The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.

S-Nitrosylation is a reversible covalent post-translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post-translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant S- nitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation. MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed. RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction. CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Repurposing AS1411 for constructing ANM-PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

PAX1 and SOX1 gene methylation as a detection and triage method for cervical intraepithelial neoplasia diagnosis.

INTRODUCTION: Methylation assays have demonstrated potential as dependable and high-precision approaches for identifying or triaging individuals with cervical cancer (CA) or cervical intraepithelial neoplasia (CIN). Our investigation aimed to assess the efficacy of diagnosis and triage of the PAX1/SOX1 methylation panel in detecting CIN or CA. METHODS: A total of 461 patients with abnormal high-risk human papillomavirus (hrHPV) or cytology test results were recruited for this study. Each patient underwent an assortment of assessments comprising cytology test, hrHPV test, colposcopy examination, and PAX1 and SOX1 methylation test. RESULTS: The extent of methylation of both genes demonstrates a positive correlation with the severity of CIN lesions and CA. To determine the correlation for patients with CIN2 or worse (CIN2+), the area under curve (AUC) was 0.821 (95%CI 0.782-0.853) for PAX1 and 0.800 (95%CI 0.766-0.838) for SOX1, while for CIN3 or worse (CIN3+),0.881 (95%CI 0.839-0.908) for PAX1 and 0.867 (95% 0.830-0.901) for SOX1. The PAX1/SOX1 methylation marker panel performed sensitivity and specificity of 77.16% and 91.67% for CIN2+, 84.76% and 90.50% for CIN3+, respectively. Regarding triaging hrHPV+ patients, the PAX1/SOX1 methylation test only referred 11.83% of the patients who are unnecessary for coloscopy examination, which is comparatively lower than cytology， thereby signifying a promising triage strategy for hr-HPV positive women. Furthermore, we observed that the positive PAX1/SOX1 methylation test result for untreated CIN1 or less patients would result in a higher likelihood of progression upon a 24-month follow-up visit. CONCLUSION: The present investigation demonstrates that the PAX1/SOX1 methylation marker panel exhibits a favorable diagnostic performance in CIN detection and holds the potential to be employed for individual CIN tests or hrHPV-positive triage.

Autoantibodes to GP210 are a metric for UDCA responses in primary biliary cholangitis.

Objectives: Antibodies to gp210 and sp100 are specific and unique anti-nuclear autoantibodies (ANAs) associated with primary biliary cholangitis (PBC). Importantly the presence of anti-gp210 and anti-sp100 responses is indicative of poor clinical outcomes. However, the utility of measuring titers of these antibodies remains unclear. Materials and methods: Using the in-house purified gp210 (HSA108-C18) and sp100 (amino acid position 296-386), we quantitatively measured serum autoantibodies to gp210 and sp100 using chemiluminescence immunoassay (CLIA) in a very large cohort of 390 patients with PBC, including 259 cases with no prior ursodesoxycholic acid (UDCA) treatment and 131 cases with UDCA treatment. We also analyzed serial changes in anti-gp210 and anti-sp100 levels in 245 sequential samples from 88 patients. Results: In our cross-sectional analysis, we detected anti-gp210 immunoglobulin G (IgG) and anti-sp100 IgG autoantibodies in 129 out of 390 (33.1%) and 80 out of 390 (20.5%) PBC patients, respectively. Multivariate analysis revealed that serum IgG (st.ß = 0.35, P = 0.003) and gamma-glutamyltransferase (GGT) (st.ß = 0.23, P = 0.042) levels at baseline were independently associated with anti-gp210 concentrations. In serial testing, we observed significant fluctuations in anti-gp210 antibody levels. These fluctuations reflected responsiveness to UDCA therapy, particularly in anti-gp210-positive patients with initially lower concentrations in the stages of disease. Conclusions: Our study reflects that quantitative changes of anti-gp210 antibody are indicative of UDCA responses. There is a great need for newer metrics in PBC and we suggest that a more detailed and longer study of these unique ANAs is warranted.

Microwave-assisted esterification and electro-enhanced solid-phase microextraction of omega-3 polyunsaturated fatty acids in eggs.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), a type of fatty acid that has many health benefits, are of increasing concern. Herein, we developed a method for the rapid esterification and enrichment of ω-3 PUFAs in eggs, which includes microwave-assisted esterification (MAE) and electrically enhanced solid-phase microextraction (EE-SPME). Combined with gas chromatographic, efficient detection of ω-3 PUFAs was achieved in eggs. Under microwave radiation, the esterification efficiency exhibited a significant increase ranging from 5.06 to 10.65 times. The EE-SPME method reduced extraction time from 50 to 15 min. In addition, improvements in extractive fiber coating materials were explored, which ensured efficient extraction of ω-3 PUFAs. Under the optimal conditions, the method displayed a low detection limit (1.01-1.54 µg L-1), good recoveries (85.82%-106.01%), and wide linear range (7.5-1000 µg L-1), which was successfully applied to determine ω-3 PUFAs in real egg samples.

A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer.

Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

Association of CCR6 functional polymorphisms with Primary Biliary Cholangitis.

The biliary epithelial cells release CC chemokine receptor 6 (CCR6) ligand 20 (CCL20), leading to recruitment of CCR6+ T cells and subsequent infiltration into the biliary epithelium in primary biliary cholangitis patients. Previous genome-wide multi-national meta-analysis, including our Han Chinese cohort, showed significant association of CCR6 and CCL20 single nucleotide polymorphisms (SNP) with PBC. We report here that significantly associated SNPs, identified in the CCR6 locus based on our Han Chinese genome-wide association study, can be separated into "protective" and "risk" groups, but only "risk" SNPs were confirmed using a separate Han Chinese PBC cohort. Only weak association of CCL20 SNPs was observed in Han Chinese PBC cohorts. Fine-mapping and logistical analysis identified a previously defined functional variant that, leads to increased CCR6 expression, which contributed to increased genetic susceptibility to PBC in Han Chinese cohort.

Natural Product Baohuoside I Impairs the Stability and Membrane Location of MRP2 Reciprocally Regulated by SUMOylation and Ubiquitination in Hepatocytes.

Epimedii Folium (EF) is a botanical dietary supplement to benefit immunity. Baohuoside I (BI), a prenylated flavonoid derived from EF, has exhibited the cholestatic risk before. Here, the mechanism of BI on the stability and membrane localization of liver MRP2, a bile acid exporter in the canalicular membrane of hepatocytes, was investigated. The fluorescent substrate of MRP2, CMFDA was accumulated in sandwich-cultured primary mouse hepatocytes (SCH) under BI stimulation, followed by reduced membrane MRP2 expression. BI triggered MRP2 endocytosis associated with oxidative stress via inhibition of the NRF2 signaling pathway. Meanwhile, BI promoted the degradation of MRP2 by reducing its SUMOylation and enhancing its ubiquitination level. Co-IP and fluorescence colocalization experiments all proved that MRP2 was a substrate protein for SUMOylation for SUMO proteins. CHX assays showed that SUMO1 prolonged the half-life of MRP2 and further increased its membrane expression, which could be reversed by UBC9 knockdown. Correspondingly, MRP2 accumulated in the cytoplasm by GP78 knockdown or under MG132 treatment. Additionally, the SUMOylation sites of MRP2 were predicted by the algorithm, and a conversion of lysines to arginines at positions 940 and 953 of human MRP2 caused its decreased stability and membrane location. K940 was further identified as the essential ubiquitination site for MRP2 by an in vitro ubiquitination assay. Moreover, the decreased ubiquitination of MRP2 enhanced the SUMOylation MRP2 and vice versa, and the crosstalk of these two modifiers could be disrupted by BI. Collectively, our findings indicated the process of MRP2 turnover from the membrane to cytoplasm at the post-translational level and further elucidated the novel toxicological mechanism of BI.

[Effect of Land Use on the Stability of Soil Organic Carbon in a Karst Region].

The composition of soil organic carbon and its stability mechanism are the key to understanding the terrestrial carbon sink capacity. The stability of soil organic carbon in a karst ecosystem greatly affects the soil carbon fixation capacity. In order to understand the impact of human activities on the stability of soil organic carbon in karst areas, the karst valley area of Zhongliang Mountain in Chongqing was selected as an example, and soil samples of four typical land use modes (mixed forest, bamboo forest, grassland, and cultivated land) were collected in layers to analyze the total organic carbon (TOC) and heavy fraction organic carbon (HFOC). The distribution characteristics of light fraction organic carbon (LFOC), labile organic carbon (LOC), and recalcitrant organic carbon (ROC) were analyzed quantitatively by using a structural equation model to provide basic data for soil carbon sink assessment and soil quality protection in karst areas. The results showed that the organic carbon components under different land use patterns in karst areas had obvious surface accumulation, and the content of organic carbon components in the surface layer was 1.2 times that in the bottom layer. Except for LFOC, the content of other organic carbon components was the highest in the mixed forest, followed by that in the bamboo forest and wasteland, with the lowest in cultivated land. Mixed forest ω(TOC) content was the highest, 42.5 g·kg-1, followed by that of bamboo forest (36.6 g·kg-1) and grassland (18.7 g·kg-1), and cultivated land content was the lowest, 13.4 g·kg-1. The soil organic carbon content of cultivated land was 68.5%, 63.5%, and 28.3% lower than that of mixed forest, bamboo forest, and grassland, respectively. Mixed forest had the highest content of ω(HFOC), 21 g·kg-1, followed by those of bamboo forest (20.9 g·kg-1), grassland (18.2 g·kg-1), and cultivated land (13.5 g·kg-1). The mixed forest ω(LOC) content was the highest, 16.3 g·kg-1, followed by those of bamboo forest (14.9 g·kg-1), grassland (11.5 g·kg-1), and cultivated land (5.3 g·kg-1). Mixed forest ω (ROC) content was the highest, 25.7 g·kg-1, followed by those of bamboo forest (21.6 g·kg-1), grassland (15.9 g·kg-1), and cultivated land (10.3 g·kg-1). The bamboo forest land ω(LFOC) content was 15.9 g·kg-1, followed by those of mixed forest (13.9 g·kg-1), grassland (7.3 g·kg-1), and cultivated land (4.9 g·kg-1). The recalcitrant organic carbon index (ROCI) was used to indicate the stability of soil organic carbon. The variation range of ROCI was 33.9%-64.5%, of which the highest was mixed forest (64.5%-66.3%), and the lowest was cultivated land (33.8%-39.6%). The ROCI of mixed forest, bamboo forest, and grassland were 1.8 times, 1.6 times, and 1.4 times that of cultivated land, respectively. Karst area ω (inert organic carbon) content and ROCI showed that human agricultural activities caused the reduction in soil organic carbon content and the destruction of soil physical structure, resulting in the accelerated decomposition and turnover rate of soil organic matter. The most important factor affecting soil stability in karst areas was soil pH. Tillage activities caused soil pH to rise, reduced soil microbial activity, and were not conducive to the accumulation of the inert organic carbon and soil organic carbon pool in the soil.

Intensive Care Unit Nurses' Attitudes Toward Truth-Telling, Life-Sustaining Treatment, and Decision-Making Intention for End-of-Life Patients: A Cross-sectional Survey.

Truth-telling and life-sustaining treatment decisions are important elements of the quality of patients' care at the end of life. As the primary caregivers of patients at the end of life in intensive care units (ICUs), ICU nurses play an important role in patient decision making and hospice care. This study aimed to investigate and analyze ICU nurses' attitudes toward truth-telling, attitudes toward end-of-life life-sustaining treatment, and end-of-life decision-making behavioral intentions. One hundred twenty-two ICU nurses participated in this cross-sectional survey. Data were collected using a validated questionnaire. The results showed that ICU nurses' attitudes toward telling patients the truth and end-of-life life-sustaining treatment were both positive, but further improvement is needed. Nurses have a higher willingness to make palliative care decisions for patients at the end of life and to help patients achieve a good death. The truth-telling attitude, the life-sustaining treatment attitude, and whether they knew that cardiopulmonary resuscitation could be legally forgone at the end of life were factors influencing ICU nurses' behavioral intention toward decision making for patients at the end of life (all P s < .05). We conclude that nurses' participation in truth-telling and end-of-life decision making should be promoted, and timely hospice care should be provided to patients to help them achieve a good death.

Membrane-protected magnetic covalent organic framework for efficient extraction of estrogens in dairy products.

The presence of estrogens residues in dairy products is a growing concern due to their potential health risk. Herein, in this study, we have developed a membrane-protected magnetic solid-phase extraction (MP-MSPE) method that utilized a magnetic adsorbent (Fe3O4@COF-LZU1) with in-situ growth for the efficient extraction of estrone (E1), 17ß-estradiol (E2), and estriol (E3). When combined with HPLC-FLD, this method allows for the efficient detection of estrogens in dairy products. The stability of the MP-MSPE was improved by the presence of a dialysis membrane, which remained a high extraction efficiency (90 %) even after ten reuse cycles. The hydrogen bonding, π-π interactions and pore size effect contribute to the excellent adsorption of three estrogens onto Fe3O4@COF-LZU1. Under optimal conditions, the method exhibits a low detection limit (0.01-0.15 µg L-1), wide linear range (0.1-800 µg L-1), and favorable recoveries (77.3 %-109.4 %) at three concentration levels (10, 50 and 100 µg L-1). This proposed method is characterized by its simplicity, high efficiency and eco-friendliness, making it a promising approach for extracting estrogens from dairy products.

Operation Status of the Mutual Aid Human Milk Bank for Preterm Infants and Data Analysis.

Objectives: This study aimed to investigate the matching degree between the donated supply and demand, clinical characteristics of both donors and recipients, along with the operation cost. Methods: From January 1, 2018 to December 31, 2021, the data on human milk donation and usage, the clinical characteristics of donors and recipients, and the cost of each operating center were collected from the Manual Donation Registration Form and Information Management System of the selected human milk bank. Results: During the four years that the human milk bank was in operation, the volume of donated milk was slightly greater than the volume of consumed milk. A total of 1364 donors donated 2434.63 liters of qualified human milk, for RMB 1,791,000 (USD 257, 202), ie, RMB 385.3 (USD 55.3)/L; 97.8% of the donors were preterm puerperae, and 59% of the donors donated between 1 week and 1 month after delivery. All recipients were preterm infants and received donated human milk for a duration of 9.4 days on average. During the four years of operation, the proportion of donors who had previously received donated milk among all donors showed an overall increasing trend, while the incidence of NEC in preterm infants gradually decreased. Conclusions: The increasingly optimized structure of donors, the more economical operation, and the fact that the use of donated milk may not affect breastfeeding of the recipients have made it a human milk bank operation mode worthy of promotion.

[Relationship between Iron Metabolic Parameters and Platelet Counts in Blood Donors].

OBJECTIVE: To investigate the correlation of iron metabolic parameters with platelet counts in blood donors. METHODS: A total of 400 blood donors who met requirements of apheresis platelet donation were collected, and their hematological parameters were analyzed. The donors were divided into low ferritin group and normal group, the differences of hematological parameters between the two groups were compared, and the correlation of iron metabolic parameters and routine hematology parameters with platelet counts were analyzed. RESULTS: Whether male or female, low ferritin group had higher platelet counts than normal group (P < 0.01). Among the iron metabolic parameters, the platelet counts was negatively correlated with serum ferritin (SF), serum iron (SI), and transferrin saturation (TSAT) (r =-0.162, r =-0.153, r =-0.256), and positively correlated with total iron binding capacity (TIBC) and unsaturated iron binding capacity (UIBC) (r =0.219, r =0.294) in female blood donors. Platelet counts was also negatively correlated with SF, SI and TSAT (r =-0.188, r =-0.148, r =-0.224) and positively correlated with UIBC (r =0.220) in male blood donors. Among the routine hematology parameters, platelet counts was negatively correlated with mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and reticulocyte hemoglobin equivalent (Ret-He) in female blood donors (r =-0.236, r =-0.267, r =-0.213, r =-0.284). Platelet counts was also negatively correlated with MCH, MCHC and Ret-He in male blood donors (r =-0.184, r =-0.221, r =-0.209). CONCLUSION: In blood donors with low C-reactive protein level, the lower the iron store capacity, the lower the iron utilization, and the platelet counts tends to rise.

CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral Deficits in a Mouse Model of Sepsis-Associated Encephalopathy.

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1ß, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.

J147 ameliorates sepsis-induced depressive-like behaviors in mice by attenuating neuroinflammation through regulating the TLR4/NF-κB signaling pathway.

Neuroinflammation is associated with the pathophysiology of depression. The molecular mechanism of depressive-like behavior caused by sepsis-associated encephalopathy (SAE) is incompletely understood. J147 (an analog of curcumin) has been reported to improve memory and has neuroprotective activity, but its biological function in the depressive-like behavior observed in SAE is not known. We investigated the effects of J147 on lipopolysaccharide (LPS)-induced neuroinflammatory, depressive-like behaviors, and the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signal pathway in the mouse hippocampus and microglia (BV2 cells). The forced-swimming test (FST) and tail-suspension test (TST) were undertaken for assessment of depressive-like behaviors. Expression of the proinflammatory genes interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were measured using RT-qPCR and ELISA. Microglia activation was detected using immunofluorescence staining. The TLR4/NF-κB signaling pathway was studied using western blotting and immunofluorescence staining. J147 pretreatment markedly downregulated expression of IL-6, IL-1ß, and TNF-α, and the mean fluorescence intensity of ionized calcium-binding adapter protein-1 in microglia. J147 restrained LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB), inhibitor of nuclear factor kappa B (IκB) degradation, and TLR4 activation in microglia. J147 administration inhibited bodyweight loss, mortality, microglia activation, and depressive-like behaviors in LPS-treated mice. In conclusion, J147 ameliorated the sepsis-induced depressive-like behaviors induced by neuroinflammation through attenuating the TLR4/NF-κB signaling pathway in microglia.

Vector flow mapping analysis of left ventricular vortex performance in type 2 diabetic patients with early chronic kidney disease.

BACKGROUND: Diabetes is the leading cause of chronic kidney disease (CKD) and contributes to an elevated incidence of diastolic dysfunction in the early stages of CKD. Intracardiac vortex is a novel hemodynamic index for perceiving cardiac status. Here, we visualized left ventricular (LV) vortex characteristics using vector flow mapping (VFM) in type 2 diabetic patients with early CKD. METHODS: This cross-sectional study included 67 controls and 89 type 2 diabetic patients with stages 2-3a CKD. All subjects underwent transthoracic echocardiographic examination. LV anterior vortex during early diastole (E-vortex), atrial contraction (A-vortex) and systole (S-vortex) were assessed using VFM in the apical long-axis view. Its relation to glycemia or LV filling echocardiographic parameters were further analyzed using correlation analysis. RESULTS: Type 2 diabetic patients with early CKD had a small area (439.94 ± 132.37 mm2 vs. 381.66 ± 136.85 mm2, P = 0.008) and weak circulation (0.0226 ± 0.0079 m2/s vs. 0.0195 ± 0.0070 m2/s, P = 0.013) of E-vortex, but a large area (281.52 ± 137.27 mm2 vs. 514.83 ± 160.33 mm2, P ˂ 0.001) and intense circulation (0.0149 ± 0.0069 m2/s vs. 0.0250 ± 0.0067 m2/s, P < 0.001) of A-vortex compared to controls. CKD patients with poorly controlled hyperglycemia had stronger A-vortex (area: 479.06 ± 146.78 mm2 vs. 559.96 ± 159.27 mm2, P = 0.015; circulation: 0.0221 ± 0.0058 m2/s vs. 0.0275 ± 0.0064 m2/s, P < 0.001) and S-vortex (area: 524.21 ± 165.52 mm2 vs. 607.87 ± 185.33 mm2, P = 0.029; circulation: 0.0174 ± 0.0072 m2/s vs. 0.0213 ± 0.0074 m2/s, P = 0.015), and a longer relative duration of S-vortex (0.7436 ± 0.0772 vs. 0.7845 ± 0.0752, P = 0.013) than those who had well-controlled hyperglycemia. Glycemia, and E/A (a LV filling parameter) were respectively found to had close correlation to the features of A-vortex and S-vortex (all P < 0.05). CONCLUSIONS: Abnormal LV vortices were detected in type 2 diabetic patients with early CKD using VFM, especially in those who neglected hyperglycemic control. LV vortex might be a promising parameter to slow or halt the hyperglycemia-induced diastolic dysfunction in early CKD.

Effects of sublingual colostrum application on oral and intestinal flora of extremely low birth weight infants.

BACKGROUND: The aim of this study is to analyze the effects of colostrum application on the establishment of normal flora in the intestinal tracts and oral cavities of extremely low birth weight infants (ELBWI). METHODS: A prospective cohort study design was adopted following the STROBE guidelines (Supplementary File 1). Colostrum was administered immediately after obtaining maternal breast milk using a special sterile cotton swab. There were no specific treatments for infants who did not receive colostrum. This experiment was completed on day 5 post-birth and the patients were divided into the colostrum and control groups, corresponding to whether or not colostrum was administered. Throat swabs and stool samples were collected on days 1 and 5 post-birth. RESULTS: Using the conventional bacteria cultivation technique, the detection rate of bacteria in 98 cases of meconium at birth was 15.31%. On day 5, the detection rates of Staphylococcus in the colostrum and control groups were 36.54% and 34.78%, with no significant difference between them (P = 0.856), and that of Enterococcus was 26.92% and 13.04%, respectively, with no statistically significant difference (P = 0.089). Likewise, at birth, the detection rate of bacteria in 98 cases of throat swabs was 27.55%. On day 5, the detection rate of Streptococcus in the colostrum and control groups was 78.85% and 50.00%, respectively, recording a statistically significant difference this time (P = 0.003). CONCLUSION: Colostrum application had limited effects on intestinal flora colonization but contributes to physiological oral flora colonization.