Association between 35 blood and urine biomarkers and oral leukoplakia: a two-sample Mendelian randomization study.

Background: Several existing studies have shown a correlation between some of the blood and urine biomarkers and oral leukoplakia (OLK). However, the causality of this relationship remains uncertain. Thus, this study aimed to examine the causal association between 35 blood and urine biomarkers and OLK. Methods: Single nucleotide polymorphisms (SNPs) associated with 35 blood and urine biomarkers were selected as instrumental variables (IVs) using a two-sample Mendelian randomization(MR) study to assess the causal relationship between the biomarkers and the risk of oral leukoplakia. We used the inverse variance weighted (IVW) method as the main analysis. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Results: Based on the selection criteria of the Inverse Variance Weighted (IVW) method, the analysis found that 5 blood and urine biomarkers were significantly associated with the development of leukoplakia, of which the results of IVW showed that abnormalities of Apolipoprotein B (Apo B), Cholesterol, Low-density Lipoprotein (LDL), Triglycerides (TG) promoted the development of oral leukoplakia, and Non Albumin Protein (NAP) had a protective effect on the development of oral leukoplakia. We then performed a Bonferroni correction for these results, and after correction Apo B was still causally associated with the development of oral leukoplakia (IVW P<0.0007), whereas the other four biomarkers could only provide some evidence of predisposition. Conclusion: Our two-sample Mendelian randomization study supports the existence of a causal relationship between these five blood and urine biomarkers and the occurrence of oral leukoplakia, and provides evidence for a number of risk and protective factors for the development of oral leukoplakia; however, the definitive mechanisms for the occurrence and development of oral leukoplakia still remain to be elucidated, and further studies on these relevant mechanisms are still needed.

Endoplasmic reticulum-targeting fluorescence turn-on probe for nitric oxide detection in living cells and serum samples.

Nitric oxide (NO) is an important gas signaling molecule, and endoplasmic reticulum (ER) stress induced by NO may be related to the pathogenesis of many diseases. Therefore, the development of ER-targeted fluorescent probes for NO is of great significance to investigate the relationship between ER stress and NO concentration changes in related diseases. Herein, an ER-targeted fluorescent probe (ER-Np) for sensing NO was constructed. ER-Np was served as an excellent tool for detection NO with high selectivity, sensitivity and ER-targetable ability. Moreover, fluorescence imaging experiments indicated that ER-Np is capable of imaging NO in living cells. Impressively, visualization of endogenous NO production during dithiothreitol (DTT)-induced ER stress in living cells was successfully observed. In addition, we found that serum NO levels were upregulated in epilepsy children, which opens up a new avenue for further understanding the relationship between the diagnostic of epilepsy.

Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure.

Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.

OsCOPT7 is involved in copper accumulation and transport through xylem.

Copper (Cu) is an essential micronutrient for humans, but excessive Cu in rice grains causes health risks. Currently, the mechanisms underlying Cu accumulation in rice are unclear. Here, we identified a novel member of the high-affinity copper transporter (Ctr)-like (COPT) protein family in rice, OsCOPT7, which controls Cu accumulation in rice grains. Mutation in the coding sequence of OsCOPT7 (mutant lc1) leads to inhibition of Cu transport through the xylem, contributing to lower Cu concentrations in the grain of lc1. Knockout or modulation of the expression of OsCOPT7 significantly impacts Cu transportation in the xylem and its accumulation in rice grains. OsCOPT7 localizes at the multi-pass membrane in the cell and the gene is expressed in the exodermis and stele cells, facilitating Cu loading into the xylem. OsCOPT7 expression is upregulated under Cu deficiency and in various organs, implying its contribution to Cu distribution within the rice plant. The variable expression pattern of OsCOPT7 suggests that OsCOPT7 expression responds to Cu stress in rice. Moreover, assays reveal that OsCOPT7 expression level is suppressed by the SQUAMOSA promoter-binding protein-like 9 (OsSPL9) and that OsCOPT7 interacts with Antioxidant Protein1 (OsATX1). This study elucidates the involvement of OsCOPT7 in Cu loading into the xylem, its subsequent distribution within the rice plant, and the potential of this protein in reducing the risk of high Cu concentrations in rice grain grown on Cu-contaminated soil.

Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice.

Objective: Microcystin-leucine-arginine (MC-LR) exposure induces lipid metabolism disorders in the liver. Secreted frizzled-related protein 5 (SFRP5) is a natural antagonist of winglesstype MMTV integration site family, member 5A (Wnt5a) and an anti-inflammatory adipocytokine. In this study, we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5, which has anti-inflammatory effects, can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase (JNK) pathway. Methods: We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders. Subsequently, mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR, and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed. Results: MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner. SFRP5 overexpression in AML12 cells suppressed MC-LR-induced inflammation. Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK. Conclusion: MC-LR can induce lipid metabolism disorders in mice, and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Mycobacterium marinum cutanous infection misdiagnosed as sporotrichosis in a patient with systemic lupus erythematosus: A case report.

Mycobacterium marinum(M. marinum ), a slow-growing bacterium in freshwater and seawater, can cause cutanous and extracutaneous infections. A fisher-woman with systemic lupus erythematosus (SLE) presented with chronic polymorphic rashes in a lymphangitic pattern was initially misdiagnosed as sporotrichosis. The final diagnosis of M. marinum and Candida dubliniensis co-infection was confirmed based on the skin histopathology, pustule culture, MetaCAP sequencing and effective antibiotic combination treatments.

Eight new dammarane-type triterpenoid saponins from Gynostemma pentaphyllum.

Phytochemical investigation of Gynostemma pentaphyllum led to the purification of five novel dammarane-type triterpene isolates, gypenosides B1 - B5 (1-5). Their structures were determined through comprehensive 1D and 2D NMR spectroscopic analyses and HRESIMS data. Of note, 1-3 are inseparable mixtures of epimers due to their unstable nature, and a total of eight dammarane-type triterpene saponins were identified. Additionally, the protective activities of these new compounds against PC12 cell injury induced by hypoxia were evaluated.

Force-enhanced sensitive and specific detection of DNA-intercalative agents directly from microorganisms at single-molecule level.

Microorganisms can produce a vast array of bioactive secondary metabolites, including DNA-intercalating agents like actinomycin D, doxorubicin, which hold great potential for cancer chemotherapy. However, discovering novel DNA-intercalating compounds remains challenging due to the limited sensitivity and specificity of conventional activity assays, which require large-scale fermentation and purification. Here, we introduced the single-molecule stretching assay (SMSA) directly to microbial cultures or extracts for discovering DNA-intercalating agents, even in trace amounts of microbial cultures (5 µl). We showed that the unique changes of dsDNA in contour length and overstretching transition enable the specific detection of intercalators from complex samples without the need for extensive purification. Applying force to dsDNA also enhanced the sensitivity by increasing both the binding affinity Ka and the quantity of ligands intercalation, thus allowing the detection of weak intercalators, which are often overlooked using traditional methods. We demonstrated the effectiveness of SMSA, identified two DNA intercalator-producing strains: Streptomyces tanashiensis and Talaromyces funiculosus, and isolated three DNA intercalators: medermycin, kalafungin and ligustrone B. Interestingly, both medermycin and kalafungin, classified as weak DNA intercalators (Ka ∼103 M-1), exhibited potent anti-cancer activity against HCT-116 cancer cells, with IC50 values of 52 ± 6 and 70 ± 7 nM, respectively.

The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present).

INTRODUCTION: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates. AREA COVERED: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present. EXPERT OPINION: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Clinical characteristics and prognostic factors of non-malignant pleural effusions in hospitalised patients: a retrospective cohort study.

OBJECTIVE: Non-malignant pleural effusions (NMPE) are common in hospitalised patients. Data on NMPE inpatients are scarce and the factors influencing the prognosis are unknown. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: We conducted a retrospective cohort of inpatients (n=86 645) admitted to the Chinese PLA General Hospital from 2018 to 2021, based on electronic medical records. The observations of 4934 subjects with effusions confirmed by chest radiological tests (CT or X-ray) without a diagnosis of malignancy were followed during admission. Logistic regression was used to analyse organ damage and other factors associated with in-hospital death. Patients were clustered according to their laboratory indicators, and the association between the clustering results and outcomes was studied. OUTCOME: The outcome of this study was in-hospital mortality. RESULTS: Among 4934 patients, heart failure + pneumonia + renal dysfunction was the most common (15.12%) among 100 different diagnostic groups. 318 (6.4%) patients died during hospitalisation. Lung (OR 3.70, 95% CI 2.42 to 5.89), kidney (OR 2.88, 95% CI 2.14 to 3.90) and heart (1.80, 95% CI 1.29 to 2.55) damage were associated with in-hospital mortality. Hierarchical clustering of laboratory indicators (estimated glomerular filtration rate, white blood cell count, platelet count, haemoglobin, N-terminal pro-B-type natriuretic peptide, serum albumin) demonstrated the ability to discriminate patients at high risk of in-hospital death. CONCLUSION: Comorbidities and multiorgan failure are the prominent characteristics of NMPE patients, which increase the risk of in-hospital mortality, and comprehensive intervention for specific comorbidity patterns is suggested.

Raspberry Ketone Attenuates Hepatic Fibrogenesis and Inflammation via Regulating the Crosstalk of FXR and PGC-1α Signaling.

Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-ß and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial-mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.

[Experimental study on treatment of retinitis pigmentosa by inducing Müller cell reprogramming with Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma].

This study aims to explore the effect of Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma(LFSMR), a drug pair possesses the function of nourishing Yin, promoting blood circulation, and brightening the eyes, in treating retinitis pigmentosa(RP)by inhibiting the gliosis of Müller cells(MCs) and inducing their reprogramming and differentiation into various types of retinal nerve cells. Twelve C57 mice were used as the normal control group, and 48 transgenic RP(rd10) mice were randomly divided into the model group, positive control group, and low and high dose LFSMR groups, with 12 mice in each group. HE staining was used to detect pathological changes in the retina, and an electroretinogram was used to detect retinal function. Retinal optical coherence tomography was used to detect retinal thickness and perform fundus photography, and laser speckle perfusion imaging was used to detect local retinal blood flow. Digital PCR was used to detect gene expression related to retinal nerve cells, and immunofluorescence was used to detect protein expression related to retinal nerve cells. LFSMR could significantly improve the pathological changes, increase the amplitude of a and b waves, increase the retinal thickness, restore retinal damage, and increase retinal blood flow in mice with RP lesions. LFSMR could also significantly inhibit the m RNA expression of the glial fibrillary acidic protein( GFAP) during the pathogenesis of RP and upregulate m RNA expression of sex determining region Y box protein 2(SOX2), paired box protein 6(Pax6),rhodopsin, protein kinase C-α(PKCα), syntaxin, and thymic cell antigen 1. 1(Thy1. 1). LFSMR could significantly inhibit GFAP protein expression and enhance protein expression of SOX2, Pax6, rhodopsin, PKCα, syntaxin, and Thy1. 1. It could also reverse the pathological changes in the retina of rd10 mice, improve retinal function and fundus performance, increase retinal thickness, enhance local retinal blood flow, and exert therapeutic effects on RP. The mechanism of action of LFSMR may be related to inhibiting the gliosis of MCs and promoting their reprogramming and differentiation into various types of retinal nerve cells.

Light and Guest Responsive Behavior in a Porous Coordination Network Enabled by Reversible [2+2] Photocycloaddition.

Stimuli-responsive physisorbents that undergo reversible structural transformations induced by external stimuli (e.g. light, guests, or heat) offer the promise of utility in gas storage and separation. Whereas reports on guest or light-responsive sorbents have increased in recent years, we are unaware of reports on sorbents that exhibit both light and guest-induced structural transformations. Herein, we report that the square lattice, sql, topology coordination network Zn(fba)(bis) ⋅ 2DMF (sql-5,6-Zn-α, 5=trans-4,4'-bis(1-imidazolyl)stilbene=bis, 6=2,2-bis(4-carboxyphenyl)hexafluoropropane=H2fba) underwent single-crystal-to-single-crystal transformation (SCSC) upon activation, affording nonporous sql-5,6-Zn-ß. Parallel alignment at 3.23 Šof olefinic moieties on adjacent bis ligands in sql-5,6-Zn-α enabled SCSC [2+2] photocycloaddition upon exposure to UV light (365 nm) or sunlight. sql-5,6-Zn-α thereby transformed to mot-5,6-Zn-α, which was subsequently activated to the narrow pore phase mot-5,6-Zn-ß. sql-5,6-Zn-ß and mot-5,6-Zn-ß both exhibited S-shaped adsorption isotherms characteristic of guest-induced structural changes when exposed to CO2 at 195 K (type-F-IV and type F-I, respectively). Cycling experiments conducted upon sql-5,6-Zn-ß reduced particle size after cycle 1 and induced transformation into a rare example of a shape memory coordination network, sql-5,6-Zn-γ. Insight into this smorgasbord of SCSC phase changes was gained from in situ PXRD, single crystal XRD and 1H NMR spectroscopy experiments.

Diallyl disulfide, the bioactive component of Allium species, ameliorates pulmonary fibrosis by mediating the crosstalk of farnesoid X receptor and yes-associated protein 1 signaling pathway.

Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.

Cross-Linking CdSO4-Type Nets with Hexafluorosilicate Anions to Form an Ultramicroporous Material for Efficient C2H2/CO2 and C2H2/C2H4 Separation.

A 44.610.8 topology hybrid ultramicroporous material (HUM), {[Cu1.5F(SiF6)(L)2.5]·G}n, (L = 4,4'-bisimidazolylbiphenyl, G = guest molecules), 1, formed by cross-linking interpenetrated 3D four-connected CdSO4-type nets with hexafluorosilicate anions is synthesized and evaluated in the context of gas sorption and separation herein. 1 is the first HUM functionalized with two different types of fluorinated sites (SiF6 2- and F- anions) lining along the pore surface. The optimal pore size (≈5 Å) combining mixed and high-density electronegative fluorinated sites enable 1 to preferentially adsorb C2H2 over CO2 and C2H4 by hydrogen bonding interactions with a high C2H2 isosteric heat of adsorption (Qst) of ≈42.3 kJ mol-1 at zero loading. The pronounced discriminatory sorption behaviors lead to excellent separation performance for C2H2/CO2 and C2H2/C2H4 that surpasses many well-known sorbents. Dynamic breakthrough experiments are conducted to confirm the practical separation capability of 1, which reveal an impressive separation factor of 6.1 for equimolar C2H2/CO2 mixture. Furthermore, molecular simulation and density functional theory (DFT) calculations validate the strong binding of C2H2 stems from the chelating fix of C2H2 between SiF6 2- anion and coordinated F- anion.

Qiangxinyin formula protects against isoproterenol-induced cardiac hypertrophy.

Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization.

Expression of endogenous UDP-glucosyltransferase in endophyte Phomopsis liquidambaris reduces deoxynivalenol contamination in wheat.

Fusarium head blight is a devastating disease that causes severe yield loses and mycotoxin contamination in wheat grain. Additionally, balancing the trade-off between wheat production and disease resistance has proved challenging. This study aimed to expand the genetic tools of the endophyte Phomopsis liquidambaris against Fusarium graminearum. Specifically, we engineered a UDP-glucosyltransferase-expressing P. liquidambaris strain (PL-UGT) using ADE1 as a selection marker and obtained a deletion mutant using an inducible promoter that drives Cas9 expression. Our PL-UGT strain converted deoxynivalenol (DON) into DON-3-G in vitro at a rate of 71.4 % after 36 h. DON inactivation can be used to confer tolerance in planta. Wheat seedlings inoculated with endophytic strain PL-UGT showed improved growth compared with those inoculated with wildtype P. liquidambaris. Strain PL-UGT inhibited the growth of Fusarium graminearum and reduced infection rate to 15.7 %. Consistent with this finding, DON levels in wheat grains decreased from 14.25 to 0.56 µg/g when the flowers were pre-inoculated with PL-UGT and then infected with F. graminearum. The expression of UGT in P. liquidambaris was nontoxic and did not inhibit plant growth. Endophytes do not enter the seeds nor induce plant disease, thereby representing a novel approach to fungal disease control.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.