Remnant cholesterol and risk of major adverse cardiovascular events: a systematic review and dose-response meta-analysis of cohort studies.

Emerging evidence indicates a significant role of remnant cholesterol in contributing to the residual risk associated with major adverse cardiovascular events (MACE). This study aims to evaluate the dose-response relationship between remnant cholesterol and the risk of MACE. PubMed, Embase and Cochrane databases were reviewed to identify cohort studies published in English up to 1 August 2023. Twenty-eight articles were selected. Pooled hazard ratios (HR) and their 95% confidence intervals (CIs) were calculated using fixed or random-effects models to evaluate the association between remnant cholesterol and the risk of MACE. The dose-response relationship between remnant cholesterol levels and the risk of MACE was analyzed using the linear model and restricted cubic spline regression models. For calculated remnant cholesterol levels, the pooled HR (95% CI) of MACE for per 1-SD increase was 1.13 (1.08, 1.17); HR (95% CI) for the second quartile (Q2), the third quartile (Q3) and the highest quartile (Q4) of remnant cholesterol levels were 1.14 (1.03, 1.25), 1.43 (1.23, 1.68) and 1.68 (1.44, 1.97), respectively, compared with the lowest quartile (Q1). For measured remnant cholesterol levels, the pooled HR (95% CI) of MACE per 1-SD increase was 1.67 (1.39, 2.01). The dose-response meta-analysis showed a dose-response relationship between remnant cholesterol levels and the risk of MACE, both on a linear trend (P < 0.0001) and a nonlinear trend (P < 0.0001). The risk of MACE is associated with increased levels of remnant cholesterol, and the dose-response relationship between remnant cholesterol levels and the risk of MACE showed both linear and nonlinear trends.

Agrobacterium-Mediated Transformation of the Dwarf Soybean MiniMax.

This study aims to establish an Agrobacterium-mediated transformation system for use with the 'MiniMax'soybean cultivar. MiniMax is a mutant soybean whose growth cycle is around 90 days, half that of most other soybean varieties, making it an optimal model cultivar to test genes of interest before investing in modification of elite lines. We describe an efficient protocol for Agrobacterium-mediated transformation using MiniMax seeds. It uses a modified 'half seed' regeneration protocol for transgenic soybean production, utilizing the rapid generation MiniMax variety to obtain T1 seeds in approximately 145 days. Addition of phloroglucinol (PG) to the regeneration protocol was key to obtaining high-efficiency rooting of the regenerated shoots. Transfer to soil was accomplished using an organic soil amendment containing nutrients and mycorrhiza for plants to thrive in the greenhouse. This combination of genotype and stimulants provides a transformation protocol to genetically engineer MiniMax seeds with a transgenic lab-to-greenhouse production efficiency of 4.0%. This is the first report of MiniMax soybean whole plant transformation and heritable T1 transmission. This protocol provides an ideal resource for enhancing the genetic transformation of any soybean cultivar.

Differentiation of Type 17 Mucosal-Associated Invariant T Cells in Circulation Contributes to the Severity of Sepsis.

Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and RAR-related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase-LDHA signaling was required for RAR-related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase-LDHA signaling as a driving force in MAIT17 responses.

Application of machine learning to analyze ozone sensitivity to influencing factors: A case study in Nanjing, China.

Ground-level ozone (O3) has been an emerging concern in China. Due to its complicated formation mechanisms, understanding the effects of influencing factors is critical for making effective efforts on the pollution control. This study aims to present and demonstrate the practicality of a data-driven technique that applies a machine learning (ML) model coupled with the SHapley Additive exPlanations (SHAP) approach in O3 simulation and sensitivity analysis. Based on hourly measured concentrations of O3 and its major precursors, as well as meteorological factors in a northern area of Nanjing, China, a Light Gradient Boosting Machine (LightGBM) model was established to simulate O3 concentrations in different seasons, and the SHAP approach was applied to conduct in-depth analysis on the impacts of influencing factors on O3 formation. The results indicated a reliable performance of the ML model in simulating O3 concentrations, with the coefficient of determination (R2) between the measured and simulated larger than 0.80, and the impacts of influencing factors were reasonably evaluated by the SHAP approach on both seasonal and diurnal time scales. It was found that although volatile organic compounds (VOCs) and nitrogen oxides (NOx), as well as temperature and relative humidity, were generally the main influencing factors, their sensitivities to O3 formation varied significantly in different seasons and with time of the day. This study suggests that the data-driven ML model is a practicable technique and may act as an alternative way to perform mechanism analysis to some extent, and has immense potential to be applied in both problem research and decision-making for air pollution control.

Therapeutic potential of natural flavonoids in pulmonary arterial hypertension: A review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease caused by pulmonary vascular remodeling, with a high incidence and mortality. At present, many clinical drugs for treating PAH mainly exert effects by relaxing the pulmonary artery, with limited therapeutic effects, so the search for viable therapeutic agents continues uninterrupted. In recent years, natural flavonoids have shown promising potential in the treatment of cardiovascular diseases. It is necessary to comprehensively elucidate the potential of natural flavonoids to combat PAH. PURPOSE: To evaluate the potential of natural flavonoids to hinder or slow down the occurrence and development of PAH, and to identify promising drug discovery candidates. METHODS: Literature was collected from PubMed, Science Direct, Web of science, CNKI databases and Google scholar. The search terms used included "pulmonary arterial hypertension", "pulmonary hypertension", "natural products", "natural flavonoids", "traditional chinese medicine", etc., and several combinations of these keywords. RESULTS: The resources, structural characteristics, mechanisms, potential and prospect strategies of natural flavonoids for treating PAH were summarized. Natural flavonoids offer different solutions as possible treatments for PAH. These mechanisms may involve various pathways and molecular targets related to the pathogenesis of PAH, such as inflammation, oxidative stress, vascular remodeling, genetic, ion channels, cell proliferation and autophagy. In addition, prospect strategies of natural flavonoids for anti-PAH including structural modification and nanomaterial delivery systems have been explored. This review suggests that the potential of natural flavonoids as alternative therapeutic agents in the prevention and treatment of PAH holds promise for future research and clinical applications. CONCLUSION: Despite displaying the enormous potential of flavonoids in PAH, some limitations need to be further explored. Firstly, using advanced drug discovery tools, including computer-aided design and high-throughput screening, to further investigate the safety, biological activity, and precise mechanism of action of flavonoids. Secondly, exploring the structural modifications of these compounds is expected to optimize their efficacy. Lastly, it is necessary to conduct well controlled clinical trials and a comprehensive evaluation of potential side effects to determine their effectiveness and safety.

Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.

Lactate is a glycolysis end product, and its levels are markedly associated with disease severity, morbidity, and mortality in sepsis. It modulates key functions of immune cells, including macrophages. In this investigation, transcriptomic analysis was performed using lactic acid, sodium lactate, and hydrochloric acid-stimulated mouse bone marrow-derived macrophages (iBMDM), respectively, to identify lactate-associated signaling pathways. After 24 h of stimulation, 896 differentially expressed genes (DEG) indicated were up-regulation, whereas 792 were down-regulated in the lactic acid group, in the sodium lactate group, 128 DEG were up-regulated, and 41 were down-regulated, and in the hydrochloric acid group, 499 DEG were up-regulated, and 285 were down-regulated. Subsequently, clinical samples were used to further verify the eight genes with significant differences, among which Tssk6, Ypel4, Elovl3, Trp53inp1, and Cfp were differentially expressed in patients with high lactic acid, indicating their possible involvement in lactic acid-induced inflammation and various physiological diseases caused by sepsis. However, elongation of very long chain fatty acids protein 3 (Elovl3) was negatively correlated with lactic acid content in patients. The results of this study provide a necessary reference for better understanding the transcriptomic changes caused by lactic acid and explain the potential role of high lactic acid in the regulation of macrophages in sepsis.

The relationship between autistic traits and the stress of social isolation: Development of an explanatory model.

Background: Social isolation can be particularly challenging for individuals with high autistic traits who struggle with social interactions. The COVID-19 pandemic led to increased isolation, exacerbating stress for those who may have difficulty in connecting with others. This study aimed to explore the relationship between autistic traits and stress associated with social isolation. Methods: A sample of 1597 Chinese adults completed measures of autistic traits, the stress of social isolation, psychological inflexibility and core self-evaluation, during an epidemic prevention and control period of COVID-19 in Chongqing, China. Measures included the Autism-Spectrum Quotient, Coronavirus Stress Measure, Acceptance and Action Questionnaire-II, and Core Self-Evaluation Scale. Results: Autistic traits were positively correlated with the stress of social isolation, which was mediated by the chain effect of core self-evaluation and psychological inflexibility. individuals with high autistic traits reported significantly higher stress than individuals with low autistic traits. Limitations: This was a cross-sectional study, which limits causal inference. In addition, data were self-reported, which may cause methodological effects. Finally, this study was conducted during China's quarantine policy and external validation of the findings is required. Conclusions: Autistic traits are positively associated with the stress of social isolation. Autistic traits affected core self-evaluation first, and psychological inflexibility subsequently, leading to the stress of social isolation. individuals with high autistic traits tended to experience higher levels of stress during pandemic quarantines. The findings provide useful evidence for developing interventions and implementing preventive measures to reduce stress in individuals with high autistic traits and autism spectrum disorder.

Ethane/Ethylene Separations in Flexible Diamondoid Coordination Networks via an Ethane-Induced Gate-Opening Mechanism.

Separating ethane (C2H6) from ethylene (C2H4) is an essential and energy-intensive process in the chemical industry. Here, we report two flexible diamondoid coordination networks, X-dia-1-Ni and X-dia-1-Ni0.89Co0.11, that exhibit gate-opening between narrow-pore (NP) and large-pore (LP) phases for C2H6, but not for C2H4. X-dia-1-Ni0.89Co0.11 thereby exhibited a type F-IV isotherm at 273 K with no C2H6 uptake and a high uptake (111 cm3 g-1, 1 atm) for the NP and LP phases, respectively. Conversely, the LP phase exhibited a low uptake of C2H4 (12.2 cm3 g-1). This C2H6/C2H4 uptake ratio of 9.1 for X-dia-1-Ni0.89Co0.11 far surpassed those of previously reported physisorbents, many of which are C2H4-selective. In situ variable-pressure X-ray diffraction and modeling studies provided insight into the abrupt C2H6-induced structural NP to LP transformation. The promise of pure gas isotherms and, more generally, flexible coordination networks for gas separations was validated by dynamic breakthrough studies, which afforded high-purity (99.9%) C2H4 in one step.

Semisupervised 3D segmentation of pancreatic tumors in positron emission tomography/computed tomography images using a mutual information minimization and cross-fusion strategy.

Background: Accurate segmentation of pancreatic cancer tumors using positron emission tomography/computed tomography (PET/CT) multimodal images is crucial for clinical diagnosis and prognosis evaluation. However, deep learning methods for automated medical image segmentation require a substantial amount of manually labeled data, making it time-consuming and labor-intensive. Moreover, addition or simple stitching of multimodal images leads to redundant information, failing to fully exploit the complementary information of multimodal images. Therefore, we developed a semisupervised multimodal network that leverages limited labeled samples and introduces a cross-fusion and mutual information minimization (MIM) strategy for PET/CT 3D segmentation of pancreatic tumors. Methods: Our approach combined a cross multimodal fusion (CMF) module with a cross-attention mechanism. The complementary multimodal features were fused to form a multifeature set to enhance the effectiveness of feature extraction while preserving specific features of each modal image. In addition, we designed an MIM module to mitigate redundant high-level modal information and compute the latent loss of PET and CT. Finally, our method employed the uncertainty-aware mean teacher semi-supervised framework to segment regions of interest from PET/CT images using a small amount of labeled data and a large amount of unlabeled data. Results: We evaluated our combined MIM and CMF semisupervised segmentation network (MIM-CMFNet) on a private dataset of pancreatic cancer, yielding an average Dice coefficient of 73.14%, an average Jaccard index score of 60.56%, and an average 95% Hausdorff distance (95HD) of 6.30 mm. In addition, to verify the broad applicability of our method, we used a public dataset of head and neck cancer, yielding an average Dice coefficient of 68.71%, an average Jaccard index score of 57.72%, and an average 95HD of 7.88 mm. Conclusions: The experimental results demonstrate the superiority of our MIM-CMFNet over existing semisupervised techniques. Our approach can achieve a performance similar to that of fully supervised segmentation methods while significantly reducing the data annotation cost by 80%, suggesting it is highly practicable for clinical application.

Activation and functional modification of mucosal-associated invariant T cells in patients with intracranial infection following craniotomy.

Intracranial infections are among the most common complications of neurosurgery, with their incidence remaining high despite advancements in current neurosurgical techniques and aseptic technology. While the role of mucosal-associated invariant T (MAIT) cells, a subset of innate-like T lymphocytes, in bacterial defense is well-established, their involvement in intracranial infections remains unclear. In this study, we utilized flow cytometry to assess the phenotype and function of circulating and CSF MAIT cells. Our findings revealed that MAIT cells were higher in the CSF compared to blood. Notably, a higher percentage of IL-17A + MAIT cells was detected in the CSF of patients with intracranial infections. Moreover, markers indicating activation and exhaustion were significantly upregulated in CSF MAIT cells. Furthermore, elevated levels of pro-inflammatory cytokines, including IL-1ß, IL-12, and IL-18, were detected in the CSF supernatants. We hypothesized that the elevated levels of IL-1ß, IL-12, and IL-18 in the inflammatory milieu synergistically activate MAIT cells in the CSF. In particular, CD25 and Tim-3 expression of MAIT cells was increased by stimulation with IL-1ß, IL-12, and IL-18 or CSF supernatants of intracranial infection patients. Collectively, these findings provide important information underlying the innate immune response of patients with intracranial infections.

A 6-Year Follow-up of a Chinese Child with Homozygous ß0-Thalaasemia and a Heterozygous KLF1 Mutation.

Patients with the genotype of ß0/ß0 for ß-thalassemia (ß-thal) usually behave as ß-thal major (ß-TM) phenotype which is transfusion-dependent. The pathophysiology of ß-thal is the imbalance between α/ß-globin chains. The degree of α/ß-globin imbalance can be reduced by the more effective synthesis of γ-globin chains, and increased Hb F levels, modifying clinical severity of ß-TM. We report a Chinese child who had homozygous ß0-thal and a heterozygous KLF1 mutation. The patient had a moderate anemia since 6 months old, keeping a baseline Hb value of 8.0-9.0 g/dL. She had normal development except for a short stature (3rd percentile) until 6 years old, when splenomegaly and facial bone deformities occurred. Although genetic alteration of KLF1 expression in ß0/ß0 patients can result in some degree of disease alleviation, our case shows that it is insufficient to ameliorate satisfactorily the presentation. This point should be borne in mind for physicians who provide the genetic counseling and prenatal diagnosis to at-risk families.

Insight into the Gas-Induced Phase Transformations in a 2D Switching Coordination Network via Coincident Gas Sorption and In Situ PXRD.

Switching coordination networks (CNs) that reversibly transform between narrow or closed pore (cp) and large pore (lp) phases, though fewer than their rigid counterparts, offer opportunities for sorption-related applications. However, their structural transformations and switching mechanisms remain underexplored at the molecular level. In this study, we conducted a systematic investigation into a 2D switching CN, [Ni(bpy)2(NCS)2]n, sql-1-Ni-NCS (1 = bpy = 4,4'-bipyridine), using coincident gas sorption and in situ powder X-ray diffraction (PXRD) under low-temperature conditions. Gas adsorption measurements revealed that C2H4 (169 K) and C2H6 (185 K) exhibited single-step type F-IVs sorption isotherms with sorption uptakes of around 180-185 cm3 g-1, equivalent to four sorbate molecules per formula unit. Furthermore, parallel in situ PXRD experiments provided insight into sorbate-dependent phase switching during the sorption process. Specifically, CO2 sorption induced single-step phase switching (path I) solely between cp and lp phases consistent with the observed single-step type F-IVs sorption isotherm. By contrast, intermediate pore (ip) phases emerged during C2H4 and C2H6 desorption as well as C3H6 adsorption, although they remained undetectable in the sorption isotherms. To our knowledge, such a cp-lp-ip-cp transformation (path II) induced by C2H4/6 and accompanied by single-step type F-IVs sorption isotherms represents a novel type of phase transition mechanism in switching CNs. By virtue of Rietveld refinements and molecular simulations, we elucidated that the phase transformations are governed by cooperative local and global structural changes involving NCS- ligand reorientation, bpy ligand twist and rotation, cavity edge (Ni-bpy-Ni) deformation, and interlayer expansion and sliding.

Individual variability in neural representations of mind-wandering.

Mind-wandering is a frequent, daily mental activity, experienced in unique ways in each person. Yet neuroimaging evidence relating mind-wandering to brain activity, for example in the default mode network (DMN), has relied on population-rather than individual-based inferences due to limited within-individual sampling. Here, three densely-sampled individuals each reported hundreds of mind-wandering episodes while undergoing multi-session functional magnetic resonance imaging. We found reliable associations between mind-wandering and DMN activation when estimating brain networks within individuals using precision functional mapping. However, the timing of spontaneous DMN activity relative to subjective reports, and the networks beyond DMN that were activated and deactivated during mind-wandering, were distinct across individuals. Connectome-based predictive modeling further revealed idiosyncratic, whole-brain functional connectivity patterns that consistently predicted mind-wandering within individuals but did not fully generalize across individuals. Predictive models of mind-wandering and attention that were derived from larger-scale neuroimaging datasets largely failed when applied to densely-sampled individuals, further highlighting the need for personalized models. Our work offers novel evidence for both conserved and variable neural representations of self-reported mind-wandering in different individuals. The previously-unrecognized inter-individual variations reported here underscore the broader scientific value and potential clinical utility of idiographic approaches to brain-experience associations.

Multi-timescale variation characteristics of PM2.5 in different regions of China during 2014-2022.

Over the past decade, China has achieved a significant reduction in PM2.5 concentrations. Due to the diversity of natural and artificial factors, regional differences are remarkable in the variation characteristics and have not been well addressed in previous studies. Based on hourly observed PM2.5 concentrations from 2014 to 2022, this study conducted a comprehensive analysis of variation characteristics on annual, seasonal, and diurnal scales, with a special focus on differences across major regions. Driving factors of the variations, the effectiveness of air pollution control efforts as well as future priorities were discussed. The annual PM2.5 concentrations in all regions showed an overall downward trend from 2014 to 2022, but the decline rates differed notably across the regions, with the maximum value nearly two times higher than the minimum value. The seasonal decline rates also differ from region to region, which could be partially attributed to the burning of crop residues and dust events. Northeast China was significantly affected by the burning of crop residues and experienced a big drop in the number of fire points in autumn, but a remarkable increase in spring. The spring dust events may greatly contribute to PM2.5 concentrations in northern and western China. For diurnal variation, nighttime concentrations were generally greater than daytime concentrations, and the nighttime concentrations were likely to increase in eastern regions and decrease in western regions. Furthermore, the daytime and nighttime ratios (calculated by daytime/nighttime concentration divided by the daily-mean concentration) exhibited different interannual trends, with the daytime ratios decreasing and nighttime ratios increasing, especially in the northeastern and western regions. The findings indicate that the air pollution control efforts have been generally successful, but with large regional disparities, and highlight the importance of controlling crop residue burning, dust events, and nighttime emissions for specific seasons and regions.

Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1.

BACKGROUND: The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator. PATIENTS AND METHODS: We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored. RESULTS: A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB > = 16(TMB > = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB > = 16 and < 16 are 35.58, and 10.71 months respectively with average 12.39 months (p < 0.0001). The median months of PFS in the TMB > = 16 and < 16 are not-obtained, and 2.79 months respectively with an average of 3.32 months (p < 0.0001). The DCR in the TMB > = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB > = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001). CONCLUSION: The TMB > = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

Assessment of Nutritional Risk Scores (the Nutritional Risk Screening 2002 and Modified Nutrition Risk in Critically Ill Scores) as Predictors of Mortality in Critically Ill Patients on Extracorporeal Membrane Oxygenation.

Nutritional risk is associated with intensive care unit (ICU) stay and mortality, the Nutritional Risk Screening 2002 (NRS 2002) and the modified Nutritional Risk in the Critically Ill (mNUTRIC) score are assessment instruments and useful in predicting the risk regarding mortality in ICU patients. Our aim was to assess the effects of mNUTRIC and NRS 2002 on mortality in patients on extracorporeal membrane oxygenation (ECMO). A retrospective cohort study was performed and 78 patients were included for final analysis. In the current study, the NRS 2002 and the mNUTRIC score within 24 hours before starting ECMO were applied to assess patients' nutritional status on ECMO and explore the relationship between nutritional status and patient outcomes. This study suggests that both mNUTRIC and NRS 2002 scores were found to be significant independent risk and prognostic factors for in-hospital and 90 day morality among ECMO patients based on multivariable logistic regression analysis (p < 0.05), with those in the high-risk group having higher in-hospital and 90 day mortality rates than those identified as being at low risk (p < 0.001). In comparison to the NRS 2002 score, the mNUTRIC score demonstrated a superior prognostic ability in ECMO patients.

APTES-mediated Cu2(OH)3(NO3) nanomaterials on the surface of silicone catheters for abscess.

Metal-based nanomaterials have remarkable bactericidal effects; however, their toxicity cannot be disregarded. To address this concern, we developed a simple synthesis route for antibacterial catheters using metal-based nanomaterials to reduce toxicity while harnessing their excellent bactericidal properties. The grafting agent (3-aminopropyl)triethoxysilane (APTES) forms -NH2 groups on the catheter surface, onto which copper ions form a nanomaterial complex known as Cu2(OH)3(NO3) (defined as SA-Cu). The synthesized SA-Cu exhibited outstanding contact antibacterial effects, as observed through scanning electron microscopy (SEM), which revealed cell membrane crumbing and bacterial rupture on the catheter surface. Furthermore, SA-Cu exhibited excellent biosafety characteristics, as evidenced by the cell counting kit-8 (CCK-8) assay, which showed no significant cytotoxicity. SA-Cu demonstrated sustained antimicrobial capacity, with in vivo experiments demonstrating over 99% bactericidal efficacy against methicillin-resistant Staphylococcus aureus (MRSA) for two weeks. The transcriptome sequencing results suggested that SA-Cu may exert its bactericidal effects by interfering with histidine and purine metabolism in MRSA. This study presents a straightforward method for synthesizing antimicrobial silicone catheters containing copper nanomaterials using copper ions.

J24335 exerts neuroprotective effects against 6-hydroxydopamine-induced lesions in PC12 cells and mice.

Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions. Therefore, we investigated the mechanism of action and potential neuroprotective function of J24335 against 6-OHDA-induced neurotoxicity in mice, and in PC12 cell models. The key target of action of J24335 was also screened. MTT assay, LDH assay, flow cytometry, RT-PCR, LC-MS, OCR and ECAR detection, and Western Blot analysis were performed to characterize the neuroprotective effects of J24335 on PC12 cells and its potential mechanism. Behavioral tests and immunohistochemistry were used to evaluate behavioral changes and brain lesions in mice. Moreover, bioinformatics was employed to assess the drug-likeness of J24335 and screen its potential targets. J24335 attenuated the degradation of mitochondrial membrane potential and enhanced glucose metabolism and mitochondrial biosynthesis to ameliorate 6-OHDA-induced mitochondrial dysfunction. Animal behavioral tests demonstrated that J24335 markedly improved motor function and loss of TH-positive neurons and dopaminergic nerve fibers, and contributed to an increase in the levels of dopamine and its metabolites in brain tissue. The activation of both the CREB/PGC-1α/NRF-1/TFAM and PKA/Akt/GSK-3ß pathways was a major contributor to the neuroprotective effects of J24335. Furthermore, bioinformatics predictions revealed that J24335 is a low toxicity and highly BBB permeable compound targeting 8 key genes (SRC, EGFR, ERBB2, SYK, MAPK14, LYN, NTRK1 and PTPN1). Molecular docking suggested a strong and stable binding between J24335 and the 8 core targets. Taken together, our results indicated that J24335, as a multi-targeted neuroprotective agent with promising therapeutic potential for PD, could protect against 6-OHDA-induced neurotoxicity via two potential pathways in mice and PC12 cells.

Urchin-like Fe3O4@Bi2S3 Nanospheres Enable the Destruction of Biofilm and Efficiently Antibacterial Activities.

Biofilm-associated infections (BAIs) have been considered a major threat to public health, which induce persistent infections and serious complications. The poor penetration of antibacterial agents in biofilm significantly limits the efficiency of combating BAIs. Magnetic urchin-like core-shell nanospheres of Fe3O4@Bi2S3 were developed for physically destructing biofilm and inducing bacterial eradication via reactive oxygen species (ROS) generation and innate immunity regulation. The urchin-like magnetic nanospheres with sharp edges of Fe3O4@Bi2S3 exhibited propeller-like rotation to physically destroy biofilm under a rotating magnetic field (RMF). The mild magnetic hyperthermia improved the generation of ROS and enhanced bacterial eradication. Significantly, the urchin-like nanostructure and generated ROS could stimulate macrophage polarization toward the M1 phenotype, which could eradicate the persistent bacteria with a metabolic inactivity state through phagocytosis, thereby promoting the recovery of implant infection and inhibiting recurrence. Thus, the design of magnetic-driven sharp-shaped nanostructures of Fe3O4@Bi2S3 provided enormous potential in combating biofilm infections.

Regulatory effects of natural products on N6-methyladenosine modification: A novel therapeutic strategy for cancer.

N6-methyladenosine (m6A) is considered to be the most common and abundant epigenetics modification in messenger RNA (mRNA) and noncoding RNA. Abnormal modification of m6A is closely related to the occurrence, development, progression, and prognosis of cancer. m6A regulators have been identified as novel targets for anticancer drugs. Natural products, a rich source of traditional anticancer drugs, have been utilized for the development of m6A-targeting drugs. Here, we review the key role of m6A modification in cancer progression and explore the prospects and structural modification mechanisms of natural products as potential drugs targeting m6A modification for cancer treatment.