Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer Cephalotaxus hainanensis.

Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer Cephalotaxus is highly endangered, creating a conflict between biotechnological valorization and preservation of biodiversity. Here, we construct the whole biosynthetic pathway to the 1-phenethylisoquinoline scaffold, as first committed compound for phenylethylisoquinoline alkaloids (PIAs), combining metabolic modeling, and transcriptome mining of Cephalotaxus hainanensis to infer the biosynthesis for PIA precursor. We identify a novel protein, ChPSS, driving the Pictet-Spengler condensation and show that this enzyme represents the branching point where PIA biosynthesis diverges from the concurrent benzylisoquinoline-alkaloids pathway. We also pinpoint ChDBR as crucial step to form 4-hydroxydihydrocinnamaldehyde diverging from lignin biosynthesis. The elucidation of the early PIA pathway represents an important step toward microbe-based production of these pharmaceutically important alkaloids resolving the conflict between biotechnology and preservation of biodiversity.

Two-dimensional MoS2-enabled flexible rectenna for Wi-Fi-band wireless energy harvesting.

The mechanical and electronic properties of two-dimensional materials make them promising for use in flexible electronics1-3. Their atomic thickness and large-scale synthesis capability could enable the development of 'smart skin'1,3-5, which could transform ordinary objects into an intelligent distributed sensor network6. However, although many important components of such a distributed electronic system have already been demonstrated (for example, transistors, sensors and memory devices based on two-dimensional materials1,2,4,7), an efficient, flexible and always-on energy-harvesting solution, which is indispensable for self-powered systems, is still missing. Electromagnetic radiation from Wi-Fi systems operating at 2.4 and 5.9 gigahertz8 is becoming increasingly ubiquitous and would be ideal to harvest for powering future distributed electronics. However, the high frequencies used for Wi-Fi communications have remained elusive to radiofrequency harvesters (that is, rectennas) made of flexible semiconductors owing to their limited transport properties9-12. Here we demonstrate an atomically thin and flexible rectenna based on a MoS2 semiconducting-metallic-phase heterojunction with a cutoff frequency of 10 gigahertz, which represents an improvement in speed of roughly one order of magnitude compared with current state-of-the-art flexible rectifiers9-12. This flexible MoS2-based rectifier operates up to the X-band8 (8 to 12 gigahertz) and covers most of the unlicensed industrial, scientific and medical radio band, including the Wi-Fi channels. By integrating the ultrafast MoS2 rectifier with a flexible Wi-Fi-band antenna, we fabricate a fully flexible and integrated rectenna that achieves wireless energy harvesting of electromagnetic radiation in the Wi-Fi band with zero external bias (battery-free). Moreover, our MoS2 rectifier acts as a flexible mixer, realizing frequency conversion beyond 10 gigahertz. This work provides a universal energy-harvesting building block that can be integrated with various flexible electronic systems.

Inhibition of circular JUN prevents the proliferation and invasion of glioblastoma via miR-3064-IGFBP5 axis.

Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumours, characterized by rapid progression and limited treatment options. This study investigated the regulatory roles of circular RNA circJUN, and its functional interaction with microRNA miR-3064 in GBM pathogenesis. We employed bioinformatic analyses and clinical sample validation to identify circJUN as a potential target in GBM. Subsequently, we engineered GBM cell lines with stable circJUN knockout or overexpression, and transfected them with miR-3064 mimic/inhibitor or IGFBP5 small interfering RNA (siRNA)/expression vector to elucidate the molecular mechanisms governing GBM proliferation and invasion. To investigate the in vivo effects, xenograft tumour models were established in nude mice using engineered cells to assess the roles of circJUN in tumour growth regulation. Our analyses revealed significant overexpression of circJUN in GBM tissues compared to healthy controls, which strongly correlated with poor patient prognosis. In vitro and in vivo experiments demonstrated that circJUN overexpression could enhance GBM cell proliferation and invasion. Mechanistic investigations uncovered EIF4A3 as an interacting factor of circJUN which promotes circJUN expression, and circJUN modulates miR-3064 activity to regulate the malignancy of GBM cells. Furthermore, we identified IGFBP5, a crucial regulator of cell growth, as a direct target of miR-3064, thereby establishing an additional layer of control over GBM proliferation and invasion. Our study unveils a complex regulatory network involving circJUN, miR-3064 and IGFBP5 in GBM pathogenesis, underscoring their potential as novel therapeutic targets for improving patient outcomes. Our findings not only contribute to the understanding of GBM biology but also pave the way for innovative therapeutic approaches in the management of this malignancy.

In-Depth Analysis of Molecular Network Based on Liquid Chromatography Coupled with Tandem Mass Spectrometry in Natural Products: Importance of Redundant Nodes Discovery.

The identification of molecules within complex mixtures is a major bottleneck in natural products (NPs) research. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as the main tool for the high-throughput characterization of NPs. The large amount of data sets by LC-MS/MS presents a challenge for data processing and interpretation, and the LC-MS/MS molecular network (MN) is one of the most prominent tools for analyzing large MS/MS data sets, widely used for rapid classification, identification, and structural speculation of unknown compounds. However, the existence of a large number of redundant nodes leads to false-positive results. To solve this problem, we proposed the in-depth analysis of MN. In this study, in-depth analysis of MN of five NPs representing the common structures of saponin, steroid, flavonoid, alkaloid, and phenolic acid revealed the presence of redundant nodes (including other adducts, isotope, and in-source fragmentation) in addition to the normal nodes, which can lead to false-positive identification results. Additionally, the reasons for different redundant nodes are discussed and experimentally verified, and it was found that the impact of redundant nodes can be mitigated by optimizing the experimental conditions and employing Feature-Based Molecular Networking. Furthermore, Ion Identity Molecular Networking can rapidly discover and screen redundant nodes, simplifying the in-depth analysis of MN and improving the network connectivity of structurally related molecules. Finally, a combination formulation of 7 NPs is used as an example to provide a guide for in-depth analysis of MN for comprehensive characterization of complex systems. This study highlights the importance of an in-depth analysis of MN for better understanding and utilization of MS/MS data in complex systems to reduce the false-positive rate of identification by screening and filtering redundant nodes.

Curvature-mediated source and sink effects on the genesis of premature ventricular complexes in long QT syndrome.

Premature ventricular complexes (PVCs) are spontaneous excitations occurring in the ventricles of the heart that are associated with ventricular arrhythmias and sudden cardiac death. Under long QT conditions, PVCs can be mediated by repolarization gradient (RG) and early afterdepolarizations (EADs), yet the effects of heterogeneities or geometry of the RG or EAD regions on PVC genesis remain incompletely understood. In this study, we use computer simulation to systematically investigate the effects of the curvature of the RG border region on PVC genesis under long QT conditions. We show that PVCs can be either promoted or suppressed by negative or positive RG border curvature depending on the source and sink conditions. When the origin of oscillation is in the source region and the source is too strong, a positive RG border curvature can promote PVCs by causing the source area to oscillate. When the origin of oscillation is in the sink region, a negative RG border curvature can promote PVCs by causing the sink area to oscillate. Furthermore, EAD-mediated PVCs are also promoted by negative border curvature. We also investigate the effects of wavefront curvature and show that PVCs are promoted by convex but suppressed by concave wavefronts; however, the effect of wavefront curvature is much smaller than that of RG border curvature. In conclusion, besides the increase of RG and occurrence of EADs caused by QT prolongation, the geometry of the RG border plays important roles in PVC genesis, which can greatly increase the risk of arrhythmias in cardiac diseases.NEW & NOTEWORTHY The effects of the curvature or geometry of the repolarization gradient region and wavefront curvature on the genesis of premature ventricular complexes are systematically investigated using computer modeling and simulation. Premature ventricular complexes can be promoted by either positive or negative curvature of the gradient region depending on the source and sink conditions. The underlying mechanisms of the curvature effects are revealed, which provides mechanistic insights into arrhythmogenesis in cardiac diseases.

Boosting Polysulfide Redox Kinetics by Temperature-Induced Metal-Insulator Transition Effect of Tungsten-Doped Vanadium Dioxide for High-Temperature Lithium-Sulfur Batteries.

The practical application of Li-S batteries is still severely restricted by poor cyclic performance caused by the intrinsic polysulfides shuttle effect, which is even more severe under the high-temperature condition owing to the inevitable increase of polysulfides' solubility and diffusion rate. Herein, tungsten-doped vanadium dioxide (W-VO2) micro-flowers are employed with first-order metal-insulator phase transition (MIT) property as a robust and multifunctional modification layer to hamper the shuttle effect and simultaneously improve the thermotolerance of the common separator. Tungsten doping significantly reduces the transition temperature from 68 to 35 °C of vanadium dioxide, which renders the W-VO2 easier to turn from the insulating monoclinic phase into the metallic rutile phase. The systematic experiments and theoretical analysis demonstrate that the temperature-induced in-suit MIT property endows the W-VO2 catalyst with strong chemisorption against polysulfides, low energy barrier for liquid-to-solid conversion, and outstanding diffusion kinetics of Li-ion under high temperatures. Benefiting from these advantages, the Li-S batteries with W-VO2 modified separator exhibit significantly improved rate and long-term cyclic performance under 50 °C. Remarkably, even at an elevated temperature (80 °C), they still exhibit superior electrochemical performance. This work opens a rewarding avenue to use phase-changing materials for high-temperature Li-S batteries.

Optimizing Surface State Electrons of Topological Semi-Metal by Atomic Doping for Enhanced Hydrogen Evolution Reaction.

Topological materials carrying topological surface states (TSSs) have extraordinary carrier mobility and robustness, which provide a new platform for searching for efficient hydrogen evolution reaction (HER) electrocatalysts. However, the majority of these TSSs originate from the sp band of topological quantum catalysts rather than the d band. Here, based on the density functional theory calculation, it is reported a topological semimetal Pd3Sn carrying TSSs mainly derived from d orbital and proposed that optimizing surface state electrons of Pd3Sn by introduction heteroatoms (Ni) can promote hybridization between hydrogen atoms and electrons, thereby reducing the Gibbs free energy (ΔGH) of adsorbed hydrogen and improving its HER performance. Moreover, this is well verified by electrocatalytic experiment results, the Ni-doped Pd3Sn (Ni0.1Pd2.9Sn) show much lower overpotential (-29 mV vs RHE) and Tafel slope (17 mV dec-1) than Pd3Sn (-39 mV vs RHE, 25 mV dec-1) at a current density of 10 mA cm-2. Significantly, the Ni0.1Pd2.9Sn nanoparticles exhibit excellent stability for HER. The electrocatalytic activity of Ni0.1Pd2.9Sn nanoparticles is superior to that of commercial Pt. This work provides an accurate guide for manipulating surface state electrons to improve the HER performance of catalysts.

Effects of Testosterone in Mediating the Relationship Between Daytime Napping and Osteoporosis in European Populations: A Mendelian Randomization Study.

We aimed to explore the causal effect of daytime napping on the risk of osteoporosis and the mediation role of testosterone in explaining this relationship. Summary data for Mendelian randomization (MR) analysis were obtained from the IEU OpenGWAS database. Univariable MR(UVMR) analysis and multiple sensitivity analyses were applied to explore the casual relationship between daytime napping and bone mineral density (BMD)/osteoporosis. We also conducted multivariable Mendelian randomization (MVMR) analysis to evaluate the correlation between testosterone-associated single-nucleotide variations and BMD/osteoporosis. Then, mediation analysis was performed to explore whether the association between daytime napping and BMD/osteoporosis was mediated via testosterone. Genetically predicted daytime napping was significantly associated with femoral neck BMD (ß [95% CI]: 0.2573 [0.0487, 0.4660]; P = 0.0156), lumbar spine BMD (ß [95% CI]: 0.2526 [0.0211, 0.4840]; P = 0.0324), and osteoporosis (OR [95% CI]: 0.5063 [0.2578, 0.9942]; P = 0.0481). ß and 95%CIs indicate the standard deviation (SD) unit of BMD increase per category increase in daytime napping. OR and 95%CIs represent the change in the odds ratio of osteoporosis per category increase in daytime napping. We observed a potentially causal effect of more frequent daytime napping on higher BMD and a lower risk of osteoporosis. Daytime napping was causally associated with a higher level of bioavailable testosterone (ß [95% CI]: 0.1397 [0.0619, 0.2175]; P = 0.0004). ß and 95%CIs represent the change in the SD of testosterone per category increase in daytime napping. Furthermore, the causal effects of daytime napping on BMD/osteoporosis were partly mediated by bioavailable testosterone. Daytime napping can efficiently increase BMD and reduce the risk of osteoporosis, and testosterone plays a key mediating role in this process.

Intraindividual comparison of CT and MRI for predicting vessels encapsulating tumor clusters in hepatocellular carcinoma.

OBJECTIVES: To establish and validate scoring models for predicting vessels encapsulating tumor clusters (VETC) in hepatocellular carcinoma (HCC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to intra-individually compare the predictive performance between the two modalities. METHODS: We retrospectively included 324 patients with surgically confirmed HCC who underwent preoperative dynamic CT and MRI with extracellular contrast agent between June 2019 and August 2020. These patients were then divided into a discovery cohort (n = 227) and a validation cohort (n = 97). Imaging features and Liver Imaging Reporting and Data System (LI-RADS) categories of VETC-positive HCCs were evaluated. Logistic regression analyses were conducted on the discovery cohort to identify clinical and imaging predictors associated with VETC-positive cases. Subsequently, separate CT-based and MRI-based scoring models were developed, and their diagnostic performance was compared using generalized estimating equations. RESULTS: On both CT and MRI, VETC-positive HCCs exhibited a higher frequency of size > 5.0 cm, necrosis or severe ischemia, non-smooth tumor margin, targetoid appearance, intratumor artery, and heterogeneous enhancement with septations or irregular ring-like structure compared to VETC-negative HCCs (all p < 0.05). Regarding LI-RADS categories, VETC-positive HCCs were more frequently categorized as LR-M than VETC-negative cases (all p < 0.05). In the validation cohort, the CT-based model showed similar sensitivity (76.7% vs. 86.7%, p = 0.375), specificity (83.6% vs. 74.6%, p = 0.180), and area under the curve value (0.80 vs. 0.81, p = 0.910) to the MRI-based model in predicting VETC-positive HCCs. CONCLUSION: Preoperative CT and MRI demonstrated comparable performance in the identification of VETC-positive HCCs, thus displaying promising predictive capabilities. CLINICAL RELEVANCE STATEMENT: Both computed tomography and magnetic resonance imaging demonstrated promise in preoperatively identifying the vessel-encapsulating tumor cluster pattern in hepatocellular carcinoma, with no statistically significant difference between the two modalities, potentially adding additional prognostic value. KEY POINTS: Computed tomography (CT) and magnetic resonance imaging (MRI) show promise in the preoperative identification of vessels encapsulating tumor clusters-positive hepatocellular carcinoma (HCC). HCC with vessels encapsulating tumor cluster patterns were more frequently LR-M compared to those without. These CT and MRI models showed comparable ability in identifying vessels encapsulating tumor clusters-positive HCC.

Systemic immunity-inflammation index is associated with body fat distribution among U.S. adults: evidence from national health and nutrition examination survey 2011-2018.

OBJECTIVE: The systemic immunity-inflammation index (SII) is a newly developed biomarker that provides an integrated measure of inflammation in the body. We aim to evaluate the relationship between SII and body fat distribution. METHODS: Adults from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were included. The SII was computed using lymphocyte (LC), neutrophil (NC), and platelet (PC) counts as its components. Body fat distribution was assessed by (total, android, gynoid) percentage fat, total abdominal fat area, subcutaneous adipose tissue area, visceral adipose tissue area, and the ratio of visceral to subcutaneous adipose tissue area (V/S ratio). Multivariable weighted linear regression and subgroup analysis were use to examine the relationships between fat distribution and SII. Restricted cubic splines (RCS) and threshold effect analysis were used to examine analyze nonlinear associations. RESULTS: After exclusions, a total of 11,192 adults with a weighted mean age of 38.46 ± 0.26 years were studied. In multivariable weighted linear regression, each level increase in log2SII was associated with increased of 0.23 SDs total percentage fat (95% CI = 0.03, 0.43) and 0.26 SDs android percentage fat (95% CI = 0.06, 0.47). Besides, the subgroup analysis showed that the positive association between SII and android percentage fat was mainly among obese individuals (BMI > 30 kg/m2) and non-obese individuals without DM or hypertension. Meanwhile, the relationship between SII and the V/S ratio was found to be significant in the female subgroup, the obese subgroup, individuals with non-alcoholic fatty liver disease (NAFLD), and those without diabetes mellitus. Finally, SII exhibited an inverted U-shaped relationship with total percentage fat, android percent fat and total abdominal fat. Accordingly, threshold effect analysis indicated a positive association between lower SII levels and total percentage fat, android percentage fat and total abdominal fat area. CONCLUSIONS: In the nationwide study, it was observed that the SII exhibited a significant correlation with higher levels of body fat, specifically android fat. This association was particularly noticeable within specific subgroups of the population.

The novel small molecule E0924G dually regulates bone formation and bone resorption through activating the PPARδ signaling pathway to prevent bone loss in ovariectomized rats and senile mice.

Osteoporosis is particularly prevalent among postmenopausal women and the elderly. In the present study, we investigated the effect of the novel small molecule E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide) on osteoporosis. E0924G significantly increased the protein expression levels of osteoprotegerin (OPG) and runt-related transcription factor 2 (RUNX2), and thus significantly promoted osteogenesis in MC3T3-E1 cells. E0924G also significantly decreased osteoclast differentiation and inhibited bone resorption and F-actin ring formation in receptor activator of NF-κB ligand (RANKL)-induced osteoclasts from RAW264.7 macrophages. Importantly, oral administration of E0924G in both ovariectomized (OVX) rats and SAMP6 senile mice significantly increased bone mineral density and decreased bone loss compared to OVX controls or SAMR1 mice. Further mechanistic studies showed that E0924G could bind to and then activate peroxisome proliferator-activated receptor delta (PPARδ), and the pro-osteoblast effect and the inhibition of osteoclast differentiation induced by E0924G were significantly abolished when PPARδ was knocked down or inhibited. In conclusion, these data strongly suggest that E0924G has the potential to prevent OVX-induced and age-related osteoporosis by dual regulation of bone formation and bone resorption through activation of the PPARδ signaling pathway.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Effects of atrazine on movement, metabolism and gene expression in Pelophylax nigromaculatus larvae under global warming.

Global warming and environmental pollutants both pose a threat to the behavior and physiology of animals, but research on the combined effects of the two is limited. Atrazine, a widely used herbicide, has toxic effects on organisms. In this study, the effects of environmental concentrations of atrazine exposure (100 µg/L) for seven days on the movement, metabolism and gene expression related to motility of Pelophylax nigromaculatus larvae (GS8) were investigated under global warming. The results showed that compared to the optimal growth temperature (18 °C), atrazine treatment under global warming (21 °C) significantly increased the average speed (about 11.2 times) and maximum acceleration (about 1.98 times) of P. nigromaculatus larvae, altered the relative abundance of 539 metabolites, including Formyl-5-hydroxykynurenamine, 2,4-Dihydroxybenzophenone, and FAPy-adenine, and changed the nucleotide metabolism, pyrimidine metabolism, glycerophospholipid metabolism, and purine metabolism, as well as increased the gene expression of SPLA2 (about 6.46 times) and CHK (about 3.25 times). In summary, atrazine treatment under global warming caused metabolic disorders in amphibian larvae and increased the expression of some movement-related genes in the brain, resulting in abnormally active.

Design, bioactivity and mechanism of N'-phenyl pyridylcarbohydrazides with broad-spectrum antifungal activity.

Succinate dehydrogenase inhibitors (SDHIs) as one of the fastest-growing fungicide categories for plant protection. In this study, a series of N'-phenyl pyridylcarbohydrazides as analogues of commercial SDHIs were designed and evaluated for inhibition activity on phytopathogenic fungi to search for potential novel SDHIs. The determination of antifungal activity in vitro and in vivo led to the discovery of a series of compounds with high activity and broad-spectrum property. Especially, N'-(4-fluorophenyl)picolinohydrazide (1c) and N'-(3,4-fluorophenyl)picolinohydrazide (1ae) showed 0.041-1.851 µg/mL of EC50 values on twelve fungi, superior to positive controls carbendazim and boscalid. In vivo activity, 1c at 50 µg/mL showed 61% of control efficacy at the post-treatment 9th day for the infection of P. piricola on apples, slightly smaller than 70% of carbendazim. In terms of action mechanism, 1c showed strong inhibition activity with IC50 of 0.107 µg/mL on SDH in Alternaria brassicae, superior to positive SDHI boscalid (IC50 0.182 µg/mL). Molecular docking indicated that 1c can well bind with the ubiquinone-binding region of SDH mainly by hydrogen bond, carbon hydrogen bond, π-alkyl, amide-π stacking, F-N and F-H interactions. Furthermore, scanning and transmission electron micrographs showed that 1c was able to obviously change the structure of mycelia and cell membrane. Fluorescence staining analysis showed that 1c could increase both the intracellular reactive oxygen species level and mitochondrial membrane potential. Finally, seed germination test, seedling growth test and cytotoxicity assay showed that 1c had very low toxicity to plant growth and mammalian cells. Thus, N'-phenyl pyridylcarbohydrazides especially 1c and 1ae can be considered promising fungicide alternatives for plant protection.

Design, synthesis, bioactivity and action mechanism of N-substituted N'-phenylpicolinohydrazides against phytopathogenic fungi.

N'-phenylpicolinohydrazide has been proven to be a promising lead compound for research and development of novel fungicides for agriculture in our previous study. As our continuing research, in this study, a series of N-substituted derivatives of N'-phenylpicolinohydrazide were synthesized and explored for the inhibition activity on nine phytopathogenic fungi and action mechanism. The results found that eleven of the compounds had excellent antifungal activity with more than 80% inhibition rates at 50 µg/mL on part or most of the fungi, especially A. solani and P. piricola. Compounds 5i, 5j and 5k showed EC50 values of < 8.0 µg/mL against A. solani superior to positive control carbendazim (EC50 = 36.0 µg/mL) while 5p and 5q exhibited the highest activity with EC50 values of 2.72 and 2.80 µg/mL against P. piricola superior to positive control boscalid (EC50 > 50.0 µg/mL). Furthermore, 5k also showed significant protective effect against A. solani infection on tomatoes in a concentration-dependent manner. Action mechanism research showed that 5k was able to increase the intracellular ROS level, change both MMP and permeability of cell membrane and damage mycelial morphology. Molecular docking studies showed that 5k could bind into ubiquinone-binding region of succinate dehydrogenase by hydrogen bonds, π-cation, π-π stacked, π-alkyl, and alkyl interactions. Additionally, the antibacterial activity was also investigated. Thus, N-substituted derivatives of N'-phenylpicolinohydrazide were emerged as novel and highly promising antifungal molecular skeletons to develop new fungicides for crop protection.

Association between composite dietary antioxidant index and epilepsy in American population: a cross-sectional study from NHANES.

BACKGROUND: Epilepsy is a major global health challenge, affecting approximately 50 million people across the globe and resulting in significant economic impacts on individuals and society. Oxidative stress is implicated in the pathogenesis of epilepsy, highlighting the potential of antioxidant-rich dietary patterns in offering preventive and protective benefits by mitigating oxidative stress. The Composite Dietary Antioxidant Index (CDAI) provides a measure for assessing dietary antioxidant intake, yet its link to epilepsy remains unexplored. METHODS: Our analysis utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning 2013 to 2018, including 20,180 screened participants. Weighted logistic regression models were employed to examine the association between the CDAI and epilepsy prevalence. Non-linear associations were explored through restricted cubic splines (RCS), and the relationships between individual antioxidant components within the CDAI and epilepsy were also assessed. RESULTS: After adjusting for potential confounders, a negative association between the CDAI and epilepsy was suggested (OR = 0.991; p = 0.087, 95% CI [0.819,1.014]). Stratification of CDAI into quartiles revealed a significantly reduced risk of epilepsy in higher CDAI quartiles (Q3 and Q4) compared to the lowest quartile (Q1) (Q3: OR = 0.419; p = 0.030, 95% CI [0.192, 0.914]; Q4: OR = 0.421; p = 0.004, 95% CI [0.239, 0.742]), with a significant trend observed across quartiles (p for trend = 0.013). RCS analysis suggested a nonlinear association between CDAI levels and epilepsy (non-linear p = 0.049), which, however, was not statistically significant after full adjustment (non-linear p = 0.103). Additionally, significant negative correlations with epilepsy were observed for vitamin A and zinc (Vitamin A: OR = 0.999; p = 0.012, 95% CI [0.998, 1.000]; Zinc: OR = 0.931; p = 0.042, 95% CI [0.869, 0.997]). CONCLUSIONS: Our research indicates a correlation where higher CDAI levels correspond to a reduced risk of epilepsy. Therefore, embracing a diet rich in antioxidants could be beneficial in preventing epilepsy. This finding holds considerable potential for shaping future strategies in both epilepsy prevention and treatment.

Chinese Medicine's Effects Against Advanced Gastric Cancer: A Single-center, Randomized, Double-blind, Controlled Clinical Trial.

Context: At present, medical practitioners commonly use surgery and perioperative chemotherapy, radiotherapy, and biological targeted therapy in clinical treatment of gastric cancer. Western medicine treatment can quickly treat patients' lesions but may cause adverse reactions. TCM can prevent the occurrence of toxic side effects and alleviate the side effects of Western medicine. Objectives: The study intended to explore the clinical efficacy of traditional Chinese medicine (TCM) combined with Western medicine in the treatment of advanced gastric cancer. Design: The research team performed a randomized, double-blind, controlled clinical trial. Setting: The study took place at the Cangzhou Central Hospital in Hebei, China. Participants: Participants were 102 patients with advanced gastric cancer who had been admitted to the hospital between February 2021 and March 2023. Interventions: The research team randomly divided participants into two groups, with 51 participants in each group: (1) the TCM group, who received TCM only, and (2) the combination group, who received chemotherapy combined with TCM. Outcome Measures: The research team measured: (1) clinical efficacy; (2) TCM syndrome efficacy; (3) levels of the blood tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen Sialyl-Lewis a (CA199), and carbohydrate antigen 72-4 (CA72-4); (4) psychological status using the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS); and (5) incidence of adverse reactions. Results: At baseline, no significant differences existed between the two groups in the clinical indicators. Postintervention compared to the TCM group, the combination group had significantly: (1) higher clinical efficacy (P = .003), (2) higher TCM syndrome efficacy (P = .003), (3) higher level of CEA and lower levels of CA199, and CA72-4 (all P = .000); (4) lower SAS scores and SDS scores (both P = .000); and (5) lower incidence of adverse reactions (P = .007). Conclusions: TCM, in the treatment of patients with advanced gastric cancer, can achieve good therapeutic effects. Combined with chemotherapy, patients' clinical efficacy can improve, level of blood tumor markers can decrease, psychological state can improve, and incidence of adverse reactions can decrease. Its clinical use had significant effects, and physicians can promote and use them.

Clinical Study of 32 Patients with Advanced Pancreatic Cancer Treated with Traditional Chinese Medicine Combined with Chemotherapy.

Objective: Our aim was to investigate the effect of the clinical application of Traditional Chinese Medicine (TCM) combined with chemotherapy in the treatment of advanced pancreatic cancer. Methods: The study participants were divided into 2 groups: the combined treatment group, comprised of 32 patients with advanced pancreatic cancer admitted to Zhejiang Provincial People's Hospital in China between June 2021 and June 2022 who received TCM combined with chemotherapy; and the control group: 32 patients with advanced pancreatic cancer admitted to Zhejiang Provincial People's Hospital in China between June 2021 and June 2022 who received chemotherapy alone. The TCM symptom score, TCM clinical efficacy, Western medicine clinical efficacy, patient quality of life (QoL) and incidence of adverse events (AEs) were compared in the 2 groups. Results: Prior to treatment, there was no significant difference in the patients' general clinical condition in the 2 groups (P > .05); after treatment, the TCM symptom score in the combined treatment group (16.62±2.77) was better than in the control group (21.44±2.53), with a P < .05. The TCM and Western medicine clinical efficacy was better than in the control group, with a P < .05; QoL score was higher than in the control group, P < .05; the incidence of AEs (3.12%) was lower than in the control group (28.12%); P < .05. Conclusion: In the treatment of patients with advanced pancreatic cancer, the application of TCM combined with chemotherapy can achieve good therapeutic results, improve the patients' prognosis, effectively reduce the occurrence of AEs and continuously restore patients' QoL.

Synergistic toxicity induced by the co-exposure of tenuazonic acid and patulin in Caenorhabditis elegans: Daf-16 plays an important regulatory role.

Tenuazonic acid (TeA) and patulin (PAT), as the naturally occurring mycotoxins with various toxic effects, are often detected in environment and food chain, has attracted more and more attention due to their widespread and high contaminations as well as the coexistence, which leads to potential human and animals' risks. However, their combined toxicity has not been reported yet. In our study, C. elegans was used to evaluate the type of combined toxicity caused by TeA+PAT and its related mechanisms. The results showed that TeA and PAT can induce synergistic toxic effects based on Combination Index (CI) evaluation model (Chou-Talalay method), that is, the body length, brood size as well as the levels of ROS, CAT and ATP were significantly affected in TeA+PAT-treated group compared with those in TeA- or PAT-treated group. Besides, the expressions of oxidative (daf-2, daf-16, cyp-35a2, ctl-1, ctl-3, pmk-1, jnk-1, skn-1) and intestinal (fat-5, pod-2, egl-8, pkc-3, ajm-1, nhx-2) stress-related genes were disrupted, among which daf-16 displayed the most significant alternation. Further study on daf-16 gene defective C. elegans showed that the damages to the mutant nematodes were significantly attenuated. Since daf-2, daf-16, jnk-1 and pmk-1 are evolutionarily conserved, our findings could hint synergistic toxic effects of TeA+PAT on higher organisms.

Differentiating the impact of fine and coarse particulate matter on cause-specific cerebrovascular mortality: An individual-level, case-crossover study.

BACKGROUND AND OBJECTIVES: Many studies suggested that short-term exposure to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) was linked to elevated risk of cerebrovascular disease. However, little is known about the potentially differential effects of PM2.5 and PM2.5-10 on various types of cerebrovascular disease. METHODS: We collected individual cerebrovascular death records for all residents in Shanghai, China from 2005 to 2021. Residential daily air pollution data were predicted from a satellite model. The associations between particulate matters (PM) and cerebrovascular mortality were investigated by an individual-level, time-stratified, case-crossover design. The data was analyzed by the conditional logistic regression combined with the distributed lag model with a maximum lag of 7 days. Furthermore, we explored the effect modifications by sex, age and season. RESULTS: A total of 388,823 cerebrovascular deaths were included. Monotonous increases were observed for mortality of all cerebrovascular diseases except for hemorrhagic stroke. A 10 µg/m3 rise in PM2.5 was related to rises of 1.35% [95% confidence interval (CI): 1.04%, 1.66%] in mortality of all cerebrovascular diseases, 1.84% (95% CI: 1.25%, 2.44%) in ischemic stroke, 1.53% (95% CI: 1.07%, 1.99%) in cerebrovascular sequelae and 1.56% (95% CI: 1.08%, 2.05%) in ischemic stroke sequelae. The excess risk estimates per each 10 µg/m3 rise in PM2.5-10 were 1.47% (95% CI: 1.10%, 1.84%), 1.53% (95% CI: 0.83%, 2.24%), 1.93% (95% CI: 1.38%, 2.49%) and 2.22% (95% CI: 1.64%, 2.81%), respectively. The associations of both pollutants with all cerebrovascular outcomes were robust after controlling for co-pollutants. The associations were greater in females, individuals > 80 years, and during the warm season. CONCLUSIONS: Short-term exposures to both PM2.5 and PM2.5-10 may independently increase the mortality risk of cerebrovascular diseases, particularly of ischemic stroke and stroke sequelae.