Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.

JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Retrospective evaluation of three types of expanded polytetrafluoroethylene grafts for upper limb vascular access.

Currently, three expanded polytetrafluoroethylene (ePTFE) prosthetic graft types are most commonly used for patients with end-stage kidney disease (ESKD) who require long-term vascular access for hemodialysis. However, studies comparing the three ePTFE grafts are limited. This study compared the clinical efficacy and postoperative complications of three ePTFE prosthetic graft types used for upper limb arteriovenous graft (AVG) surgery among patients with ESKD. Patients with ESKD requiring upper limb AVG surgery admitted to our center between January 2016 and September 2019 were enrolled. Overall, 282 patients who completed the 2-year follow-up were included and classified into the following three groups according to the ePTFE graft type: the GPVG group with the PROPATEN® graft, the GAVG group with the straight-type GORE® ACUSEAL, and the BVVG group with the VENAFLO® II. The patency rate and incidence of access-related complications were analyzed and compared between groups. The patients were followed up postoperatively, and data were collected at 6, 12, 18, and 24 months postoperatively. Respective to these follow-up time points, in the GPVG group, the primary patency rates were 74.29%, 65.71%, 51.43%, and 42.86%; the assisted primary patency rates were 85.71%, 74.29%, 60.00%, and 48.57%; and the secondary patency rates were 85.71%, 80.00%, 71.43%, and 60.00%. In the GAVG group, the primary patency rates were 73.03%, 53.93%, 59.42%, and 38.20%; the assisted primary patency rates were 83.15%, 68.54%, 59.55%, and 53.93%; and the secondary patency rates were 85.39%, 77.53%, 68.54%, and 62.92%, respectively. In the BVVG group, the primary patency rates were 67.24%, 53.45%, 41.38%, and 29.31%; the assisted primary patency rates were 84.48%, 67.24%, 55.17%, and 44.83%; and the secondary patency rates were 86.21%, 81.03%, 68.97%, and 60.34%, respectively. The differences in patency rates across the three grafts were not statistically significant. Overall, 18, 4, and 12 patients in the GPVG, GAVG, and BVVG groups, respectively, experienced seroma. Among the three grafts, GORE® ACUSEAL had the shortest anastomosis hemostatic time. The first cannulation times for the three grafts were GPVG at 16 (±8.2), GAVG at 4 (±4.9), and BVVG at 18 (±12.7) days. No significant difference was found in the postoperative swelling rate between the GPVG group and the other two groups. Furthermore, no statistically significant differences were found across the three graft types regarding postoperative vascular access stenosis and thrombosis, ischemic steal syndrome, pseudoaneurysm, or infection. In conclusion, no statistically significant differences in the postoperative primary, assisted primary, or secondary graft patency rates were observed among the three groups. A shorter anastomosis hemostatic time, first cannulation time, and seroma occurrence were observed with the ACUSEAL® graft than with its counterparts. The incidence of upper extremity swelling postoperatively was greater with the PROPATEN® graft than with the other grafts. No statistically significant differences were observed among the three grafts regarding the remaining complications.

Improvement and exacerbation of multiple disparities in sexually transmitted infections among children and adolescents aged 6-22 years: An analysis of national surveillance data from 2013 to 2021.

To investigate the progress of disparities in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), gonorrhea, and syphilis among children and adolescents aged 6-22 years in China during 2013-2021. A total of 614 325 cases data were extracted from the Chinese Information System for Infectious Diseases Control and Prevention during 2013-2021. Puberty health education data were drew from the Student Health Surveillance in 2021. Disparity patterns and average annual percentage changes (AAPCs) in sexually transmitted infections (STIs) incidence or new cases in China were examined using descriptive statistics and joinpoint regression. The incidence across 345 cities was stratified by gross domestic product (GDP). Between 2013 and 2021, there were 614 325 reported cases of HIV/AIDS, gonorrhea, and syphilis among children and adolescents aged 6-22, with an annual average incidence of 24.0967 per 100 000. The expansion of HIV/AIDS has halted, yet the surge in gonorrhea and syphilis remains notably pronounced. The ratio of male to female AIDS incidence increased from 2.75 (2.60, 2.90) to 7.13 (6.68, 7.62), but that of syphilis changed from 0.33 (0.32, 0.34) to 0.56 (0.55, 0.57). Students and out-of-school individuals aged 13-15 experienced a notably high increase in STI cases, surpassing other age groups, with an average annual percentage increase of 29.2% and 26.3%, respectively. Nonstudents consistently had a higher incidence rate than students, with an IRR reaching 31.80 (31.24, 32.37) in 2021. A noticeable clustering pattern of new cases emerged in the southeastern region of the Heihe-Tengchong line, extending inland from the coastal areas. Districts and counties with lower rates of puberty sexual health education tended to have higher average STI incidence rates. At the prefecture and city levels, there was a noticeable upward trend on average STI incidence rates in cities with per capita GDPs. Strategies to address those disparities include promoting equitable health education, and widespread sexual health education, particularly in areas with limited access to education and experiencing rapid economic development. The effectiveness of sexual health education intervention needs to be further evaluated in well-designed studies.

Upconverting Ultra-Thin Bi2O2CO3 Nanosheets for Synergistic Photodynamic Therapy and Radiotherapy.

Synergistic therapy has become the major therapeutic method for malignant tumors in clinical. Photodynamic therapy (PDT) and radiotherapy (RT) always combine together because of their identical anti-tumor mechanisms, that is reactive oxygen species are generated by the use of radiosensitizers after irradiation by X-ray to efficiently kill cancer cells, PDT also follows similar mechanism. Full exposure of energy-absorbing species in nanomaterials to X-ray or near-infrared light irradiation makes the energy interchange between nanomaterials and surrounding H2O or dissolved oxygen easier, however, it remains challenging. Herein, an ultrathin two-dimensional (2D) nanosheet (NS) is developed, Bi2O2CO3, doped with lanthanide ions to give out upconversion luminescence, where the high Z elements Bi, Yb, and Er promote the radio-sensitizing effect. To the surprise, lanthanide activator ions gave out completely different luminescence properties compared with traditional upconversion nanoparticles. Less dopant of Er ions in nanosheets lattice resulted in brighter red emission, which provides more efficient PDT. Under RT/PDT combined treatment, NS shows a good tumor growth-inhibiting effect. In addition, synergistic therapy requires lower radiation dose than conventional radiotherapy and lower light power than single photodynamic therapy, thus greatly reducing radiation damage caused by RT and thermal damage caused by PDT.

Properties and functions of acylated starch with short-chain fatty acids: a comprehensive review.

Short-chain fatty acids (SCFAs) are the primary energy source of colonic epithelial cells, but oral SCFAs are digested, absorbed, or degraded before reaching the colon. The acylated starch with SCFAs can be fermented and release specific SCFAs under the action of colonic intestinal microbiota. This review first introduces the preparation method, reaction mechanism, and substitution factors. Second, the structure, physical and chemical properties, in vitro function, and mechanism of acylated starch were expounded. Finally, the application of acylated starch in foods is introduced, and its safety is evaluated, providing a basis for the further development of acylated starch-based foods. The acylated starch obtained by different acylation types and preparation methods is different in particle, molecular, and crystal structures, leading to changes in the function and physicochemical properties. Meanwhile, acylated starch has the functional potential of targeted delivery of SCFAs to the colon, which can increase SCFAs in feces and intestine, selectively regulate the intestinal microbiota, and produce a prebiotic effect conducive to host health. The safety of acetylated starch has been supported by relevant studies, which have been widely used in various food fields and have great potential in the food industry.

Research progress on the correlation between cataract occurrence and nutrition.

Cataract is a common eye disease characterized by lens opacity, leading to blurred vision and progressive blindness of the eye. Factors affecting the development of cataracts include nutrition, oxidative stress, micronutrients and inflammatory factors, and also include genetics, toxicity, infrared exposure, hyperuricemia, and mechanical injuries. Among the nutritional factors, a balanced diet, vegetarian diet, dairy products and vegetables are protective against cataracts; high-sodium diet, high intake of carbohydrates and polyunsaturated fatty acids may increase the risk of cataracts; and increased intake of proteins, especially animal proteins, may prevent nuclear cataracts. Intake of antioxidants such as ß-carotene, lutein, or zeaxanthin is associated with a reduced risk of cataracts. Minerals such as zinc, selenium, calcium and sodium have also been associated with cataract development. Oxidative stress plays an important role in the development of cataracts and is associated with several antioxidative enzymes and biomarkers such as glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Insulin resistance is also an essential risk factor for cataracts, especially in diabetic patients. In conclusion, understanding these influencing factors helps us to better prevent cataracts. And in this article, we will focus on the important factor of diet and nutrition for a detailed discussion.

Solvent-Mediated Synthesis and Characterization of Li3InCl6 Electrolytes for All-Solid-State Li-Ion Battery Applications.

Superionic halides have attracted widespread attention as solid electrolytes due to their excellent ionic conductivity, soft texture, and stability toward high-voltage electrode materials. Among them, Li3InCl6 has aroused interest since it can be easily synthesized in water or ethanol. However, investigations into the influence of solvents on both the crystal structure and properties remain unexplored. In this work, Li3InCl6 is synthesized by three different solvents: water, ethanol, and water-ethanol mixture, and the difference in properties has been studied. The results show that the product obtained by the ethanol solvent demonstrates the largest unit cell parameters with more vacancies, which tend to crystallize on the (131) plane and provide the 3D isotropic network migration for lithium-ions. Thus, it exhibits the highest ionic conductivity (1.06 mS cm-1) at room temperature and the lowest binding energy (0.272 eV). The assembled all-solid-state lithium metal batteries (ASSLMBs) employing Li3InCl6 electrolytes demonstrate a high initial discharge capacity of 153.9 mA h g-1 at 0.1 C (1 C = 170 mA h g-1) and the reversible capacity retention rate can reach 82.83% after 50 cycles. This work studies the difference in ionic conductivity between Li3InCl6 electrolytes synthesized by different solvents, which can provide a reference for the future synthesis of halide electrolytes and enable their practical application in halide-based ASSLMBs with a high energy density.

Effects of steam explosion pretreatment on the digestive properties and gut microbiota of Laminaria japonica polysaccharide.

BACKGROUND: Laminaria japonica polysaccharide, which is an important bioactive substance of Laminaria japonica with anti-inflammatory and antioxidant effects. In this study, the molecular weight, functional groups and surface morphology were investigated to evaluate the digestive properties of Laminaria japonica polysaccharide before and after steam explosion. RESULTS: The results indicated that the Laminaria japonica polysaccharide entered the large intestine to be utilized by the gut microbiota after passing through the oral, gastric and small intestinal. Meanwhile, Laminaria japonica polysaccharide of steam explosion promoted the growth of beneficial bacteria Phascolarctobacterium and Intestinimonas, and increased the content of acetic, propionic and butyric acids, which was 2.29-folds, 2.60-folds and 1.63-folds higher than the control group after 48 h of fermentation. CONCLUSION: This study reveals that the effect of steam explosion pretreatment on the digestion in vitro and gut microbiota of Laminaria japonica polysaccharide will provide a basic theoretical basis for the potential application of Laminaria japonica polysaccharide as a prebiotic in the food industry. © 2024 Society of Chemical Industry.

Reliability and validity study of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale in patients with cerebellar injury.

PURPOSE: To preliminarily investigate the reliability and validity of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale (CCAS scale) in the cerebellar injury population. METHODS: In this study, 40 patients with cerebellar injury and 39 normal individuals hospitalized in a stroke center were assessed using the Chinese version of the CCAS scale A, MMSE, and PHQ2, and the results were analyzed using content validity, structural validity, internal consistency, inter- rater agreement, and test-retest reliability. RESULTS: The correlation coefficients of semantic fluency, phonemic fluency, category switching, digit span forward, digit span backward, cube, verbal recall, similarities and Go No-Go subscores in the Chinese version of the CCAS scale A were 0.586-0.831 (P ≤ 0.05) with the total score, but there was no significant correlation between the affect and the total score (P = 0.110). The total cognitive score of the Chinese version of the CCAS scale A was correlated with the (r = 0.807, P ≤ 0.01), and the total score of the Chinese version of the CCAS scale A affect was correlated with the total score of PHQ2 (r = 0.884, P ≤ 0.01). The 2 factors were extracted using principal component analysis, and the cumulative variance contribution rate was 59.633%. The factor loadings of each of the corresponding factors were > 0.5, indicating good structural validity of the Chinese version of the CCAS scale A. Cronbach α = 0.827 indicated good internal consistency, and inter-rater reliability (ICC > 0.95) and test-retest reliability (ICC = 0.717-0.895)indicated that the Chinese version of the CCAS scale A had good inter-rater reliability and test-retest reliability. CONCLUSION: The Chinese version of the CCAS scale A has good reliability and validity in the cerebellar injury population and is useful for screening cerebellar cognitive-emotional syndrome.

Reduced actual vapor pressure exerts a significant influence on maize yield through vapor pressure deficit amid climate warming.

Understanding the impact of climate warming on crop yield and its associated mechanisms is paramount for ensuring food security. Here, we conduct a thorough analysis of the impact of vapor pressure deficit (VPD) on maize yield, leveraging a rich dataset comprising temporal and spatial observations spanning 40 years across 31 maize-growing locations in Northeast and North China. Our investigation extends to the influencing meteorological factors that drive changes in VPD during the maize growing phase. Regression analysis reveals a linear negative relationship between VPD and maize yield, demonstrating diverse spatiotemporal characteristics. Spatially, maize yield exhibits higher sensitivity to VPD in Northeast China (NEC), despite the higher VPD levels in North China Plain (NCP). The opposite patterns reveal that high VPD not invariably lead to detrimental yield impacts. Temporal analysis sheds light on an upward trend in VPD, with values of 0.05 and 0.02 kPa/10yr, accompanied by significant abrupt changes around 1996 in NEC and 2006 in NCP, respectively. These temporal shifts contribute to the heightened sensitivity of maize yield in both regions. Importantly, we emphasize the need to pay closer attention to the substantial the impact of actual vapor pressure on abrupt VPD changes during the maize growing phase, particularly in the context of ongoing climate warming.

Differences in Genomic Alterations and Accumulations of Heavy Metals Between Advanced Non-small Cell Lung Cancer Patients with and without Bone Metastasis.

Purpose: Bone metastasis (BoM) has been closely associated with increased morbidity and poor survival outcomes in patients with non-small cell lung cancer (NSCLC). Given its significant implications, this study aimed to systematically compare the biological characteristics between advanced NSCLC patients with and without BoM. Methods: In this study, the genomic alterations from the tumor tissue DNA of 42 advanced NSCLC patients without BoM and 67 patients with BoM and were analyzed by a next-generation sequencing (NGS) panel. The serum concentrations of 18 heavy metals were detected by inductively coupled plasma emission spectrometry (ICP-MS). Results: A total of 157 somatic mutations across 18 mutated genes and 105 somatic mutations spanning 16 mutant genes were identified in 61 out of 67 (91.05%) patients with BoM and 37 of 42 (88.10%) patients without BoM, respectively. Among these mutated genes, NTRK1, FGFR1, ERBB4, NTRK3, and FGFR2 stood out exclusively in patients with BoM, whereas BRAF, GNAS, and AKT1 manifested solely in those without BoM. Moreover, both co-occurring sets of genes and mutually exclusive sets of genes in patients with BoM were different from those in patients without BoM. In addition, the serum concentrations of Cu and Sr in patients with BoM were significantly higher than in patients without BoM. One of our aims was to explore how these heavy metals associated with BoM interacted with other heavy metals, and significant positive correlations were observed between Cu and Co, between Cu and Cr, between Sr and Ba, and between Sr and Ni in patients with BoM. Given the significant impacts of molecular characteristics on patients' prognosis, we also observed a noteworthy negative correlation between EGFR mutations and Co, alongside a significant positive correlation between TP53 mutations and Cd. Conclusions: The genomic alterations, somatic interactions, key signaling pathways, functional biological information, and accumulations of serum heavy metals were markedly different between advanced NSCLC patients with and without BoM, and certain heavy metals (e.g., Cu, Sr) might have potentials to identify high-risk patients with BoM.

Assessment of circulating proteins in thyroid cancer: Proteome-wide Mendelian randomization and colocalization analysis.

The causality between circulating proteins and thyroid cancer (TC) remains unclear. We employed five large-scale circulating proteomic genome-wide association studies (GWASs) with up to 100,000 participants and a TC meta-GWAS (nCase = 3,418, nControl = 292,703) to conduct proteome-wide Mendelian randomization (MR) and Bayesian colocalization analysis. Protein and gene expressions were validated in thyroid tissue. Through MR analysis, we identified 26 circulating proteins with a putative causal relationship with TCs, among which NANS protein passed multiple corrections (P BH = 3.28e-5, 0.05/1,525). These proteins were involved in amino acids and organic acid synthesis pathways. Colocalization analysis further identified six proteins associated with TCs (VCAM1, LGMN, NPTX1, PLEKHA7, TNFAIP3, and BMP1). Tissue validation confirmed BMP1, LGMN, and PLEKHA7's differential expression between normal and TC tissues. We found limited evidence for linking circulating proteins and the risk of TCs. Our study highlighted the contribution of proteins, particularly those involved in amino acid metabolism, to TCs.

Alterations of pathogen transmission patterns and attenuated immune stimulation might be the cause of increased adult respiratory infections cases in 2023, results from a multi-center study in mainland China.

Background: Several respiratory infections outbreaks have been observed in mainland China after reduction of non-pharmaceutical interventions. Other countries have seen increases in respiratory infections outside typical seasons post-COVID-19, warranting investigation into underlying causes. Methods: We established monitoring networks for suspected respiratory infection in 14 tertiary hospitals nationwide. PCR for SARS-CoV-2, influenza A and B were performed on 3708 respiratory specimens and deep sequencing were conducted to identify co-infections or newly emerging microbes in 2023. Viral evolutionary analysis was completed. We retrospectively detected serum antibody level for various respiratory pathogens from 4324 adults without respiratory infections over 7 years to observe its dynamic curves. Findings: SARS-CoV-2 and influenza A were the main pathogens during outbreaks in 2023, bacterial-virus and bacterial-bacterial co-infections were most detected, but community co-infections didn't significantly increase pneumonia incidence. Different SARS-CoV-2 and influenza variants were present in different outbreaks, and no novel pathogens were found. The epidemiological patterns of influenza A, COVID-19 and etc. were altered, exhibiting characteristics of being "staggered" compared to most global regions, and potentially led to "overlapping prevalence". Binding antibody testing showed regular fluctuation, without significant decrease against common respiratory pathogens in adults. Influenza A antibody stimulation was attenuated during the 2023 outbreak. Conclusions: "Misaligned" alteration in seasonal respiratory disease patterns possibly caused combined epidemics, leading to cases spike in China, 2023. In adults, antibody levels didn't show significant decline, but reduced immune response to influenza during 2020-2023 emphasizes the need for consistent vaccination during pandemics.

Investigating the therapeutic mechanism of Jiedu-Quyu-Ziyin Fang on systemic lupus erythematosus through the ERα-miRNA-TLR7 immune axis.

Jiedu-Quyu-Ziyin Fang (JQZF) is a formula that has been empirically used for the treatment of SLE in clinical practice. JQZF has become an approved hospital prescription in China. Fifteen MRL/lpr mice were randomly divided into three groups: Model, JQZF, and JQZF + GC, with five mice in each group. Five MRL/MPJ mice were used as the Blank group. After 8 weeks of administration, peripheral blood serum was collected to detect anti-dsDNA antibodies and complement C3 levels. Spleen B cells were collected to detect the expression of TLR7 and NF-κBp65 mRNA, and correlation analysis was performed. Transcriptome sequencing analysis was also performed on spleen B cells. Further, key miRNA and key gene mRNA expression were detected by RT-qPCR, and key protein expression levels were detected by Western blot method. Bioinformatics methods predicted that ESR1 is a key target of JQZF action on SLE, hsa-miR-146a-5p is one of the key miRNAs, and KEGG pathway analysis showed that NF-κB signaling pathway is its key signaling pathway. Transcriptome sequencing of MRL/lpr mouse spleen B cells revealed that the differential genes between the JQZF and Model groups were enriched in Toll-like receptor signaling pathway, NF-κB signaling pathway, Estrogen signaling pathway, etc. Animal studies show that JQZF treatment significantly boosts serum C3 and lowers anti-dsDNA antibodies (P < 0.01). On the molecular level, JQZF suppresses TLR7 and NF-κBp65 mRNA in spleen B cells, with TLR7 mRNA positively linked to anti-dsDNA titers and negatively to serum C3. Further cellular work demonstrates that JQZF reverses the increased IRAK1 and TRAF6 expression seen after miR146a inhibition. Additionally, post-ERα inhibition, JQZF continues to upregulate miR146a and more significantly reduces TLR7 mRNA expression (P < 0.01), pointing to ERα's pivotal role in the miR146a-TLR7 axis. These results indicate JQZF alleviates SLE by adjusting the ERα-miR146a-TLR7 loop, showcasing its mechanism and therapeutic potential for SLE.

Modularized supramolecular assemblies for hypoxia-activatable fluorescent visualization and image-guided theranostics.

Rationale: Molecular imaging of microenvironment by hypoxia-activatable fluorescence probes has emerged as an attractive approach to tumor diagnosis and image-guided treatment. Difficulties remain in its translational applications due to hypoxia heterogeneity in tumor microenvironments, making it challenging to image hypoxia as a reliable proxy of tumor distribution. Methods: We report a modularized theranostics platform to fluorescently visualize hypoxia via light-modulated signal compensation to overcome tumor heterogeneity, thereby serving as a diagnostic tool for image-guided surgical resection and photodynamic therapy. Specifically, the platform integrating dual modules of fluorescence indicator and photodynamic moderator using supramolecular host-guest self-assembly, which operates cooperatively as a cascaded "AND" logic gate. First, tumor enrichment and specific fluorescence turn-on in hypoxic regions were accessible via tumor receptors and cascaded microenvironment signals as simultaneous inputs of the "AND" gate. Second, image guidance by a lighted fluorescence module and light-mediated endogenous oxygen consumption of a photodynamic module as dual inputs of "AND" gate collaboratively enabled light-modulated signal compensation in situ, indicating homogeneity of enhanced hypoxia-related fluorescence signals throughout a tumor. Results: In in vitro and in vivo analyses, the biocompatible platform demonstrated several strengths including a capacity for dual tumor targeting to progressively facilitate specific fluorescence turn-on, selective signal compensation, imaging-time window extension conducive to precise normalized image-guided treatment, and the functionality of tumor glutathione depletion to improve photodynamic efficacy. Conclusion: The hypoxia-activatable, image-guided theranostic platform demonstrated excellent potential for overcoming hypoxia heterogeneity in tumors.

CT semi-quantitative score used as risk factor for hyponatremia in patients with COVID-19: a cross-sectional study.

Purpose: Chest computed tomography (CT) is used to determine the severity of COVID-19 pneumonia, and pneumonia is associated with hyponatremia. This study aims to explore the predictive value of the semi-quantitative CT visual score for hyponatremia in patients with COVID-19 to provide a reference for clinical practice. Methods: In this cross-sectional study, 343 patients with RT-PCR confirmed COVID-19, all patients underwent CT, and the severity of lung lesions was scored by radiologists using the semi-quantitative CT visual score. The risk factors of hyponatremia in COVID-19 patients were analyzed and combined with laboratory tests. The thyroid function changes caused by SARS-CoV-2 infection and their interaction with hyponatremia were also analyzed. Results: In patients with SARS-CoV-2 infection, the total severity score (TSS) of hyponatremia was higher [M(range), 3.5(2.5-5.5) vs 3.0(2.0-4.5) scores, P=0.001], implying that patients with hyponatremia had more severe lung lesions. The risk factors of hyponatremia in the multivariate regression model included age, vomiting, neutrophils, platelet, and total severity score. SARS-CoV-2 infection impacted thyroid function, and patients with hyponatremia showed a lower free triiodothyronine (3.1 ± 0.9 vs 3.7 ± 0.9, P=0.001) and thyroid stimulating hormone level [1.4(0.8-2.4) vs 2.2(1.2-3.4), P=0.038]. Conclusion: Semi-quantitative CT score can be used as a risk factor for hyponatremia in patients with COVID-19. There is a weak positive correlation between serum sodium and free triiodothyronine in patients with SARS-CoV-2 infection.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.