Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. METHODS: The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe-/-) and Apoe-/- DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe-/- mice to explore the effects on atherosclerosis. RESULTS: DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe-/- mice. CONCLUSIONS: Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Impact of geochemistry and microbes on the methylmercury production in mangrove sediments.

Unraveling the geochemical and microbial controls on methylmercury (MeHg) dynamics in mangrove sediments is important, as MeHg can potentially pose risks to marine biota and people that rely on these ecosystems. While the important role of sulfate-reducing bacteria in MeHg formation has been examined in this ecologically important habitat, the contribution of non-Hg methylating communities on MeHg production remains particularly unclear. Here, we collected sediment samples from 13 mangrove forests in south China and examined the geochemical parameters and microbial communities related to the Hg methylation. MeHg concentrations were significantly correlated to the OM-related parameters such as organic carbon content, total nitrogen, and dissolved organic carbon concentrations, suggesting the importance of OM in the MeHg production. Sulfate-reducing bacteria were the major Hg-methylators in mangrove sediments. Desulfobacteraceae and Desulfobulbaceae dominated the Hg-methylating microbes. Classification random forest analysis detected strong co-occurrence between Hg methylators and putative non-Hg methylators, thus suggesting that both types of microorganisms contribute to the MeHg dynamics in the sediments. Our study provides an overview of MeHg contamination in south China and advances our understanding of Hg methylation in mangrove ecosystems.

Lignan Intake and Type 2 Diabetes Incidence Among US Men and Women.

Importance: Lignans are phytoestrogens abundant in Western diets and may be associated with type 2 diabetes (T2D) risk. Objective: To prospectively investigate associations between lignan intake and T2D incidence. Design, Setting, and Participants: Population-based cohort study of US men and women enrolled in the Nurses' Health Study (NHS, 1984-2018), NHSII (1991-2019), and Health Professionals Follow-Up Study (HPFS, 1986-2020), as well as 496 participants from the Men's Lifestyle Validation Study (MLVS). Participants were free of T2D, cardiovascular disease, and cancer at baseline. Data were analyzed from November 2022 to July 2023. Exposures: Total and individual lignans were assessed using a validated food frequency questionnaire, which was updated every 2 to 4 years. In the MLVS, lignan intake was measured using 2 sets of 7-day diet records (7DDRs). Main Outcomes and Measures: Incident T2D cases were confirmed using American Diabetes Association diagnostic criteria. Cox proportional hazards models were used to assess multivariable-adjusted associations. Results: The current study included 201 111 participants (mean [SD] age, 44.7 [10.1] years; 161 169 female participants [80.2%]; 2614 African American participants [1.3%], 1609 Asian participants [0.8%], 2414 Hispanic and other race or ethnicity participants [1.2%], and 194 474 White participants [96.7%]) from the HPFS, NHS, and NHSII studies. The median (IQR) total lignan intake of the highest quintile ranged from 355.1 (330.2-396.9) µg/d in NHS to 459.9 (422.2-519.5) µg/d in HPFS at the median follow-up time. Over 5 068 689 person-years, 20 291 incident cases of T2D were identified. Higher lignan intake was inversely associated with T2D incidence, except for lariciresinol. The multivariable-adjusted pooled hazard ratios (HRs) for the highest vs lowest quintiles were 0.87 (95% CI, 0.83-0.91) for total lignans, 0.72 (95% CI, 0.69-0.76) for secoisolariciresinol, 0.92 (95% CI, 0.87-0.96) for pinoresinol, 0.93 (95% CI, 0.89-0.98) for matairesinol, and 0.99 (95% CI, 0.94-1.04) for lariciresinol. Secoisolariciresinol intake exhibited a significant inverse association with T2D risk among individuals with obesity (HR, 0.75 for body mass index [BMI] ≥30; 95% CI, 0.71-0.79 vs HR, 0.82 for BMI <25; 95% CI, 0.81-0.83; P < .001 for interaction) and premenopausal women (HR, 0.67 for premenopausal women; 95% CI, 0.65-0.69 vs HR, 0.82 for the past use of hormones; 95% CI, 0.76-0.88; P = .003 for interaction). Dietary lignan assessed with 7DDRs was associated with lower HbA1c levels (percentage change range from -0.92% to 1.50%), as well as lower C-reactive protein levels and better lipid profiles. Conclusions and Relevance: This cohort study found that long-term lignan consumption was associated with a lower T2D risk, particularly among individuals with obesity and premenopausal women.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries.

BACKGROUND: Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. METHODS: This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. FINDINGS: Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. INTERPRETATION: The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. FUNDING: The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

Chromosome-level genome assemblies of vulnerable male and female elongate loach (Leptobotia elongata).

Endemic to the upper and middle reaches of the Yangtze River in China, elongate loach (Leptobotia elongata) has become a vulnerable species mainly due to overfishing and habitat destruction. Thus far, no genome data of this species are reported. As a result, lacking of such genomic information has restricted practical conservation and utilization of this economic fish. Here, we constructed chromosome-level genome assemblies for both male and female elongate loach by integration of MGI, PacBio HiFi and Hi-C sequencing technologies. Two primary genome assemblies (586-Mb and 589-Mb) were obtained for female and male fishes, respectively. Indeed, 98.22% and 98.61% of the contig sequences were anchored onto 25 chromosomes, with identification of 26.22% and 25.92% repeat contents in both assembled genomes. Meanwhile, a total of 25,215 and 25,253 protein-coding genes were annotated, of which 97.41% and 98.8% could be predicted with functions. Taken together, our genome data presented here provide a valuable genomic resource for in-depth evolutionary and functional research, as well as molecular breeding and conservation of this economic fish species.

Investigating the impact of temporal instability in smart roadway retrofitting on terrain-related crash injury severity.

The advancement of intelligent road systems in developing countries poses unique challenges in identifying risk factors and implementing safety strategies. The variability of factors affecting crash injury severity leads to different risks across levels of roadway smartness, especially in hazardous terrains, complicating the adaptation of smart technologies. Therefore, this study investigates the temporal instability of factors affecting injury severities in crashes across various terrains, with a focus on the evolution of road smartness. Crash data from selected complex terrain regions in Shaanxi Province during smart road adaptation were used, and categorized into periods before, during, and after smart road implementations. A series of mixed logit models were employed to account for unobserved heterogeneity in mean and variance, and likelihood ratio tests were conducted to assess the spatio-temporal instability of model parameters across different topographic settings and smart processes. Moreover, a comparison between partially constrained and unconstrained temporal modeling approaches was made. The findings reveal significant differences in injury severity determinants across terrain conditions as roadway intelligence progressed. On the other hand, certain factors like pavement damage, truck and pedestrian involvement were identified that had relatively stable effects on crash injury severities. Out-of-sample predictions further emphasize the need for modeling across terrain and roadway development stages. These insights are crucial for developing tailored safety measures for smart road retrofitting in different terrain conditions, thereby supporting the transition towards smarter road systems in developing regions.

PD-L1 expression and tumor-infiltrating lymphocytes: Correlations and prognostic values in Chinese triple-negative breast cancer patients with different molecular subtyping.

OBJECTIVE: To investigate the correlation between programmed death ligand-1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) and evaluate the prognostic value of PD-L1 and TILs in Chinese triple-negative breast cancer (TNBC) patients with different molecular subtype METHODS: This retrospective study was conducted at 2020. Specifically, the pre-chemotherapy clinical data and non-stained tissue blocks of 465 TNBC patients visited the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014 were collected, with their blocks sliced and stained using PD-L1(SP142), and the outcome of subsequent chemotherapy obtained in 2020. The relapse-free survival (RFS) of the study population was calculated. The baseline PD-L1 expression status correlations with TILs and molecular subtypes were assessed using Spearman's rank correlation analysis and the Kruskal-Wallis test. Kaplan-Meier survival analyses were undertaken to evaluate the prognosis value of TILs and PD-L1 expression. RESULTS: PD-L1 expression status on IC was moderately and positively correlated with stromal tumor-infiltrating lymphocytes (sTILs) (rs = 0.502, P <0.001) and iTILs (rs = 0.410, P < 0.001), respectively. PD-L1 expression status and TILs showed significant differences among molecular subtypes (P < 0.001), with the highest proportion of PD-L1+ and high TILs patients observed in the immunomodulatory (IM) subtype. TILs were significantly associated with RFS. Moreover, sTILs could act as an independent predictor of RFS (RR 0.953, 95 % CI 0.920 ∼ 0.987, P = 0.007), while PD-L1 expression status did not show the same prognostic significance. CONCLUSIONS: The incorporation of pre-treatment TILs and PD-L1 expression status as valuable tools for optimizing patient selection for immunotherapy and managing the risks associated with chemotherapy in Chinese TNBC patients. DATA AVAILABILITY: The data sets generated and analyzed during the current study are available from the corresponding author.

Development of new dehydrocostuslactone derivatives for treatment of atopic dermatitis via inhibition of the NF-κB signaling pathway.

Atopic dermatitis (AD), a recurrent inflammatory systemic skin disease, is difficult to cure. In the present study, several ethylenediamine-derived dehydrocostuslactone (DHCL) derivatives were prepared to assess their in vitro and in vivo anti-inflammatory activities. The results indicated that DHCL derivatives inhibited NO generation with low cytotoxicity. In particular, compound 5d exhibited the best anti-inflammatory activity. Subsequent experiments revealed that 5d not only inhibited the LPS-induced inflammatory response in RAW264.7 cells via the MAPK-NF-κB signaling pathway inhibition but also significantly decreased Th2-type cytokine levels and inhibited the NF-κB signaling pathway activation in mice with MC903-induced AD. Therefore, DHCL derivatives may be considered as new agents for the treatment of AD.

Plant-based and planetary-health diets, environmental burden, and risk of mortality: a prospective cohort study of middle-aged and older adults in China.

BACKGROUND: Plant-based diets (PBDs) and planetary-health diets (PHDs) are recommended for their potential health and environmental benefits, but population-based evidence in diverse cultures is scarce. METHODS: We included 9364 adults aged 45 years and older (52·3% female, 47·7% male) from the open cohort of the China Health and Nutrition Survey. Dietary intake was assessed using 3-day 24 h dietary recalls combined with weighing methods from 1997 to 2011, and mortality was documented from 1997 to 2015. We calculated the overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI; ranges 18-90), and the PHD score (range 0-140). We also estimated the related greenhouse gas emissions, land appropriation, and total water footprint and examined their associations with mortality. FINDINGS: PBD indices were inversely related to greenhouse gas emissions, land appropriation, and total water footprint, whereas higher PHD score was related to higher environmental burdens (p<0·0001). During follow-up (mean 9·2 years), 792 (8·5%) death cases were documented. PDI (HR 1·08 [95% CI 0·88-1·32]) and hPDI (0·98 [0·80-1·21]) were not significantly associated with mortality, whereas higher uPDI was related to a higher mortality risk (1·55 [1·26-1·91]). In contrast, higher PHD score was associated with lower mortality risk (0·79 [0·63-0·99]). INTERPRETATION: The PBDs showed environmental benefits, but are not necessarily associated with lower mortality risk. The PHD, developed mainly in western populations, was related to lower mortality risk but higher environmental burdens in the Chinese population. FUNDING: Fundamental Research Funds for the Central Universities, Zhejiang University Global Partnership Fund, and National Natural Science Foundation of China.

MYBL2 is a Novel Independent Prognostic Biomarker and Correlated with TMB in pancreatic cancer.

Background: Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. Methods: The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. Results: The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. Conclusion: MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.

Novel identification of mixed infection of Lactococcus garvieae and Cryptocaryon irritans isolated from cultured Trachinotus ovatus in China.

Lactococcus garvieae has recently been identified and listed as one of the causative agents of hyperacute hemorrhagic sepsis in fish. In intensive recirculating aquaculture systems where there are high fish densities and minimal water changes, not only will it be conducive to the growth of bacteria, but Cryptocaryon irritans as a marine protozoan fish parasite is also prone to appear. This study reports the disease status of Trachinotus ovatus in an aquaculture area in Yangjiang City, Guangdong Province. Through the diagnosis of clinical symptoms of the diseased fish, identification of specific primers, 16s rRNA sequences phylogenetic tree analysis, physiological and biochemical identification, and observation of histopathological sections, the result of the experiment is that the mass death of T. ovatus is caused by a mixture of L. garvieae and C. irritants infections. Subsequently, regression infection experiments were performed to verify Koch's law. It was confirmed that the pathogen had strong virulence to T. ovatus. This is the first time that the co-infection of L. garvieae and C. irritans to T. ovatus was found in South China. The research results of this experiment have certain enlightenment significance for the epidemic trend of fish diseases in relevant sea areas.

B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity.

Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of ß-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

A thematic content analysis of the structure and effects of good doctor abilities in China.

BACKGROUND: The efforts to explore and build the structure of good doctor abilities are important because they help improve the quality of education for medical students and better standardize the working performance of doctors. However, at present, no worldwide standards for such a structure have been established. In this study, we endeavoured to map the structure of good doctor abilities and identify their effects. METHODS: With a focus on China, a thematic content analysis was adopted in this study to analyse the personal profiles of 50 widely recognized good doctors. NVivo11 software was used. RESULTS: The Structure and Effects of Good Doctor Abilities in China model was proposed, and interpretations were made based on AMO theory. Good doctor abilities fall within six categories: rigorous clinical thinking, skilled in diagnosis and therapy, clinical empathy, continuous learning and innovation, enhancing and sharing experiences, and communication and coordination. These abilities have positive impacts on doctors' work performances and social benefits by encouraging good behaviours, ultimately promoting the sustainable development of the hospitals where they serve. CONCLUSIONS: In this study, we established a model of the structure and effects of good-doctor abilities in China and interpreted its mechanism, innovation and theory diversification in "good-doctor" research. Moreover, this study has practical significance because it provides systematic and well-targeted criteria for improving the professionalism of doctors, promoting more good doctor behaviours, providing guidance for regulating doctors' conduct and providing a reference for medical education and working performance reviews worldwide.

P/N-Type Conversion of 2D MoTe2 Controlled by Top Gate Engineering for Logic Circuits.

Two-dimensional (2D) transition-metal dichalcogenides (TMDCs) are regarded as promising materials for next-generation logic circuits. Top gate field-effect transistors (FETs) have independent gate control ability and can be fabricated directly on TMDC materials without a transfer process. Therefore, it has the merits of device reliability and complementary metal-oxide semiconductor (CMOS) process compatibility, which are demanded in practical circuit-level integration. However, the fabrication of the top gate FET involves depositing an insulating dielectric layer and a gate electrode in sequence on the TMDC channel material, which may affect the device performance. Insightfully investigating the influences of different top-gate-deposition methods on the electrical properties of the TMDC channel and further harnessing these influences to realize a homogeneous CMOS device on an identical 2D TMDC platform are with practice significance. In this work, p/n-type controllable top gate FET arrays based on 2H-MoTe2 are fabricated by using different top-gate-deposition methods. The electron-beam evaporation (EBE) of top metal gate exhibits an obvious n-doping effect on the 2H-MoTe2 channel and converts it from p-type to n-type, whereas the thermal evaporation of top gate affects little to the channel. High-resolution transmission electron microscopy (HR-TEM) analysis reveals that the high-energy metal atoms from the EBE process can penetrate through the 30 nm gate dielectric layers (including 10 nm Al2O3 seeding layer), leading to multiple atomic defects in both MoTe2 and the interface between MoTe2 and Al2O3. Furthermore, by utilizing the top gate engineering, a large-scale double-top-gate MoTe2 homogeneous CMOS inverter array is fabricated. The CMOS inverters exhibit clear logic swing, negligible hysteresis, and high device yield (∼93%), indicating high device reliability and stability. Notably, the fabrication process is facile, free from transfer procedure, and compatible with traditional silicon technology. This work promotes the application of 2D TMDCs in nanoelectronics integration.

Disruption of BACH1 Protects AC16 Cardiomyocytes Against Hypoxia/Reoxygenation-Evoked Injury by Diminishing CDKN3 Transcription.

Reperfusion after myocardial infarction (MI) can lead to myocardial ischemia/reperfusion (I/R) damage. The transcription factor (TF) broad-complex, tramtrack, and bric-a-brac (BTB) and cap'n'collar (CNC) homology 1 (BACH1) is implicated in the injury. However, the downstream mechanisms of BACH1 in affecting myocardial hypoxia/reoxygenation (H/R) damage are still fully understood. AC16 cells were stimulated with H/R conditions to model cardiomyocytes under H/R. mRNA analysis was performed by quantitative real-time PCR. Protein levels were gauged by immunoblot analysis. The effect of BACH1/cyclin-dependent kinase inhibitor 3 (CDKN3) on H/R-evoked injury was assessed by measuring cell viability via Cell Counting Kit-8 (CCK-8), apoptosis (flow cytometry and caspase 3 activity), ferroptosis via Fe2+, glutathione (GSH), reactive oxygen species (ROS) and malondialdehyde (MDA) markers and inflammation cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor alpha (TNF-α). The BACH1/CDKN3 relationship was examined by chromatin immunoprecipitation (ChIP) experiment and luciferase assay. BACH1 was increased in MI serum and H/R-stimulated AC16 cardiomyocytes. Functionally, disruption of BACH1 mitigated H/R-evoked in vitro apoptosis, ferroptosis and inflammation of AC16 cardiomyocytes. Mechanistically, BACH1 activated CDKN3 transcription and enhanced CDKN3 protein expression in AC16 cardiomyocytes. Our rescue experiments validated that BACH1 disruption attenuated H/R-evoked AC16 cardiomyocyte apoptosis, ferroptosis and inflammation by downregulating CDKN3. Additionally, BACH1 disruption could activate the adenosine monophosphate-activated protein kinase (AMPK) signaling by downregulating CDKN3 in H/R-stimulated AC16 cardiomyocytes. Our study demonstrates that BACH1 activates CDKN3 transcription to induce H/R-evoked damage of AC16 cardiomyocytes partially via AMPK signaling.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor ß1 (TGF-ß1) induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone for these two lung diseases, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

Disproportionality Analysis of Nusinersen in the Food and Drug Administration Adverse Event Reporting System: A Real-World Postmarketing Pharmacovigilance Assessment.

BACKGROUND: Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection. RESULTS: We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post-lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest. CONCLUSIONS: Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety.

Effect of cordyceps militaris on growth performance, antioxidant capacity, and intestinal epithelium functions in weaned pigs.

To explore the effects of cordyceps militaris (CM) on growth performance and intestinal epithelium functions, 180 weaned pigs were randomly assigned into 5 treatments with 6 replicate pens per treatment (6 pigs per pen). Pigs were fed with basal diet (control) or basal diet supplemented with 100, 200, 400, and 800 mg/kg CM. The trial lasted for 42 d, and pigs from the control and optimal-dose groups (based on growth performance) were picked for blood and tissue collection (n = 6). Results showed that CM elevated the average daily gain (ADG) and decreased the ratio of feed intake to gain (F:G) in the weaned pigs (P < 0.05). CM supplementation at 100 mg/kg improved the digestibilities of dry matter (DM), crude protein (CP), and gross energy (GE) (P < 0.05). CM not only increased the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) but also increased the concentration of interleukin-10 (IL-10) in serum (P < 0.05). The serum concentrations of malondialdehyde (MDA), d-lactate, and diamine oxidase (DAO) were reduced by CM (P < 0.05). Interestingly, CM elevated the villus height and the ratio of villus height to crypt depth in the duodenum and jejunum and increased the activities of duodenal sucrase and maltase (P < 0.05). Moreover, CM elevated the expression levels of tight-junction proteins ZO-1, claudin-1, and occluding, as well as critical functional genes such as the fatty acid transport protein (FATP1), cationic amino acid transporter 1 (CAT1), and NF-E2-related factor 2 (Nrf2) in the duodenum and jejunum (P < 0.05). Importantly, CM increased the concentrations of acetic acid and butyric acid, and elevated the abundances of Bacillus and Lactobacillus in the cecum and colon, respectively (P < 0.05). These results indicated potential benefits of CM in improving the growth of weaned pigs, and such effect may be tightly associated with improvement in antioxidant capacity and intestinal epithelium functions.

In last decades, antibiotics have been widely used as growth-promoting agents to relieve weaning stress and prevent intestinal injury. However, overdose and misuse of antibiotics led to bacterial resistance and drug residues in animal products. Therefore, the development of healthy alternatives for pork production has attracted considerable research interest worldwide. Cordyceps militaris (CM) is an entomopathogenic fungus with various biological effects, including anti-inflammatory, lipid-lowering, and antioxidant activities. This study was conducted to investigate the effects of dietary CM supplementation on growth performance, antioxidant capacity, and intestinal epithelium functions in weaned pigs. Our results showed that CM supplementation could enhance the growth performance by improving antioxidant capacity and intestinal epithelium functions.

A study on the structure-functionality relationship of Solenaia oleivora protein under high-intensity ultrasonication processing.

Solenaia oleivora is a valuable freshwater mussel endemic to China with a high content of high-quality proteins, but the lack of structural information and limited functionality of Solenaia oleivora proteins constrained their application in the food industry. This study investigates the changes in structural characteristics and functionality of Solenaia oleivora protein under ultrasound processing at power from 200 to 600 W. The ultrasound treatment caused increased contents of ß-turn and α-helix, and the exposure of interior hydrophobic groups, resulting in the increased hydrophobicity by around 3 folds. The ultrasound treatment could significantly decrease particle size and increase surface charges of Solenaia oleivora proteins, facilitating the increase of hydrosolubility from 10.2% to 81.7%. These structural changes and increased hydrosolubility contributed to the enhancement of emulsifying and foaming properties, and in vitro digestibility. The results suggested that the ultrasound-treated Solenaia oleivora proteins possessed the potential as an alternative protein in food applications.