Design of vilazodone-donepezil chimeric derivatives as acetylcholinesterase inhibitors by QSAR, molecular docking and molecular dynamics simulations.

Alzheimer's disease (AD) is a disease that affects the cognitive abilities of older adults, and it is one of the biggest global medical challenges of the 21st century. Acetylcholinesterase (AChE) can increase acetylcholine concentrations and improve cognitive function in patients, and is a potential target to develop small molecule inhibitors for the treatment of Alzheimer's disease (AD). In this study, 29 vilazodone-donepezil chimeric derivatives are systematically studied using 3D-QSAR modeling, and a robust and reliable Topomer CoMFA model was obtained with: q2 = 0.720, r2 = 0.991, F = 287.234, N = 6, and SEE = 0.098. Based on the established model and combined with the ZINC20 database, 33 new compounds with ideal inhibitory activity are successfully designed. Molecular docking and ADMET property prediction also show that these newly designed compounds have a good binding ability to the target protein and can meet the medicinal conditions. Subsequently, four new compounds with good comprehensive ability are selected for molecular dynamics simulation, and the simulation results confirm that the newly designed compounds have a certain degree of reliability and stability. This study provides guidance for vilazodone-donepezil chimeric derivatives as a potential AChE inhibitor and has certain theoretical value.

Ergone Derivatives from the Deep-Sea-Derived Fungus Aspergillus terreus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (1-10) and five known analogues (11-15) were isolated from the deep-sea-derived fungus Aspergillus terreus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus. Structurally, compound 2 bearing a 15-carbonyl group and compounds 5-7 possessing a 15ß-OH/OCH3 group are rarely encountered in ergone derivatives. Bioassay results showed that compounds 1 and 11 demonstrated cytotoxic effects on human colon cancer SW620 cells with IC50 values of 8.4 and 3.1 µM, respectively. Notably, both compounds exhibited negligible cytotoxicity on the human normal lung epithelial cell BEAS-2B. Compound 11 was selected for preliminary mechanistic study and was found to inhibit cell proliferation and induce apoptosis in human colon cancer SW620 cells. In addition, compound 1 displayed cytotoxic activity against five human leukemia cell lines with IC50 values ranging from 5.7 to 8.9 µM. Our study demonstrated that compound 11 may serve as a potential candidate for the development of anticolorectal cancer agents.

Coupling Antisite Defect and Lattice Tensile Stimulates Facile Isotropic Li-Ion Diffusion.

Despite widely used as a commercial cathode, the anisotropic 1D channel hopping of lithium ions along the [010] direction in LiFePO4 prevents its application in fast charging conditions. Herein, an ultrafast nonequilibrium high-temperature shock technology is employed to controllably introduce the Li-Fe antisite defects and tensile strain into the lattice of LiFePO4. This design makes the study of the effect of the strain field on the performance further extended from the theoretical calculation to the experimental perspective. The existence of Li-Fe antisite defects makes it feasible for Li+ to move from the 4a site of the edge-sharing octahedra across the ab plane to 4c site of corner-sharing octahedra, producing a new diffusion channel different from [010]. Meanwhile, the presence of a tensile strain field reduces the energy barrier of the new 2D diffusion path. In the combination of electrochemical experiments and first-principles calculations, the unique multiscale coupling structure of Li-Fe antisite defects and lattice strain promotes isotropic 2D interchannel Li+ hopping, leading to excellent fast charging performance and cycling stability (high-capacity retention of 84.4% after 2000 cycles at 10 C). The new mechanism of Li+ diffusion kinetics accelerated by multiscale coupling can guide the design of high-rate electrodes.

Effectiveness of Global Leadership Initiative on Malnutrition and Subjective Global Assessment for diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers.

Malnutrition significantly hampers wound healing processes. This study aimed to compare the effectiveness of the Global Leadership Initiative on Malnutrition (GLIM) and Subjective Global Assessment (SGA) in diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers (DFU). GLIM criteria were evaluated for sensitivity (SE), specificity (SP), positive predictive value, negative predictive value and kappa (κ) against SGA as the reference. Modified Poisson regression model and the DeLong test investigated the association between malnutrition and non-healing ulcers over 6 months. This retrospective cohort study included 398 patients with DFU, with a mean age of 66·3 ± 11·9 years. According to SGA and GLIM criteria, malnutrition rates were 50·8 % and 42·7 %, respectively. GLIM criteria showed a SE of 67·3 % (95 % CI 60·4 %, 73·7 %) and SP of 82·7 % (95 % CI 76·6 %, 87·7 %) in identifying malnutrition, with a positive predictive value of 80·0 % and a negative predictive value of 71·1 % (κ = 0·50) compared with SGA. Multivariate analysis demonstrated that malnutrition, as assessed by SGA, was an independent risk factor for non-healing (relative risk (RR) 1·84, 95 % CI 1·45, 2·34), whereas GLIM criteria were associated with poorer ulcer healing in patients with estimated glomerular filtration rate ≥ 60 ml/min/1·73m2 (RR: 1·46, 95 % CI 1·10, 1·94). SGA demonstrated a superior area under the receiver's operating characteristic curve for predicting non-healing compared with GLIM criteria (0·70 (0·65-0·75) v. 0·63 (0·58-0·65), P < 0·01). These findings suggest that both nutritional assessment tools effectively identify patients with DFU at increased risk, with SGA showing superior performance in predicting non-healing ulcers.

Ferroptosis is involved in trophoblast cells cytotoxicity induced by black phosphorus nanoparticles.

Black phosphorus (BP) is a new type of nanomaterial, which has been widely used in many biomedical fields due to its superior properties, but there are few studies on the toxicity of BP, especially in the reproductive system. To explore the effects of BP exposure on reproduction and reveal its molecular mechanism, we firstly investigated the potential toxicity of black phosphorus nanoparticles (BPNPs) in vivo. The results showed that BP exposure in pregnant mice can reduce the weight of fetal mice and placenta. H&E staining further indicated the changes of placental cross-section and vascular remodeling after BP treatment. Then, human exvillous trophoblast HTR8/SVneo was treated with different concentrations of BPNPs. We found that BPNPs induced significant cytotoxicity, including dose-dependent reduction of cell viability and proliferation. Trophoblast cell migration and invasion were also impaired by BPNPs exposure. Moreover, pretreatment with Cytochalasin D (Cyto-D), a classical phagocytic inhibitor, alleviated the decline of cell viability induced by BPNPs. Transcriptome sequencing showed that BPNPs exposure led to ferroptosis. Subsequently, the related indexes of ferroptosis were detected, including increase of iron ion concentration, decrease of the ferroptosis marker, GPX4 (Glutathione Peroxidase 4), increase of FTL (Ferritin Light Chain), and increase of lipid peroxidation indexes (MDA level and decrease of GSH level). In addition, ferroptosis inhibitors (Fer-1 and DFO) pretreatment can alleviate both the cytotoxic effects and functional impairment induced by BPNPs. In summary, our study confirmed the reproductive toxicity of BPNPs for the first time, and constructed BPNPs injury model in vitro using human villus trophoblast cells and revealed the role of ferroptosis in this process, which deepened our understanding of the biosafety of black phosphorus nanomaterials.

A Potential Multitarget Insect Growth Regulator Candidate: Design, Synthesis, and Biological Activity of Novel Acetamido Derivatives Containing Hexacyclic Pyrazole Carboxamides.

Insect growth regulators (IGRs) are important green insecticides that disrupt normal growth and development in insects to reduce the harm caused by pests to crops. The ecdysone receptor (EcR) and three chitinases OfChtI, OfChtII, and OfChi-h are closely associated with the molting stage of insects. Thus, they are considered promising targets for the development of novel insecticides such as IGRs. Our previous work identified a dual-target compound 6j, which could act simultaneously on both EcR and OfChtI. In the present study, 6j was first found to have inhibitory activities against OfChtII and OfChi-h, too. Subsequently, taking 6j as a lead compound, 19 novel acetamido derivatives were rationally designed and synthesized by introducing an acetamido moiety into the amide bridge based on the flexibility of the binding cavities of 6j with EcR and three chitinases. Then, their insecticidal activities against Plutella xylostella (P. xylostella), Ostrinia furnacalis (O. furnacalis), and Spodoptera frugiperda (S. frugiperda) were carried out. The bioassay results revealed that most of these acetamido derivatives possessed moderate to good larvicidal activities against three lepidopteran pests. Especially, compound I-17 displayed excellent insecticidal activities against P. xylostella (LC50, 93.32 mg/L), O. furnacalis (LC50, 114.79 mg/L), and S. frugiperda (86.1% mortality at 500 mg/L), significantly better than that of 6j. In addition, further protein validation and molecular docking demonstrated that I-17 could act simultaneously on EcR (17.7% binding activity at 8 mg/L), OfChtI (69.2% inhibitory rate at 50 µM), OfChtII (71.5% inhibitory rate at 50 µM), and OfChi-h (73.9% inhibitory rate at 50 µM), indicating that I-17 is a potential lead candidate for novel multitarget IGRs. This work provides a promising starting point for the development of novel types of IGRs as pest management agents.

Pcgf5: An important regulatory factor in early embryonic neural induction.

Polycomb group RING finger (PCGF) proteins, a crucial subunits of the Polycomb complex, plays an important role in regulating gene expression, embryonic development, and cell fate determination. In our research, we investigated Pcgf5, one of the six PCGF homologs, and its impact on the differentiation of P19 cells into neural stem cells. Our findings revealed that knockdown of Pcgf5 resulted in a significant decrease in the expression levels of the neuronal markers Sox2, Zfp521, and Pax6, while the expression levels of the pluripotent markers Oct4 and Nanog increased. Conversely, Pcgf5 overexpression upregulated the expression of Sox2 and Pax6, while downregulating the expression of Oct4 and Nanog. Additionally, our analysis revealed that Pcgf5 suppresses Wnt3 expression via the activation of Notch1/Hes1, and ultimately governs the differentiation fate of neural stem cells. To further validate our findings, we conducted in vivo experiments in zebrafish. We found that knockdown of pcgf5a using morpholino resulted in the downregulated expression of neurodevelopmental genes such as sox2, sox3, and foxg1 in zebrafish embryos. Consequently, these changes led to neurodevelopmental defects. In conclusion, our study highlights the important role of Pcgf5 in neural induction and the determination of neural cell fate.

AtERF13 and AtERF6 double knockout fine-tunes growth and the transcriptome to promote cadmium tolerance in Arabidopsis.

The toxic heavy metal cadmium (Cd) restricts plant growth. However, how plants fine-tune their growth to modulate Cd resistance has not been determined. Ethylene response factors (ERFs) are key regulators of Cd stress, and Arabidopsis thaliana ERF13 and ERF6 (AtERF13 and AtERF6) negatively regulate growth. We previously demonstrated that AtERF13 is a transcriptional activator that binds a Cd-responsive element. Herein, we report that Arabidopsis plants improve Cd tolerance by repressing AtERF13 and AtERF6. We found that AtERF13 and AtERF6 were strongly downregulated by Cd stress and that AtERF6 weakly bound Cd-responsive elements. Moreover, AtERF13 physically interacted with AtERF6. Importantly, AtERF13 and AtERF6 double knockout mutants, but not single mutants or overexpression lines, grew better, tolerated more Cd and had higher Cd contents than did the wild type. Comparative transcriptome analysis revealed that the double mutants regulate the defense response to cope with Cd toxicity. Accordingly, we propose that, upon Cd stress, Arabidopsis plants repress AtERF13 and AtERF6 to relieve their growth inhibition effects and adjust the transcriptome to adapt to Cd stress, leading to increased Cd tolerance. Our findings thereby provide deep mechanical insights into how dual-function transcription factors fine-tune growth and the transcriptome to promote Cd tolerance in plants.

Effects of the adjunctive therapy of Sun's abdominal acupuncture on acute ischemic stroke and inflammatory factors: a randomized controlled trial. / å­™æ°è ¹é’ˆè¾ åŠ©æ²»ç–—æ€¥æ€§è„‘æ¢—æ­»åŠå¯¹ç‚Žæ€§å› å­çš„å½±å“ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To compare the clinical effect on acute ischemic stroke (AIS) between the combined treatment of Sun's abdominal acupuncture combined with the routine acupuncture and the simple routine acupuncture, and explore the influences on inflammatory factors i.e. interleukin (IL)-1ß and IL-10. METHODS: Eighty patients with AIS were randomly divided into an observation group (40 cases, 1 case dropped out) and a control group (40 cases, 1 case dropped out). The routine regimens of western medicine were administered in the two groups. In addition, the routine scalp acupuncture and the body acupuncture were used in the patients of the control group. The scalp acupuncture stimulation region and acupoints included the anterior parietal-temporal oblique line, Hegu (LI 4), Chize (LU 5), Shousanli (LI 10), etc. of affected side. In the observation group, on the base of the intervention of the control group, electroacupuncture was applied to "fouth abdominal area" of Sun's abdominal acupuncture, with the continuous wave and the frequency of 5 Hz. In the two groups, the intervention was given twice per day, once in every morning and afternoon separately, with the needles retained for 40 min in each intervention. The interventions were delivered for 6 days a week, lasting 3 weeks. The scores of Fugl-Meyer assessment scale (FMA), Berg balance scale (BBS) and the modified Barthel index (MBI), and the levels of IL-1ß and IL-10 in the serum were observed before and after treatment in the two groups; the effect and safety of interventions were compared between the two groups. RESULTS: After treatment, the scores of FMA, BBS and MBI increased in comparison with those before treatment in the two groups (P<0.01), and these scores in the observation group were higher than those in the control group (P<0.05, P<0.01). After treatment, in the two groups, the levels of IL-1ß in the serum were reduced in comparison with those before treatment (P<0.01), and the IL-1ß level in the observation group was lower than that in the control group (P<0.05); the levels of IL-10 in the serum were elevated in comparison with those before treatment in the two groups (P<0.01) and the IL-10 level in the observation group was higher than that in the control group (P<0.05). The total effective rate was 92.3% (36/39) in the observation group, which was superior to that in the control group (84.6% [33/39], P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). CONCLUSIONS: Sun's abdominal acupuncture combined with the routine acupuncture can ameliorate the motor impairment, adjust the balance dysfunction and improve the activities of daily living in the patients with AIS. The therapeutic effect of this combined regimen is better than that of the routine acupuncture, which may be associated with the regulation of the inflammatory factors after cerebral infarction.

Effect of early serum phosphate disorder on in-hospital and 28-day mortality in sepsis patients: a retrospective study based on MIMIC-IV database.

BACKGROUND: This study aims to assess the influence of early serum phosphate fluctuation on the short-term prognosis of sepsis patients. METHODS: This retrospective study used the Medical Information Mart for Intensive Care IV database to analyze serum phosphate levels in sepsis patients within 3 days of ICU admission. According to the absolute value of delta serum phosphate (the maximum value minus the minimum value of serum phosphorus measured within three days), the patients were divided into four groups, 0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl. Meanwhile, the direction of delta serum phosphate was compared. With the serum phosphate change group of 0-1.3 mg/dl as the reference group, the relationship between delta serum phosphate and in-hospital mortality and 28-day mortality was analyzed by multivariate Logistics regression analysis. RESULTS: The study involved 1375 sepsis patients. Serum phosphate changes (0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl) correlated with in-hospital and 28-day mortality variations (p = 0.005, p = 0.008). Much higher serum phosphate fluctuation elevated in-hospital and 28-day mortality. Compared to the 0-1.3 mg/dl change group, adjusted odds ratios (OR) in other groups for in-hospital mortality were 1.25 (0.86-1.81), 1.28 (0.88-1.86), and 1.63 (1.10-2.43), and for 28-day mortality were 1.21 (0.86-1.72), 1.10 (0.77-1.57), and 1.49 (1.03-2.19). Under the trend of increasing serum phosphate, the ORs of in-hospital mortality and 28-day mortality in ≥ 3.2 mg/dl group were 2.52 and 2.01, respectively. CONCLUSION: In conclude, the delta serum phosphate ≥ 3.2 mg/dl was associated with in-hospital mortality and 28-day mortality in patients with sepsis.

Pd-CeO2 catalyst facilely derived from one-pot generated Pd@Ce-BTC for low temperature CO oxidation.

Due to the capacity to offer abundant catalytic sites within porous solids featuring high surface areas, metal-organic frameworks (MOFs) and their derivatives have garnered considerable attention as prospective catalysts in environmental catalysis. To promote the industrial application of MOFs, there is an urgent need for an effective and environmental-friendly preparation approach. Breaking through the limitation of the traditional two-step preparation method that Pd was introduced to the already prepared Ce-BTC (Pd/Ce-BTC, BTC = 1, 3, 5 benzenetricarboxylate), in this work, we present a novel one-pot solvothermal method for synthesizing the Pd material supported by Ce-BTC (Pd@Ce-BTC). After pyrolysis in N2 flow or air flow, Pd-CeO2 catalysts derived from Pd@Ce-BTC exhibited much higher CO oxidation activity than those from Pd/Ce-BTC. Moreover, Pd/Ce-BTC and Pd@Ce-BTC pyrolyzed in N2 flow (Pd/Ce-BTC-N and Pd@Ce-BTC-N) could better catalyze the oxidation of CO than Pd/Ce-BTC and Pd@Ce-BTC pyrolyzed in air flow (Pd/Ce-BTC-A and Pd@Ce-BTC-A). Further characterizations revealed that the abundant surface Ce3+ species, rich surface adsorbed oxygen species and superior redox properties were the main reasons for the superior CO oxidation activity of Pd@Ce-BTC-N.

Gut microbiota composition and changes in patients with sepsis: potential markers for predicting survival.

BACKGROUND: Sepsis can cause immune dysregulation and multiple organ failure in patients and eventually lead to death. The gut microbiota has demonstrated its precise therapeutic potential in the treatment of various diseases. This study aimed to discuss the structural changes of the gut microbiota in patients with sepsis and to analyze the differences in the gut microbiota of patients with different prognoses. METHODS: We conducted a multicenter study in which rectal swab specimens were collected on the first and third days of sepsis diagnosis. A total of 70 specimens were collected, and gut microbiota information was obtained by 16S rRNA analysis. RESULTS: The relative abundance of Enterococcus decreased in rectal swab specimens during the first three days of diagnosis in patients with sepsis, while the relative abundance of inflammation-associated Bacillus species such as Escherichia coli, Enterobacteriaceae, and Bacteroidetes increased. By comparing the differences in the flora of the survival group and the death group, we found that the abundance of Veillonella and Ruminococcus in the death group showed an increasing trend (p < 0.05), while the abundance of Prevotella_6 and Prevotella_sp_S4_BM14 was increased in surviving patients (p < 0.05). CONCLUSIONS: The Firmicutes/Bacteroidetes ratio, reflecting overall gut microbial composition, was significantly lower on day three of sepsis diagnosis. Changes in the abundance of specific gut microbiota may serve as prognostic markers in patients with sepsis.

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

Gestational exposure to 1-NP induces ferroptosis in placental trophoblasts via CYP1B1/ERK signaling pathway leading to fetal growth restriction.

Fetal growth restriction (FGR) is a prevalent complication in obstetrics, yet its exact aetiology remains unknown. Numerous studies suggest that the degradation of the living environment is a significant risk factor for FGR. 1-Nitropyrene (1-NP) is a widespread environmental pollutant as a representative substance of nitro-polycyclic aromatic hydrocarbons. In this study, we revealed that 1-NP induced FGR in fetal mice by constructing 1-NP exposed pregnant mice models. Intriguingly, we found that placental trophoblasts of 1-NP exposed mice exhibited significant ferroptosis, which was similarly detected in placental trophoblasts from human FGR patients. In this regard, we established a 1-NP exposed cell model in vitro using two human trophoblast cell lines, HTR8/SVneo and JEG-3. We found that 1-NP not only impaired the proliferation, migration, invasion and angiogenesis of trophoblasts, but also induced severe cellular ferroptosis. Meanwhile, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued 1-NP-induced trophoblast biological function impairment. Mechanistically, we revealed that 1-NP regulated ferroptosis by activating the ERK signaling pathway. Moreover, we innovatively revealed that CYP1B1 was essential for the activation of ERK signaling pathway induced by 1-NP. Overall, our study innovatively identified ferroptosis as a significant contributor to 1-NP induced trophoblastic functional impairment leading to FGR and clarified the specific mechanism by which 1-NP induced ferroptosis via the CYP1B1/ERK signaling pathway. Our study provided novel insights into the aetiology of FGR and revealed new mechanisms of reproductive toxicity of environmental pollutants.

Causal relationship between gut Prevotellaceae and risk of sepsis: a two-sample Mendelian randomization and clinical retrospective study in the framework of predictive, preventive, and personalized medicine.

Objective: Gut microbiota is closely related to sepsis. Recent studies have suggested that Prevotellaceae could be associated with intestinal inflammation; however, the causal relationship between Prevotellaceae and sepsis remains uncertain. From the perspective of predictive, preventive, and personalized medicine (PPPM), exploring the causal relationship between gut Prevotellaceae and sepsis could provide opportunity for targeted prevention and personalized treatment. Methods: The genome-wide association study (GWAS) summary-level data of Prevotellaceae (N = 7738) and sepsis were obtained from the Dutch Microbiome Project and the UK Biobank (sepsis, 1380 cases; 429,985 controls). MR analysis was conducted to estimate the associations between Prevotellaceae and sepsis risk. The 16S rRNA sequencing analysis was conducted to calculate the relative abundance of Prevotellaceae in sepsis patients to explore the relationship between Prevotellaceae relative abundance and the 28-day mortality. Results: Genetic liability to f__Prevotellaceae (OR, 1.91; CI, 1.35-2.71; p = 0.0003) was associated with a high risk of sepsis with inverse-variance weighted (IVW). The median Prevotellaceae relative abundance in non-survivors was significantly higher than in survivors (2.34% vs 0.17%, p < 0.001). Multivariate analysis confirmed that Prevotellaceae relative abundance (OR, 1.10; CI, 1.03-1.22; p = 0.027) was an independent factor of 28-day mortality in sepsis patients. ROC curve analysis indicated that Prevotellaceae relative abundance (AUC: 0.787, 95% CI: 0.671-0.902, p = 0.0003) could predict the prognosis of sepsis patients. Conclusion: Our results revealed that Prevotellaceae was causally associated with sepsis and affected the prognosis of sepsis patients. These findings may provide insights to clinicians on developing improved sepsis PPPM strategies. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00340-6.

Kinetics of ester-105 degradation by La/TiO2 photocatalysis.

Lanthanum-doped titanium (La/TiO2) nano-photocatalysts were prepared using the sol-gel method and characterized by X-ray diffraction (XRD), zeta potential, and low-temperature nitrogen adsorption analyses. Ester-105, a flotation collector from beneficiation wastewater, was chosen as the target pollutant. The influence of the initial ester-105 concentration, pH, and photocatalyst dosage on the photocatalytic degradation of ester-105 was investigated. To examine the kinetics of the adsorption and photocatalytic degradation of ester-105, a Langmuir adsorption model and Langmuir-Hinshelwood kinetic models were established and discussed. The synthesized photocatalyst comprised anatase-phase TiO2, with an isoelectric point of pH = 6.5, specific surface area of 56.1626 m2·g-1, and average pore size of 7.78 nm. The maximum adsorption and the adsorption equilibrium constant of La/TiO2 for ester-105 were determined as 0.338 mg·g-1 and 1.008 L·mg-1, respectively. The first-order kinetic reaction rate constant (k) exhibited a linear relationship with the initial ester-105 concentration. The optimal pH for ester degradation was theoretically determined to be 6.95, and the optimum photocatalyst dosage was found to be 0.2739 g·L-1. Experiments confirmed that the photocatalytic degradation of ester-105 using La/TiO2 followed the Langmuir-Hinshelwood kinetics model, thereby providing a theoretical foundation for the photocatalytic degradation of ester-105 for industrial application.

[Component identification and analysis in vivo of Sanhan Huashi formula].

Sanhan Huashi formula(SHF) is the intermediate of a newly approved traditional Chinese medicine(TCM) Sanhan Huashi Granules for the treatment of COVID-19 infection. The chemical composition of SHF is complex since it contains 20 single herbal medicines. In this study, UHPLC-Orbitrap Exploris 240 was used to identify the chemical components in SHF and in rat plasma, lung and feces after oral administration of SHF, and heat map was plotted for characterizing the distribution of the chemical components. Chromatographic separation was conducted on a Waters ACQUITY UPLC BEH C_(18)(2.1 mm×100 mm, 1.7 µm) using 0.1% formic acid(A)-acetonitrile(B) as mobile phases in a gradient elution. Electrospray ionization(ESI) source was used to acquire data in positive and negative mode. By reference to quasi-molecular ions and MS/MS fragment ions and in combination with MS spectra of reference substances and compound information in literature reports, 80 components were identified in SHF, including 14 flavonoids, 13 coumarins, 5 lignans, 12 amino-compounds, 6 terpenes and 30 other compounds; 40 chemical components were identified in rat plasma, 27 in lung and 56 in feces. Component identification and characterization of SHF in vitro and in vivo lay foundations for disclosure of its pharmacodynamic substances and elucidation of the scientific connotation.