cTBS to Right DLPFC Modulates Physiological Correlates of Conflict Processing: Evidence from a Stroop task.

Conflict typically occurs when goal-directed processing competes with more automatic responses. Though previous studies have highlighted the importance of the right dorsolateral prefrontal cortex (rDLPFC) in conflict processing, its causal role remains unclear. In the current study, the behavioral experiment, the continuous theta burst stimulation (cTBS), and the electroencephalography (EEG) were combined to explore the effects of behavioral performance and physiological correlates during conflict processing, after the cTBS over the rDLPFC and vertex (the control condition). Twenty-six healthy participants performed the Stroop task which included congruent and incongruent trials. Although the cTBS did not induce significant changes in the behavioral performance, the cTBS over the rDLPFC reduced the Stroop effects of conflict monitoring-related frontal-central N2 component and theta oscillation, and conflict resolution-related parieto-occipital alpha oscillation, compared to the vertex stimulation. Moreover, a significant hemispheric difference in alpha oscillation was exploratively observed after the cTBS over the rDLPFC. Interestingly, we found the rDLPFC stimulation resulted in significantly reduced Stroop effects of theta and gamma oscillation after response, which may reflect the adjustment of cognitive control for the next trial. In conclusion, our study not only demonstrated the critical involvement of the rDLPFC in conflict monitoring, conflict resolution processing, and conflict adaptation but also revealed the electrophysiological mechanism of conflict processing mediated by the rDLPFC.

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.

Investigating the interplay of smoking, cardiovascular risk factors, and overall cardiovascular disease risk: NHANES analysis 2011-2018.

BACKGROUND: This study explores the intricate relationship between smoking, cardiovascular disease (CVD) risk factors and their combined impact on overall CVD risk, utilizing data from NHANES 2011-2018. METHODS: Participants were categorized based on the presence of CVD, and we compared their demographic, social, and clinical characteristics. We utilized logistic regression models, receiver operating characteristics (ROC) analysis, and the chi-squared test to examine the associations between variables and CVD risk. RESULTS: Significant differences in characteristics were observed between those with and without CVD. Serum cotinine levels exhibited a dose-dependent association with CVD risk. The highest quartile of cotinine levels corresponded to a 2.33-fold increase in risk. Smoking, especially in conjunction with lower HDL-c, significantly increases CVD risk. Combinations of smoking with hypertension, central obesity, diabetes, and elevated triglycerides also contributed to increased CVD risk. Waist-to-Height Ratio, Visceral Adiposity Index, A Body Shape Index, Conicity Index, Triglyceride-Glucose Index, Neutrophil, Mean platelet volume and Neutrophil to Lymphocyte ratio demonstrated significant associations with CVD risk, with varying levels of significance post-adjustment. When assessing the combined effect of smoking with multiple risk factors, a combination of smoking, central obesity, higher triglycerides, lower HDL-c, and hypertension presented the highest CVD risk, with an adjusted odds ratio of 14.18. CONCLUSION: Smoking, when combined with central obesity, higher triglycerides, lower HDL-c, and hypertension, presented the highest CVD risk, with an adjusted odds ratio of 14.18.

QSAR aided design of potent c-Met inhibitors using molecular docking, molecular dynamics simulation and binding free energy calculation.

Mesenchymal-epithelial transition factor (c-Met) is a tyrosine kinase receptor. Under certain disease conditions, the cellular transformation process may be over-activated, resulting in carcinogenesis. Therefore, molecularly targeted therapy targeting the receptor tyrosine kinase c-Met is achieved by inhibiting c-Met activity and thus effectively suppressing cancer propagation. In this paper, 41 compounds were selected from the reported literature as a dataset to build stable Topomer CoMFA and HQSAR models. The feasibility of the constructed models was evaluated by internal and external validation techniques. Based on the Topomer CoMFA model basis the fragments with higher contribution values were screened and the combination yielded 19 compounds with higher than template molecules. Through molecular docking, the ligand complexes formed hydrogen and hydrophobic bonds with strong stable structures. The ligand-protein complexes with better scoring results were selected for MD simulations, and Y14 exhibited a stable and favourable binding pocket. In addition, ADMET results showed that the ligand-complexes have potential medicinal effects on c-Met inhibition. This study provides a reference for molecularly targeted therapy targeting receptor tyrosine-kinetic c-Met.

Biochemical and protein nutritional potential of mulberry (Morus alba L.) leaf: partial substitution improves the nutrition of conventional protein.

BACKGROUND: With the requirements of environmental, cost and economic sustainability, new sources of alternative proteins in the livestock industry are receiving increasing attention. Mulberry (Morus alba L.) leaves are a unique feed resource because of their high protein content and large availability. Therefore, mining sustainable protein suitable for the animal husbandry industry in sericulture resources could achieve a win-win situation. RESULTS: The protein content in mulberry leaves is 232.10-386.16 g kg-1 , and the mean value of crude fat content is 43.76 ± 8.48 g kg-1 , which has the advantages of protein content and energy. In addition, the average content of phytic acid in mulberry leaves is only 1.88 ± 0.56 g kg-1 , which means that it is not inhibited in terms of nutrient absorption. Meanwhile, the digestibility of protein was Bean pulp > Sample 8 ≈ Alfalfa ≈ Sample 13 ≈ Cottonseed meal > Fish meal, and the ß-turn and particle size of mulberry leaf protein are more conducive to digestion in vitro. Furthermore, the protein of Sample 13 had the richest essential amino acids (252.00 g kg-1 ) and the highest essential amino acid index (EAAI), which was superior to conventional feed protein. In addition, the partial substitution of mulberry leaf protein (15%) significantly increased the EAAI value of conventional feed protein. However, to balance nutrition, it is necessary to combine mulberry leaf protein with other proteins to further broaden its application field. CONCLUSION: Mulberry leaves are a new source of feed protein, which helps to alleviate the two major problems of mulberry resource surplus and feed protein resource shortage. © 2023 Society of Chemical Industry.

Mechanically and Thermally Stable Cathode Electrolyte Interphase Enables High-temperature, High-voltage Li||LiCoO2 Batteries.

The development of high-energy-density Li||LiCoO2 batteries is severely limited by the instability of cathode electrolyte interphase (CEI) at high voltage and high temperature. Here we propose a mechanically and thermally stable CEI by electrolyte designing for achieving the exceptional performance of Li||LiCoO2 batteries at 4.6 V and 70 °C. 2,4,6-tris(3,4,5-trifluorophenyl)boroxin (TTFPB) as the additive could preferentially enter into the first shell structure of PF6 - solvation and be decomposed on LiCoO2 surface at low oxidation potential to generate a LiBx Oy -rich/LiF-rich CEI. The LiBx Oy surface layer effectively maintained the integrity of CEI and provided excellent mechanical and thermal stability while abundant LiF in CEI further improved the thermal stability and homogeneity of CEI. Such CEI drastically alleviated the crack and regeneration of CEI and irreversible phase transformation of the cathode. As expected, the Li||LiCoO2 batteries with the tailored CEI achieved 91.9 % and 74.0 % capacity retention after 200 and 150 cycles at 4.6 and 4.7 V, respectively. Moreover, such batteries also delivered an unprecedented high-temperature performance with 73.6 % capacity retention after 100 cycles at 70 °C and 4.6 V.

Plasma-Membrane-Localized Transporter NREET1 is Responsible for Rare Earth Element Uptake in Hyperaccumulator Dicranopteris linearis.

Rare earth elements (REEs) are critical for numerous modern technologies, and demand is increasing globally; however, production steps are resource-intensive and environmentally damaging. Some plant species are able to hyperaccumulate REEs, and understanding the biology behind this phenomenon could play a pivotal role in developing more environmentally friendly REE recovery technologies. Here, we identified a REE transporter NRAMP REE Transporter 1 (NREET1) from the REE hyperaccumulator fern Dicranopteris linearis. Although NREET1 belongs to the natural resistance-associated macrophage protein (NRAMP) family, it shares a low similarity with other NRAMP members. When expressed in yeast, NREET1 exhibited REE transport capacity, but it could not transport divalent metals, such as zinc, nickel, manganese, or iron. NREET1 is mainly expressed in D. linearis roots and predominantly localized in the plasma membrane. Expression studies in Arabidopsis thaliana revealed that NREET1 functions as a transporter mediating REE uptake and transfer from root cell walls into the cytoplasm. Moreover, NREET1 has a higher affinity for transporting light REEs compared to heavy REEs, which is consistent to the preferential enrichment of light REEs in field-grown D. linearis. We therefore conclude that NREET1 may play an important role in the uptake and consequently hyperaccumulation of REEs in D. linearis. These findings lay the foundation for the use of synthetic biology techniques to design and produce sustainable, plant-based REE recovery systems.

Genetic mapping and analysis of candidate leaf color genes in common winter wheat (Triticum aestivum L.).

Leaf color-related genes play key roles in chloroplast development and photosynthetic pigment biosynthesis and affect photosynthetic efficiency and grain yield in crops. In this study, a recessive homozygous individual displaying yellow leaf color (yl1) was identified in the progeny population derived from a cross between wheat cultivars Xingmai1 (XM1) and Yunong3114 (YN3114). Phenotypic identification showed that yl1 exhibited the yellow character state over the entire growth period. Compared with XM1, yl1 plants had significantly lower chlorophyll content and net photosynthetic rate, and similar results were found between the green-type lines and yellow-type lines in the BC2F3 XM1 × yl1 population. Gene mapping via the bulked segregant exome capture sequencing (BSE-seq) method showed that the target gene TaYL1 was located within the region of 582,556,971-600,837,326 bp on chromosome 7D. Further analysis by RNA-seq suggested TraesCS7D02G469200 as a candidate gene for yellow leaf color in common wheat, which encodes a protein containing the AP2 domain. Moreover, comparative transcriptome profiling revealed that most differentially expressed genes (DEGs) were enriched in chlorophyll metabolism and photosynthesis pathways. Together, these results indicate that TaYL1 potentially affects chlorophyll synthesis and photosynthesis. This study further elucidates the biological mechanism of chlorophyll synthesis, metabolism, and photosynthesis in wheat and provides a theoretical basis for high photosynthetic efficiency in wheat breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01395-z.

Efficacy and pregnancy outcomes of focused ultrasound for cervical high-grade squamous intraepithelial lesions.

OBJECTIVE: To investigate the efficacy and adverse effects of focused ultrasound (FU) in the treatment of high-grade squamous intraepithelial lesions (HSIL) and follow up on pregnancy outcomes in patients. METHODS: This retrospective study recruited 57 patients aged 20-40 years with cervical HSIL combined with HR-HPV infection who received FU treatment between September 2019 and April 2022. Clinical data of the patients were obtained from hospital records. HSIL cure rate and cumulative HR-HPV clearance rate were assessed after treatment. Patients were followed up on fertility and pregnancy outcomes after treatment by telephone interviews until April 1, 2023. RESULTS: During a 6-month follow-up, the HSIL cure rate was 73.7%, and a statistical difference between CIN2 and CIN3 (75.6% vs. 66.7%, p = 0.713) was not present. HSIL -recurrence was not observed during the follow-up period, and the median follow-up duration was 12 months. The cumulative HR-HPV clearance rates at the 6- and 12-month follow-ups were 56.1% and 75.4%, respectively. The median clearance time of HR-HPV was 6 (95% confidence interval, 5.46-6.54) months. The clearance rate was higher in HPV16/18 than in non-HPV16/18 (86.7% vs. 62.9%, p = 0.038). After treatment, the successful pregnancy rate in patients with fertility intentions and spontaneous abortion rate were 73.9% and 5.9%, respectively. Preterm birth, preterm premature rupture of membranes, or low-birth-weight infants were not observed. CONCLUSION: FU treatment can regress HSIL and accelerate HR-HPV clearance in young women of childbearing age with cervical HSIL associated with HR-HPV infection, and has no significant adverse effects on pregnancy outcomes.

The Transcription Factor CsgD Contributes to Engineered Escherichia coli Resistance by Regulating Biofilm Formation and Stress Responses.

The high cell density, immobilization and stability of biofilms are ideal characteristics for bacteria in resisting antibiotic therapy. CsgD is a transcription activating factor that regulates the synthesis of curly fimbriae and cellulose in Escherichia coli, thereby enhancing bacterial adhesion and promoting biofilm formation. To investigate the role of CsgD in biofilm formation and stress resistance in bacteria, the csgD deletion mutant ΔcsgD was successfully constructed from the engineered strain E. coli BL21(DE3) using the CRISPR/Cas9 gene-editing system. The results demonstrated that the biofilm of ΔcsgD decreased by 70.07% (p < 0.05). Additionally, the mobility and adhesion of ΔcsgD were inhibited due to the decrease in curly fimbriae and extracellular polymeric substances. Furthermore, ΔcsgD exhibited a significantly decreased resistance to acid, alkali and osmotic stress conditions (p < 0.05). RNA-Seq results revealed 491 differentially expressed genes between the parent strain and ΔcsgD, with enrichment primarily observed in metabolism-related processes as well as cell membrane structure and catalytic activity categories. Moreover, CsgD influenced the expression of biofilm and stress response genes pgaA, motB, fimA, fimC, iraP, ompA, osmC, sufE and elaB, indicating that the CsgD participated in the resistance of E. coli by regulating the expression of biofilm and stress response. In brief, the transcription factor CsgD plays a key role in the stress resistance of E. coli, and is a potential target for treating and controlling biofilm.

Armor-like Inorganic-rich Cathode Electrolyte Interphase Enabled by the Pentafluorophenylboronic Acid Additive for High-voltage Li||NCM622 Batteries.

Lithium metal batteries (LMBs) comprising Li metal anode and high-voltage nickel-rich cathode could potentially realize high capacity and power density. However, suitable electrolytes to tolerate the oxidation on the cathode at high cut-off voltage are urgently needed. Herein, we present an armor-like inorganic-rich cathode electrolyte interphase (CEI) strategy for exploring oxidation-resistant electrolytes for sustaining 4.8 V Li||LiNi0.6 Co0.2 Mn0.2 O2 (NCM622) batteries with pentafluorophenylboronic acid (PFPBA) as the additive. In such CEI, the armored lithium borate surrounded by CEI up-layer represses the dissolution of inner CEI moieties and also improves the Li+ conductivity of CEI while abundant LiF is distributed over whole CEI to enhance the mechanical stability and Li+ conductivity compared with polymer moieties. With such robust Li+ conductive CEI, the Li||NCM622 battery delivered excellent stability at 4.6 V cut-off voltage with 91.2 % capacity retention after 400 cycles. The excellent cycling performance was also obtained even at 4.8 V cut-off voltage.

Matrix-Directed Mineralization for Bulk Structural Materials.

Mineral-based bulk structural materials (MBSMs) are known for their long history and extensive range of usage. The inherent brittleness of minerals poses a major problem to the performance of MBSMs. To overcome this problem, design principles have been extracted from natural biominerals, in which the extraordinary mechanical performance is achieved via the hierarchical organization of minerals and organics. Nevertheless, precise and efficient fabrication of MBSMs with bioinspired hierarchical structures under mild conditions has long been a big challenge. This Perspective provides a panoramic view of an emerging fabrication strategy, matrix-directed mineralization, which imitates the in vivo growth of some biominerals. The advantages of the strategy are revealed by comparatively analyzing the conventional fabrication techniques of artificial hierarchically structured MBSMs and the biomineral growth processes. By introducing recent advances, we demonstrate that this strategy can be used to fabricate artificial MBSMs with hierarchical structures. Particular attention is paid to the mass transport and the precursors that are involved in the mineralization process. We hope this Perspective can provide some inspiring viewpoints on the importance of biomimetic mineralization in material fabrication and thereby spur the biomimetic fabrication of high-performance MBSMs.

Enhanced Electrochemical O2 -to-H2 O2 Synthesis Via Cu-Pb Synergistic Interplay.

Electrocatalytic reduction of oxygen (O2 ) to produce hydrogen peroxide (H2 O2 ) frequently suffers from the low activity and poor selectivity of catalysts owing to the lack of systematic strategies. The resulting enhancement to enable the further design of a new bimetallic catalyst with the synergistic interplay, as exemplified by Cu-Pb catalyst for two-electron oxygen reduction reaction (2e- ORR), is reported here. Critically, in-depth evidence, including density functional theory (DFT) calculations, electrochemical signals, in-situ Raman, and H2 O2 -proof work, allude to a catalytic favor to the 2e- ORR of Cu-Pb.

Frozen embryo transfer in the menstrual cycle after moderate-severe ovarian hyperstimulation syndrome: a retrospective analysis.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a rare but serious complication of controlled ovarian stimulation. Frozen-embryo transfer (ET) is prompted to be performed in the next menstrual cycles after cancellation of fresh-ET after occurrence of OHSS. However, effects of frozen-ET in the second menstrual cycle have never been investigated. Therefore, this study aimed to assess this in the menstrual cycle after OHSS. METHODS: The OHSS group included 342 women with moderate-severe OHSS who underwent the first frozen-ET in the second menstrual cycle in the First Affiliated Hospital of Anhui Medical University from June 2018 to September 2019. A total of 342 women without OHSS who received frozen-ET in the second menstrual cycle were selected as control group matched by age, body mass index, fertility history, ovulation induction scheme. Uni- and multi-variable conditional logistic regression was used to estimate the association between moderate-severe OHSS and pregnancy outcomes. RESULTS: There were no significant differences in maternal outcomes (miscarriage, preterm birth and pregnancy complications including gestational diabetes mellitus, pregnancy-induced hypertension, placenta previa, premature rupture of membranes and postpartum hemorrhage) and in neonatal outcome (birth-weight and body length, neonatal congenital diseases and other complications) between the two groups in either uni- or multi-variable models. CONCLUSIONS: Frozen-ET in the menstrual cycle after OHSS has similar maternal and neonatal outcomes as in women without OHSS. This study indicates that frozen-ET could be performed in the second menstrual cycle in women who recovered from moderate-severe OHSS.

Association between serum hemoglobin and major cardiovascular adverse event in Chinese patients with ST-segment elevation myocardial infarction after percutaneous coronary intervention.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is a common clinical acute and severe disease, and it is of great significance to evaluate the prognosis of these patients. Hemoglobin levels are associated with a variety of diseases, but studies on Chinese patients with STEMI after percutaneous coronary intervention (PCI) have not been sufficient. METHODS: This was a secondary analysis based on a prospective cohort study of patients undergoing PCI in Taizhou, Zhejiang, China. We performed multivariable logistic regression to explore the association between the serum hemoglobin and the incidence of major cardiovascular adverse event (MACE) in patients after PCI. We also used a generalized additive model and smooth curve fitting to explain the nonlinear relationship after adjusting the potential confounders. Finally, the heterogeneity among specific groups was examined by subgroup analysis. RESULTS: Of all 462 patients enrolled in this study, 118 (25.54%) developed MACE. There was a negative correlation between serum hemoglobin and MACE in all three models (hazard ratio [HR] 0.82, 95% confidence interval [CI 0.72, 0.93], HR 0.86, 95% CI [0.76,0.98], and HR 0.87, 95% CI [0.74,0.98], respectively). In the subgroup analysis, the negative correlation existed between the patients who had myocardial infarction (MI) history (p for interaction = 0.0059) after adjusting covariates. However, no significant differences were found between age and sex groups (p for interaction = 0.1381, 0.4103, respectively). CONCLUSION: Our results indicated that patients who received PCI with low preoperative hemoglobin were more likely to develop MACE, especially if they have already had a history of MI.

Development and Identification of a Novel Wheat-Thinopyrum scirpeum 4E (4D) Chromosomal Substitution Line with Stripe Rust and Powdery Mildew Resistance.

Stripe rust caused by Puccinia striiformis f. sp. tritici and powdery mildew caused by Blumeria graminis f. sp. tritici are devastating diseases of wheat worldwide. Exploration of new disease-resistant genes from cultivated wheat and wild relatives are the most effective means of reducing the amounts of fungicides applied to combat these diseases. Thinopyrum scirpeum (2n = 4x = 28, EEEE) is an important promising reservoir of useful genes, including stripe rust and powdery mildew resistance, and may be useful for increasing wheat disease resistance. Here, we characterize a novel wheat-Th. scirpeum disomic substitution line, K16-730-3, and chromosome-specific markers were developed that can be used to trace the Th. scirpeum chromosome or chromosome segments transferred into wheat. Genomic in situ hybridization and fluorescence in situ hybridization analyses indicated that K16-730-3 is a new 4E (4D) chromosomal substitution line. Evaluation of seedling and adult disease responses revealed that K16-730-3 is resistant to stripe rust and powdery mildew. In addition, no obvious difference in grain yield was observed between K16-730-3 and its wheat parents. Genotyping-by-sequencing analyses indicated that 74 PCR-based markers can accurately trace chromosome 4E, which were linked to the disease resistance genes in the wheat background. Further marker validation analyses revealed that 13 specific markers can distinguish between the E-genome chromosomes of Th. scirpeum and the chromosomes of other wheat-related species. The new substitution line K16-730-3 carrying the stripe rust and powdery mildew resistance genes will be useful as novel germplasm in breeding for disease resistance. The markers developed in this study can be used in marker-assisted selection for increasing disease resistance in wheat.

Genetic diversity of Asian and European common wheat lines assessed by fluorescence in situ hybridization.

Understanding the genetic diversity of wheat is important for wheat breeding and improvement. However, there have been limited attempts to evaluate wheat diversity using fluorescence in situ hybridization (FISH). In this study, the chromosomal structures of 149 wheat accessions from 13 countries located between the latitudes of 30°N and 45°N, the principal growing region for wheat, were characterized using FISH with pTa535 and pSc119.2 probes. The ranges of the numbers of FISH types in the A-, B-, and D-genome chromosomes were 2-8, 3-7, and 2-4, respectively, and the average numbers in the A and B genomes were greater than in the D genome. Chromosomal translocations were detected by these probes, and previously undescribed translocations were also observed. Using the FISH, the genetic relationships among the 149 common wheat lines were divided into three groups (G1, G2, and G3). G1 mainly consisted of southern European lines, G2 consisted of most lines from Japan and some lines from western Asia, China, and Korea, and G3 consisted of the other lines from southern Europe and most of the lines from western Asia, China, and Korea. FISH karyotypes of wheat chromosomes distinguished chromosomal structural variations, revealing the genetic diversity among wheat varieties. Furthermore, these results provide valuable information for the further genetic improvement of wheat in China.

Human Placental Mesenchymal Stem Cells-Exosomes Alleviate Endothelial Barrier Dysfunction via Cytoskeletal Remodeling through hsa-miR-148a-3p/ROCK1 Pathway.

Background: Endothelial barrier disruption of human pulmonary vascular endothelial cells (HPVECs) is an important pathogenic factor for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Mesenchymal stem cells-exosome (MSCs-Exo) represents an ideal carrier for cell-free therapy. The therapeutic implication and underlying mechanism of human placental MSCs-Exo (HPMSCs-Exo) in ALI/ARDS need to be further explored. Materials and Methods: HPMSCs-Exo was extracted from HPMSCs and characterized. Then, the therapeutic effects of exosomes were evaluated in ALI mice and HPVECs. RNA-sequencing was applied to reveal the miRNA profile of HPMSCs-Exo and differentially expressed genes (DEGs) in HPMSCs-Exo-pretreated HPVECs. The targets of miRNAs were predicted by bioinformatics methods and correlated to DEGs. Finally, the role of hsa-miR-148a-3p/ROCK1 pathway in HPVECs has been further discussed. Results: The results showed that HPMSCs-Exo could downregulate Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), upregulate the expression of zonula occludens-1 (ZO-1) and F-actin, promote HPVECs migration and tube formation, reduce cytoskeletal disorders and cell permeability, and thus improve ALI/ARDS. RNA-sequencing revealed the DEGs were mainly enriched in cell junction, angiogenesis, inflammation, and energy metabolism. HPMSCs-Exo contains multiple miRNAs which are associated with cytoskeletal function; the expression abundance of hsa-miR-148a-3p is the highest. Bioinformatic analysis identified ROCK1 as a target of hsa-miR-148a-3p. The overexpression of hsa-miR-148a-3p in HPMSCs-Exo promoted the migration and tube formation of HPVECs and reduced ROCK1 expression. However, the overexpression of ROCK1 on HPVECs reduced the therapeutic effect of HPMSCs-Exo. Conclusions: HPMSCs-Exo represents a protective regimen against endothelial barrier disruption of HPVECs in ALI/ARDS, and the hsa-miR-148a-3p/ROCK1 pathway plays an important role in this therapeutics implication.

RBM3 Promotes Anti-inflammatory Responses in Microglia and Serves as a Neuroprotective Target of Ischemic Stroke.

Ischemic stroke is a major cause of death and disability in adults. Hypothermic treatment is successful in treating neonatal cerebral ischemia, but its application is restricted in adult patients due to complex management strategies and severe adverse effects. Two homologous RNA-binding proteins, RBM3 and CIRP, are the only known cold-inducible proteins in vertebrates, and their expression levels are robustly elevated by mild to moderate hypothermia. In previous studies, we and others have demonstrated that both RBM3 and CIRP mediate the neuroprotective and neurogenic effects of hypothermia in cell and animal models. However, CIRP can also be detrimental to neurons by triggering neuroinflammatory responses, complicating its post-stroke functions. In this study, we compared the properties of the two cold-inducible RNA-binding proteins after ischemic stroke. Our results indicated that RBM3 expression was stimulated in the ischemic brain of stroke patients, while CIRP expression was not. In an experimental model, RBM3 can ameliorate ischemic-like insult by promoting neuronal survival and eliciting anti-inflammatory responses in activated microglia, while the impact of CIRP was intriguing. Collectively, our data supported the notion that RBM3 may be a more promising therapeutic target than CIRP for treating ischemic stroke. We further demonstrated that zr17-2, a small molecule initially identified to target CIRP, can specifically target RBM3 but not CIRP in microglia. zr17-2 demonstrated anti-inflammatory and neuroprotective effects after ischemic stroke both in vitro and in vivo, suggesting its potential therapeutic value.

Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.