RVFScan predicts virulence factor genes and hypervirulence of the clinical metagenome.

Bacterial infections often involve virulence factors that play a crucial role in the pathogenicity of bacteria. Accurate detection of virulence factor genes (VFGs) is essential for precise treatment and prognostic management of hypervirulent bacterial infections. However, there is a lack of rapid and accurate methods for VFG identification from the metagenomic data of clinical samples. Here, we developed a Reads-based Virulence Factors Scanner (RVFScan), an innovative user-friendly online tool that integrates a comprehensive VFG database with similarity matrix-based criteria for VFG prediction and annotation using metagenomic data without the need for assembly. RVFScan demonstrated superior performance compared to previous assembly-based and read-based VFG predictors, achieving a sensitivity of 97%, specificity of 98% and accuracy of 98%. We also conducted a large-scale analysis of 2425 clinical metagenomic datasets to investigate the utility of RVFScan, the species-specific VFG profiles and associations between VFGs and virulence phenotypes for 24 important pathogens were analyzed. By combining genomic comparisons and network analysis, we identified 53 VFGs with significantly higher abundances in hypervirulent Klebsiella pneumoniae (hvKp) than in classical K. pneumoniae. Furthermore, a cohort of 1256 samples suspected of K. pneumoniae infection demonstrated that RVFScan could identify hvKp with a sensitivity of 90%, specificity of 100% and accuracy of 98.73%, with 90% of hvKp samples consistent with clinical diagnosis (Cohen's kappa, 0.94). RVFScan has the potential to detect VFGs in low-biomass and high-complexity clinical samples using metagenomic reads without assembly. This capability facilitates the rapid identification and targeted treatment of hvKp infections and holds promise for application to other hypervirulent pathogens.

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

Intratumoral microbial heterogeneity affected tumor immune microenvironment and determined clinical outcome of HBV-related HCC.

BACKGROUND AND AIMS: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. APPROACH AND RESULTS: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve.IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. CONCLUSIONS: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.

Efficacy and safety of Qingda granule versus valsartan capsule in Chinese grade 1 hypertensive patients with low-moderate risk: A randomized, double-blind, double dummy, non-inferiority, multi-center trial.

BACKGROUND: The efficacy and safety of Qingda granule (QDG) in managing blood pressure (BP) among grade 1 hypertensive patients with low-moderate risk remain uncertain. METHODS: In the randomized, double-blind, double dummy, non-inferiority and multicenter trial, 552 patients with grade 1 hypertension at low-moderate risk were assigned at a ratio of 1:1 to receive either QDG or valsartan for 4 weeks, followed up by a subsequent 4 weeks. RESULTS: Post-treatment, clinic systolic/diastolic BPs (SBP/DBP) were reduced by a mean change of 9.18/4.04 mm Hg in the QDG group and 9.85/5.05 mm Hg in the valsartan group (SBP P = 0.47, DBP P = 0.16). Similarly, 24-hour, daytime and nighttime BPs were proportional in both groups (P > 0.05) after 4 weeks treatment. After discontinuing medications for 4 weeks, the mean reduction of clinic SBP/DBP were 0.29/0.57 mm Hg in the QDG group compared to -1.59/-0.48 mm Hg in the valsartan group (SBP P = 0.04, DBP P = 0.04). Simultaneously, the 24-hour SBP/DBP were reduced by 0.9/0.31 mm Hg in the QDG group and -1.66/-1.08 mm Hg in the valsartan group (SBP P = 0.006, DBP P = 0.02). And similar results were observed regarding the outcomes of daytime and nighttime BPs. There was no difference in occurrence of adverse events between two groups (P > 0.05). CONCLUSION: QDG proves to be efficacious for grade 1 hypertension at a low-to-medium risk, even after discontinuation of the medication for 4 weeks. These findings provide a promising option for managing grade 1 hypertension and suggest the potential for maintaining stable BP through intermittent administration of QDG. TRIAL REGISTRATION: ChiCTR2000033890.

Maximizing Electrostatic Interaction in Ultramicroporous Metal-Organic Frameworks for the One-Step Purification of Acetylene from Ternary Mixture.

Developing efficient adsorbents for acetylene purification from multicomponent mixtures is of critical significance in the chemical industry, but the trade-off between regenerability and selectivity significantly restricts practical industrial applications. Here, we report ultramicroporous metal-organic frameworks with acetylene-affinity channels to enhance electrostatic interaction between C2H2 and frameworks for the efficient one-step purification of C2H2 from C2H2/CO2/C2H4 mixtures, in which the electrostatic interaction led to high regenerability. The obtained SNNU-277 exhibits significantly higher adsorption capacity for C2H2 than that for both C2H4 and CO2 at 298 K and 0.1 bar, while an ultrahigh selectivity of C2H2/C2H4 (100.6 at 298 K) and C2H2/CO2 (32.8 at 298 K) were achieved at 1 bar. Breakthrough experiments validated that SNNU-277 can efficiently separate C2H2 from C2H2/C2H4/CO2 mixtures. CO2 and C2H4 broke through the adsorption column at 4 and 14.8 min g-1, whereas C2H2 was detected until 177.6 min g-1 at 298 K. Theoretical calculations suggest that the framework is electrostatically compatible with C2H2 and electrostatically repels C2H4 and CO2 in the mixed components. This work highlights the importance of rational pore engineering for maximizing the electrostatic effect with the preferentially absorbed guest molecule for efficient multicomponent separation.

CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/ß-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

A multifactorial screening model based on the Graves ophthalmopathy quality of life scores in dysthyroid optic neuropathy.

PURPOSE: To validate the Graves ophthalmopathy quality of life (GO-QOL) questionnaire in screening DON and to construct an effective model. METHODS: A total of 194 GO patients were recruited and divided into DON and non-DON (mild and moderate-to-severe) groups. Eye examinations were performed, and quality of life was assessed by the GO-QOL questionnaire. The random forest, decision tree model, receiver operator characteristic (ROC) curve, accuracy and Brier score were determined by R software. RESULTS: In GO-QOL, age, best corrected visual acuity (BCVA), exophthalmos, CAS, severity, and Gorman score were found to be factors related to visual function scores. On the appearance scale, gender, duration of GO, BCVA, exophthalmos, CAS and severity of GO were relevant. Both the visual function scores and appearance scores were significantly lower in DON groups than in non-DON groups (33.18 ± 24.54 versus 81.26 ± 17.39, 60.08 ± 24.82 versus 76.14 ± 27.56). The sensitivity, specificity, and AUC of the visual function scores were 91.1%, 81.7% and 0.939, respectively Visual function scores were used to construct a decision tree model. The sensitivity, specificity, and AUC of the model were 92.9%, 88.0% and 0.941, respectively, with an accuracy of 89.7% and a Brier score of 0.024. CONCLUSIONS: Visual function scores were qualified as a screening method for DON, with a cutoff point of 58. A multifactorial screening model based on visual function scores was constructed.

Syphilis as the great mimicker: A case of full-house pattern membranous nephropathy.

Syphilis is a known cause of membranous nephropathy. We describe a case of a patient presenting with nephrotic syndrome whose renal biopsy demonstrated a 'full house' immunohistochemical pattern with positive IgG, IgM, C1q, IgA, C3c, and C4d staining. He was treated with immunosuppressive agents for minimal change nephropathy and subsequently class V lupus nephritis, before syphilis infection was confirmed. Following treatment with a single dose of intramuscular benzathine penicillin there was complete and rapid resolution of nephrotic syndrome. With progressive rising incidence in the western world, syphilis is an important and under-recognised differential diagnosis in cases of nephrotic syndrome.

MyoD Over-Expression Rescues GST-bFGF Repressed Myogenesis.

During embryogenesis, basic fibroblast growth factor (bFGF) is released from neural tube and myotome to promote myogenic fate in the somite, and is routinely used for the culture of adult skeletal muscle (SKM) stem cells (MuSC, called satellite cells). However, the mechanism employed by bFGF to promote SKM lineage and MuSC proliferation has not been analyzed in detail. Furthermore, the question of if the post-translational modification (PTM) of bFGF is important to its stemness-promoting effect has not been answered. In this study, GST-bFGF was expressed and purified from E.coli, which lacks the PTM system in eukaryotes. We found that both GST-bFGF and commercially available bFGF activated the Akt-Erk pathway and had strong cell proliferation effect on C2C12 myoblasts and MuSC. GST-bFGF reversibly compromised the myogenesis of C2C12 myoblasts and MuSC, and it increased the expression of Myf5, Pax3/7, and Cyclin D1 but strongly repressed that of MyoD, suggesting the maintenance of myogenic stemness amid repressed MyoD expression. The proliferation effect of GST-bFGF was conserved in C2C12 over-expressed with MyoD (C2C12-tTA-MyoD), implying its independence of the down-regulation of MyoD. In addition, the repressive effect of GST-bFGF on myogenic differentiation was almost totally rescued by the over-expression of MyoD. Together, these evidences suggest that (1) GST-bFGF and bFGF have similar effects on myogenic cell proliferation and differentiation, and (2) GST-bFGF can promote MuSC stemness and proliferation by differentially regulating MRFs and Pax3/7, (3) MyoD repression by GST-bFGF is reversible and independent of the proliferation effect, and (4) GST-bFGF can be a good substitute for bFGF in sustaining MuSC stemness and proliferation.

Ceftriaxone improves impairments in synaptic plasticity and cognitive behavior in APP/PS1 mouse model of Alzheimer's disease by inhibiting extrasynaptic NMDAR-STEP61 signaling.

Abnormal activation of the extrasynaptic N-methyl-d-aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by upregulating glutamate transporter-1 and promoting the glutamate-glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive-behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno-associated virus (AAV)-striatal enriched tyrosine phosphatase 61 (STEP61 ) and AAV-STEP61 -shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long-term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m-calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef-induced inhibition of the expressions of GluN2B, GluN2BTyr1472 , and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef-induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.

In Situ Probing of the Intrinsic Adhesion Strength of Single Anaerobic Microbial Cells.

Probing the single-cell mechanobiology in situ is imperative for microbial processes in the medical, industrial, and agricultural realms, but it remains a challenge. Herein, we present a single-cell force microscopy method that can be used to measure microbial adhesion strength under anaerobic conditions in situ. This method integrates atomic force microscopy with an anaerobic liquid cell and inverted fluorescence microscopy. We obtained the nanomechanical measurements of the single anaerobic bacterium Ethanoligenens harbinense YUAN-3 and the methanogenic archaeon Methanosarcina acetivorans C2A and their nanoscale adhesion forces in the presence of sulfoxaflor, a successor of neonicotinoid pesticides. This study presents a new tool for in situ single-cell force measurements of various anoxic and anaerobic species and provides new perspectives for evaluating the potential environmental risk of neonicotinoid applications in ecosystems.

Pore Environmental Modification by Alkoxy Groups in Pore-Space-Partitioned Metal-Organic Frameworks to Achieve Gas Uptake-Selectivity Balance.

Due to the trade-off barrier between high storage capacity and high selectivity, the controllable and systematic design of metal-organic frameworks (MOFs) aiming at performance optimization is still challenging. Herein, considering the effectiveness of alkoxy group functionalization and a pore-space partition strategy, a series of rigid Mg-pacs-MOFs (SNNU-10-n, n = 1-6) with flexible side chains are built for the first time, realizing systematic pore environmental modification. The steric hindrance effects, electron-donating ability, and the flexibility of alkoxy groups are considered as key factors, which lead to a regular change of gas adsorption capacity and selectivity. Notably, methoxy-modified SNNU-10-1 with moderately high storage capacities of C2H2 (139.4 cm3 g-1), C2H4 (100.4 cm3 g-1), CO2 (105.0 cm3 g-1), and high selectivity values for equimolar C2H2/CH4 (431.8), C2H4/CH4 (164.2), and CO2/CH4 (16.1) mixture separation at 273 K and 100 kPa achieves an ideal gas uptake-selectivity balance. Breakthrough experiments verified that it could effectively separate the above-mentioned mixtures under ambient conditions, and GCMC simulation provides a deep understanding of methoxy group functionalization. Undoubtedly, this work not only realizes controllable regulation of gas adsorption behavior but also proves the validity of improving selectivity by alkoxy groups in those platforms with high gas-uptake potential to overcome the trade-off barrier.

Substituent Engineering in Pore-Space-Partitioned Metal-Organic Frameworks for CO2 Selective Adsorption and Fixation.

Comprehensive understanding of substituent groups located on the pore surface of metal-organic frameworks (which we call substituent engineering herein) can help to promote gas adsorption and catalytic performance through ligand functionalization. In this work, pore-space-partitioned metal-organic frameworks (PSP MOFs) were selected as a platform to evaluate the effect of organic functional groups on CO2 adsorption, separation, and catalytic conversion. Twelve partitioned acs metal-organic frameworks (pacs-MOFs, named SNNU-25-Rn here) containing different functional groups were synthesized, which can be classified into electron-donor groups (-OH, -NH2, -CH3, and -OCH3) and electron-acceptor groups (-NO2, -F, -Cl, and -Br). The experimental results showed that SNNU-25-Rn with electron donors usually perform better than those with electron acceptors for the comprehensive utilization of CO2. The CO2 uptake of the 12 SNNU-25-Rn MOFs ranged from 30.9 to 183.6 cm3 g-1 at 273 K and 1 bar, depending on the organic functional groups. In particular, SNNU-25-OH showed the highest CO2 adsorption, SNNU-25-CH3 had the highest IAST of CO2/CH4 (36.1), and SNNU-25-(OH)2 showed the best catalytic activity for the CO2 cycloaddition reaction. The -OH functionalized MOFs with excellent performance may be attributed to the Lewis acid-base and hydrogen-bonding interactions between -OH groups and the CO2 molecules. This work modulated the effect of the microenvironment of MOFs on CO2 adsorption, separation, and catalysis in terms of substituents, providing valuable information for the precise design of porous MOFs with a comprehensive utilization of CO2.

Diagnostic Value of MRI Features in Dual-phenotype Hepatocellular Carcinoma: A Preliminary Study.

This study aimed to explore the magnetic resonance imaging (MRI) features of dual-phenotype hepatocellular carcinoma (DPHCC) and their diagnostic value.The data of 208 patients with primary liver cancer were retrospectively analysed between January 2016 and June 2021. Based on the pathological diagnostic criteria, 27 patients were classified into the DPHCC group, 113 patients into the noncholangiocyte-phenotype hepatocellular carcinoma (NCPHCC) group, and 68 patients with intrahepatic cholangiocarcinoma (ICC) were classified into the ICC group. Two abdominal radiologists reviewed the preoperative MRI features by a double-blind method. The MRI features and key laboratory and clinical indicators were compared between the groups. The potentially valuable MRI features and key laboratory and clinical characteristics for predicting DPHCC were identified by univariate and multivariate analyses, and the odds ratios (ORs) were recorded. In multivariate analysis, tumour without capsule (P = 0.046, OR = 9.777), dynamic persistent enhancement (P = 0.006, OR = 46.941), and targetoid appearance on diffusion-weighted imaging (DWI) (P = 0.021, OR = 30.566) were independently significant factors in the detection of DPHCC compared to NCPHCC. Serum alpha-fetoprotein (AFP) > 20 µg/L (P = 0.036, OR = 67.097) and prevalence of hepatitis B virus (HBV) infection (P = 0.020, OR = 153.633) were independent significant factors in predicting DPHCC compared to ICC. The differences in other tumour marker levels and imaging features between the groups were not significant. In MR enhanced and diffusion imaging, tumour without capsule, persistent enhancement and DWI targetoid findings, combined with AFP > 20 µg/L and HBV infection-positive laboratory results, can help to diagnose DPHCC and differentiate it from NCPHCC and ICC. These results suggest that clinical, laboratory and MRI features should be integrated to construct an AI diagnostic model for DPHCC.

De-Linker-Enabled Exceptional Volumetric Acetylene Storage Capacity and Benchmark C2 H2 /C2 H4 and C2 H2 /CO2 Separations in Metal-Organic Frameworks.

An ideal adsorbent for separation requires optimizing both storage capacity and selectivity, but maximizing both or achieving a desired balance remain challenging. Herein, a de-linker strategy is proposed to address this issue for metal-organic frameworks (MOFs). Broadly speaking, the de-linker idea targets a class of materials that may be viewed as being intermediate between zeolites and MOFs. Its feasibility is shown here by a series of ultra-microporous MOFs (SNNU-98-M, M=Mn, Co, Ni, Zn). SNNU-98 exhibit high volumetric C2 H2 uptake capacity under low and ambient pressures (175.3 cm3 cm-3 @ 0.1 bar, 222.9 cm3 cm-3 @ 1 bar, 298 K), as well as extraordinary selectivity (2405.7 for C2 H2 /C2 H4 , 22.7 for C2 H2 /CO2 ). Remarkably, SNNU-98-Mn can efficiently separate C2 H2 from C2 H2 /CO2 and C2 H2 /C2 H4 mixtures with a benchmark C2 H2 /C2 H4 (1/99) breakthrough time of 2325 min g-1 , and produce 99.9999 % C2 H4 with a productivity up to 64.6 mmol g-1 , surpassing values of reported MOF adsorbents.

Functional traits explain the consistent resistance of biodiversity to plant invasion under nitrogen enrichment.

Elton's biotic resistance hypothesis, which posits that diverse communities should be more resistant to biological invasions, has received considerable experimental support. However, it remains unclear whether such a negative diversity-invasibility relationship would persist under anthropogenic environmental change. By using the common ragweed (Ambrosia artemisiifolia) as a model invader, our 4-year grassland experiment demonstrated consistently negative relationships between resident species diversity and community invasibility, irrespective of nitrogen addition, a result further supported by a meta-analysis. Importantly, our experiment showed that plant diversity consistently resisted invasion simultaneously through increased resident biomass, increased trait dissimilarity among residents, and increased community-weighted means of resource-conservative traits that strongly resist invasion, pointing to the importance of both trait complementarity and sampling effects for invasion resistance even under resource enrichment. Our study provides unique evidence that considering species' functional traits can help further our understanding of biotic resistance to biological invasions in a changing environment.

m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Nicotinamide N-Methyltransferase inhibits HBV replication by suppressing NR5A1 expression invitro.

Chronic hepatitis B virus (HBV) infection can lead to fibrosis, liver cirrhosis, and primary hepatocellular carcinoma. Investigating host factors that regulate HBV replication helps to identify antiviral targets. In the current study, we identified Nicotinamide N-Methyltransferase gene (NNMT) as a novel factor that regulates HBV transcription. NNMT is up-regulated at both the mRNA and protein levels in HepG2.2.15 cells compared to HepG2 cells. Overexpression of NNMT reduces HBV replication in several cell models, while knockdown of NNMT enhances HBV DNA levels. Mechanistically, NNMT suppresses HBV DNA replication by inhibiting HBV RNA transcription. The region required for the inhibitory effect of NNMT was narrowed to nt 1672-1708 in enhancer II by luciferase assays. On the other hand, ChIP assays and EMSA results showed that NNMT does not bind to this region substantially, either directly or indirectly. Next, a collection of hepatic nuclear receptor transcription factors was screened to determine whether they were affected by NNMT overexpression. NR5A1, a positive regulator of HBV replication, decreased significantly after NNMT overexpression. Collectively, the findings of this study shed light on the regulation of HBV transcription.

Synthesis and biological evaluation of marine natural product, Cryptoechinuline D derivatives as novel antiangiogenic agents.

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.

Physiological integration between Bermudagrass ramets improves overall salt resistance under heterogeneous salt stress.

Connected ramets of colonal plants often suffer from different environmental conditions such as light, nutrient, and stress. Colonal Bermudagrass (Cynodon dactylon [L.] Pers.) can form interconnected ramets and this connection facilitates the tolerance to abiotic stress, which is a kind of physiological integration. However, how bermudagrass responds to heterogeneously distributed salt stress needs to be further elucidated. Here, we demonstrated that severance of stolons aggravated the damage of salt-stressed ramets, displaying higher relative electrolytic leakage (EL), lower content of chlorophyll, higher accumulation of Na+ , and serious oxidative damages. This finding implied the positive effects of the physiological integration of bermudagrass on salt tolerance. The unstressed ramets connected with the stressed one were mildly injured, implying the supporting and sacrifice function of the unstressed ramets. Physiological integration did not mediate the translocation of Na+ among ramets, but induced a higher expression of salt overly sensitive (SOS) genes in the stressed ramets, consequently reducing the accumulation of Na+ in leaves and roots. In addition, physiological integration upregulated the genes expression and enzymes activity of catalase (CAT) and peroxidase (POD) in both stressed and unstressed ramets. This granted a stronger antioxidant ability of the whole clonal plants under salt stress. Enhanced Na+ transfer and increased reactive oxygen species (ROS) scavenging are mechanisms that likely contribute to the physiological integration leading to the salt tolerance of bermudagrass.