To elucidate the complex dynamic process of the immune system's response in ARDS, we construct the intercellular communication network of immune cells in ARDS based on a single-cell RNA sequencing dataset (including three sepsis-induced ARDS patients and four sepsis-only patients). The results show that macrophages relayed most of the intercellular signals (ligand-receptor pairs) in both groups. Many genes related to immune response (IFI44L, ISG, and HLA-DQB1) and biological functions (response to virus, negative regulation of viral life cycle, and response to interferon-beta) were detected via differentially expressed gene analysis of macrophages between the two groups. Deep analysis of the intercellular signals related to the macrophage found that sepsis-induced ARDS harbored distinctive intercellular signals related to chemokine-chemokine receptors (CCL3/4/5-CCR1), which mainly are involved in the disturbance of the STAT family transcription factors (TFs), such as STAT2 and STAT3. These signals and downstream TFs might play key roles in macrophage M1/M2 polarization in the process of sepsis-induced ARDS. This study provides a comprehensive view of the intercellular communication landscape between sepsis and sepsis-induced ARDS and identifies key intercellular communications and TFs involved in sepsis-induced ARDS. We believe that our study provides valuable clues for understanding the immune response mechanisms of ARDS.

Comprehensive Analysis of the Molecular Characteristics and Prognosis value of AT II-associated Genes in Non-small Cell Lung Cancer.

Alveolar type II (AT II) is a key structure of the distal lung epithelium and essential to maintain normal lung homeostasis. Dedifferentiation of AT II cells is significantly correlated with lung tumor progression. However, the potential molecular mechanism and clinical significance of AT II-associated genes for lung cancer has not yet been fully elucidated. In this study, we comprehensively analyzed the gene expression, prognosis value, genetic alteration, and immune cell infiltration of eight AT II-associated genes (AQP4, SFTPB, SFTPC, SFTPD, CLDN18, FOXA2, NKX2-1, and PGC) in Nonsmall Cell Lung Cancer (NSCLC). The results have shown that the expression of eight genes were remarkably reduced in cancer tissues and observably relating to clinical cancer stages. Survival analysis of the eight genes revealed that low-expression of CLDN18, FOXA2, NKX2-1, PGC, SFTPB, SFTPC, and SFTPD were significantly related to a reduced progression-free survival (FP), and low CLDN18, FOXA2, and SFTPD mRNA expression led to a short postprogression survival (PPS). Meanwhile, the alteration of 8 AT II-associated genes covered 273 out of 1053 NSCLC samples (26%). Additionally, the expression level of eight genes were significantly correlated with the infiltration of diverse immune cells, including six types of CD4+T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. In summary, this study provided clues of the values of eight AT II-associated genes as clinical biomarkers and therapeutic targets in NSCLC and might provide some new inspirations to assist the design of new immunotherapies.

Light-Decomposable Polymeric Micelles with Hypoxia-Enhanced Phototherapeutic Efficacy for Combating Metastatic Breast Cancer.

Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and hypoxia-activatable bioreductive therapy has achieved remarkably improved antitumor efficacy compared to single PDT modality. However, controllable release and activation of prodrug and safety profiles of nanocarrier are still challenging in the combined PDT/hypoxia-triggered bioreductive therapy. Herein, we developed a near infrared (NIR) light-decomposable nanomicelle, consisting of PEGylated cypate (pCy) and mPEG-polylactic acid (mPEG2k-PLA2k) for controllable delivery of hypoxia-activated bioreductive prodrug (tirapazamine, TPZ) (designated TPZ@pCy), for combating metastatic breast cancer via hypoxia-enhanced phototherapies. TPZ@pCy was prepared by facile nanoprecipitation method, with good colloidal stability, excellent photodynamic and photothermal potency, favorable light-decomposability and subsequent release and activation of TPZ under irradiation. In vitro experiments demonstrated that TPZ@pCy could be quickly internalized by breast cancer cells, leading to remarkable synergistic tumor cell-killing potential. Additionally, metastatic breast tumor-xenografted mice with systematic administration of TPZ@pCy showed notable tumor accumulation, promoting tumor ablation and lung metastasis inhibition with negligible toxicity upon NIR light illumination. Collectively, our study demonstrates that this versatile light-decomposable polymeric micelle with simultaneous delivery of photosensitizer and bioreductive agent could inhibit tumor growth as well as lung metastasis, representing a promising strategy for potent hypoxia-enhanced phototherapies for combating metastatic breast cancer.

Network Analysis Reveals the Combination of Controlled-Release and Regular Urea Enhances Microbial Interactions and Improves Maize Yields.

Increased complexity of microbial networks can contribute to increased biodiversity and multifunctionality and thus crop productivity. However, it is not clear which combination ratio of regular and controlled-release urea will increase the soil microbial community complexity and improve maize yield in the North China Plain. To address this knowledge gap, a 2-year field experiment was conducted to explore the effects of the combination of regular (U) and controlled release (S) urea ratios [no fertilizer control (CT), regular urea alone (U), controlled-release urea alone (S), controlled-release urea mixed with regular urea 3:7 (SU3), controlled-release urea mixed with regular urea 5:5 (SU5), and controlled-release urea mixed with regular urea 7:3 (SU7)] on XianYu 688 yield and its rhizosphere and bulk soil microbial community composition and network complexity at different fertility stages. The combination of controlled-release and regular urea increased the N agronomic efficiency, N partial factors productivity, maize yield, and grain number per spike, with the maximum maize yield (9,186 kg ha-1) being achieved when the ratio of controlled-release urea to regular urea was 3:7 (SU3, p < 0.05). Maize yield increased by 13% in the SU3 treatment compared to the CT treatment. Rhizosphere soil microbial diversity remained stable at the silking stage of maize while increased at the physiological maturity stage of maize, with the increasing controlled-release to regular N fertilizer ratios (from 3:7 to 7:3, p < 0.05). This result suggests that a combination of regular and controlled-release N fertilizer can still substantially increase soil microbial diversity in the later stages of maize growth. The combination of controlled-release and regular urea is more effective in improving microbial network total links and average degree, and N agronomic efficiency (R 2 = 0.79, p < 0.01), N partial factor productivity (R 2 = 0.79, p < 0.01), spikes per unit area (R 2 = 0.54, p < 0.05), and maize yield (R 2 = 0.42, p < 0.05) increased with the microbial network complexity. This result indicates that the higher microbial network complexity is strongly associated with the higher N agronomic efficiency and N partial factors productivity and maize yield. In conclusion, the ratio of controlled-release to regular urea at SU3 not only increases the yield of maize and N agronomic efficiency but also enhances microbial diversity and network complexity in the North China Plain.

Prediction of Differentially Expressed Genes and a Diagnostic Signature of Preeclampsia via Integrated Bioinformatics Analysis.

Background: Preeclampsia (PE), which has a high incidence rate worldwide, is a potentially dangerous syndrome to pregnant women and newborns. However, the exact mechanism of its pathogenesis is still unclear. In this study, we used bioinformatics analysis to identify hub genes, establish a logistic model, and study immune cell infiltration to clarify the physiopathogenesis of PE. Methods: We downloaded the GSE75010 and GSE10588 datasets from the GEO database and performed weighted gene coexpression network analysis (WGCNA) as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The online search tool for the retrieval of interacting genes and Cytoscape software were used to identify hub genes, which were then used to establish a logistic model. We also analyzed immune cell infiltration. Finally, we verified the expression of the genes included in the predictive model via RT-PCR. Results: A total of 100 and 212 differently expressed genes were identified in the GSE75010 and GSE10588 datasets, respectively, and after overlapping with WGCNA results, 17 genes were identified. KEGG and GO analyses further indicated the involvement of these genes in bioprocesses, such as gonadotropin secretion, immune cell infiltration, and the SMAD and MAPK pathways. Additionally, protein-protein interaction network analysis identified 10 hub genes, six (FLT1, FLNB, FSTL3, INHA, TREM1, and SLCO4A1) of which were used to establish a logistic model for PE. RT-PCR analysis also confirmed that, except FSTL3, these genes were upregulated in PE. Our results also indicated that macrophages played the most important role in immune cell infiltration in PE. Conclusion: This study identified 10 hub genes in PE and used 6 of them to establish a logistic model and also analyzed immune cell infiltration. These findings may enhance the understanding of PE and enable the identification of potential therapeutic targets for PE.

[Anti-HIV-1 activity and structure-activity relationship of pyranocoumarin analogs].

The purpose of this study is to find out anti-HIV-1 reverse transcriptase (RT)/protease (PR) activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship. Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system. It also shows inhibition effects to HIV-1 replication in cell culture. Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design, analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system. Seven compounds were designed and tested. Several compounds showed anti-HIV-1 activity in varying degrees, especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 micromol x L(-1) of IC50 against HIV-1 PR/RT and 0.036 micromol x L(-1) against HIV-1 replication in PBMC cultures. V0201 with a novel structure may be a new leading compound. These new compounds are valuable for development of new anti-HIV drugs in the future.

[Synthesis and antiviral activities of geldanamycin analog TC-GM in vitro].

In order to find antiviral compounds with novel structures, geldanamycin and lamivudine with different antiviral mechanisms were conjunctively synthesized to acquire a new compound TC-GM, and the antiviral activity of TC-GM was measured. The antiviral activity against HIV-1 was examined by p24 antigen ELISA kit. The activity against HBV was examined by dotblot. The activity against HSV and CoxB virus was examined by CPE. TC-GM exhibited broad-spectrum antiviral activities similarly like geldanamycin. TC-GM inhibited the replication of different viruses, including HIV-1, HBV, HSV 1 and 2, CoxB6. TC-GM showed more potent inhibitory activity against HIV-1 and HBV than other detected virus.

Attenuation and Structural Transformation of Crassicauline A During Sand Frying Process and Antiarrhythmic Effects of its Transformed Products.

To ensure safety and efficacy, most Aconitum herbs should be processed before clinical application. The processing methods include boiling, steaming, and sand frying. Among these methods, the transformation pathways of diterpenoid alkaloids in the process of sand frying are more complicated. Therefore, crassicauline A, a natural product with two ester bonds, was chosen as the experimental object. Consequently, a known alkaloid, together with three new alkaloids, was derived from crassicauline A. Meanwhile, the cardiotoxicity of converted products was reduced compared with their parent compound. Interestingly, some diterpenoid alkaloids have similar structures but opposite effects, such as arrhythmia and antiarrhythmic. Considering the converted products are structural analogues of crassicauline A, herein, the antiarrhythmic activity of the transformed products was further investigated. In a rat aconitine-induced arrhythmia assay, the three transformed products, which could dose-dependently delay the ventricular premature beat (VPB) incubation period, reduce the incidence of ventricular tachycardia (VT), combined with the increasing arrhythmia inhibition rate, exhibited prominent antiarrhythmic activities. Our experiments speculated that there might be at least two transformation pathways of crassicauline A during sand frying. The structure-activity data established in this paper constructs the critical pharmacophore of diterpenoid alkaloids as antiarrhythmic agents, which could be helpful in searching for the potential drugs that are equal or more active and with lower toxicity, than currently clinical used antiarrhythmic drugs.