Effects of postprandial exercise timing on blood glucose and fluctuations in patients with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to assess how moderate-intensity aerobic exercise performed 45 minutes and 90 minutes after a meal affects blood glucose levels and fluctuations in individuals diagnosed with type 2 diabetes mellitus (T2DM). METHODS: Twenty-two patients with T2DM, who were solely receiving oral hypoglycemic medication, were enrolled and divided randomly into two categories: those exercising 45 minutes after a meal (45-minute postprandial exercise group) and those exercising 90 minutes post-meal (90-minute postprandial exercise group). Both groups engaged in a 30-minute session of moderate-intensity aerobic stationary bike exercise following breakfast. This aerobic exercise regimen consisted of two stages, with the groups switching exercise timings after the initial phase. Continuous glucose monitoring (CGM) was utilized to evaluate the blood glucose levels and fluctuations in the participants. RESULTS: After breakfast, both overall daily blood glucose levels and the area under the curve for blood glucose following breakfast were reduced in the 45-minute postprandial exercise group compared to the 90-minute postprandial exercise group. The 45-minute postprandial exercise group demonstrated greater time spent within the target glucose range and less time above the target range than the 90-minute postprandial exercise group. Additionally, measures such as standard deviation, mean amplitude of glycemic excursions, largest amplitude of glycemic excursions, and postprandial glucose excursion for breakfast, peak postprandial glucose levels, and duration of elevated glucose levels were all lower in the 45-minute postprandial exercise group compared to the 90-minute postprandial exercise group. CONCLUSIONS: Moderate-intensity aerobic exercise lasting 45 minutes after meals was found to be more efficient in decreasing blood glucose levels and minimizing fluctuations compared to exercising 90 minutes after meals in patients with T2DM. Additionally, it notably reduced the peak in blood glucose levels after meals.

Synthesis and antibacterial activities of heterocyclic ring-fused 20(S)-protopanaxadiol derivatives.

Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5-4 µg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo, following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner.

Symptom Cluster Assessment Tools for Gastric Cancer Care in China: A Comprehensive Review.

Gastric cancer is a common malignant tumor, and its incidence rate ranks first among malignant tumors of the digestive tract, seriously endangering human physical and mental health. Changes in the physiological state of gastric cancer patients can bring about many physical and psychological symptoms and have a serious impact on their quality of life. Symptom clusters are 2 or more concurrently occurring and interrelated symptoms, with the core symptoms within the cluster remaining stable over time and the symptoms in the cluster being independent of each other. The prerequisite for solving this problem is to screen out appropriate symptom assessment tools according to the clinical situation. The aim of this study was to provide a reference for the development of assessment tools suitable for symptom clusters of gastric cancer patients in China, and to provide evidence for the subsequent optimization of symptom management and some clinical decisions. The contents, application, advantages, and disadvantages of symptom cluster assessment tools for gastric cancer patients in China and abroad were reviewed, and the basic situation and contents of each assessment tool were compared. In China, most of the assessment tools used in domestic gastric cancer research institutes were imported from foreign scales, with a long time span and low specificity for symptoms in various stages of disease development at present. Scholars should be encouraged to develop time-specific assessment tools for the disease characteristics of gastric cancer patients in China, and actively explore the pathogenesis and influencing factors of symptom clusters in this population.

Ultrasound-Activated Probiotics Vesicles Coating for Titanium Implant Infections Through Bacterial Cuproptosis-Like Death and Immunoregulation.

Implant-associated infections (IAIs) are the main cause of prosthetic implant failure. Bacterial biofilms prevent antibiotic penetration, and the unique metabolic conditions in hypoxic biofilm microenvironment may limit the efficacy of conventional antibiotic treatment. Escaping survival bacteria may not be continually eradicated, resulting in the recurrence of IAIs. Herein, a sonosensitive metal-organic framework of Cu-TCPP (tetrakis(4-carboxyphenyl) porphyrin) nanosheets and tinidazole doped probiotic-derived membrane vesicles (OMVs) with high-penetration sonodynamic therapy (SDT), bacterial metabolic state interference, and bacterial cuproptosis-like death to eradicate IAIs is proposed. The Cu-TCPP can convert O2 to toxic 1O2 through SDT in the normoxic conditions, enhancing the hypoxic microenvironment and activating the antibacterial activity of tinidazole. The released Cu(II) under ultrasound can be converted to Cu(I) by exogenous poly(tannic acid) (pTA) and endogenous glutathione. The disruption of the bacterial membrane by SDT can enhance the Cu(I) transporter activity. Transcriptomics indicate that the SDT-enhanced Cu(I) overload and hypoxia-activated therapy hinder the tricarboxylic acid cycle (TCA), leading to bacterial cuproptosis-like death. Moreover, the OMVs-activated therapy can polarize macrophages to a M2-like phenotype and facilitate bone repair. The sonodynamic biofilm microenvironment modulation strategy, whereby the hypoxia-enhanced microenvironment is potentiated to synergize SDT with OMVs-activated therapy, provides an effective strategy for antibacterial and osteogenesis performance.

The Beijing angle closure progression study: design and methodology.

Purpose: The purpose of this study is to summarize the design and methodology of a large-scale trial in northern China, the Beijing Angle Closure Progression Study (BAPS). This trial is designed to explore the 5-year incidence of primary angle-closure suspect (PACS) progressing to primary angle-closure (PAC) or primary angle-closure glaucoma (PACG) and to determine the possible risk factors of disease progression. Methods/design: The BAPS is a clinic-based, multicenter, noninterventional trial conducted on a sample of urban Chinese adults. Consecutive eligible patients who meet PACS diagnostic criteria will be recruited from eight participating centers, with the trial commencing on August 4, 2022. The target sample size is set at 825 subjects, with follow up planned for a minimum period of 5 years. Baseline examination will include presenting visual acuity, best corrected visual acuity, intraocular pressure (IOP), undilated slit-lamp biomicroscopy, stereoscopic evaluation of the optic disc, visual field test, optical coherence tomography evaluation of retinal nerve fiber layer, ultrasound biomicroscopy and IOLMaster. Questionnaires will also be used to collect detailed personal history. Patients are scheduled to visit the glaucoma clinic every 12 months and may visit the emergency room in case of acute attack of angle closure. Study endpoints include acute PAC episodes, elevated IOP, peripheral anterior synechiae, glaucomatous visual field defect, or glaucomatous abnormality of optic nerve. Discussion: The BAPS will provide data on the 5-year incidence of PACS progressing to PAC or PACG and determine the risk factors for disease progression. This study will also help redefine high-risk patients with PACS.

Biomimetic Phthalocyanine-Based Covalent Organic Frameworks with Tunable Pendant Groups for Electrocatalytic CO2 Reduction.

Electrocatalytic carbon dioxide reduction reaction (CO2RR) is an effective way of converting CO2 into value-added products using renewable energy, whose activity and selectivity can be in principle maneuvered by tuning the microenvironment near catalytic sites. Here, we demonstrate a strategy for tuning the microenvironment of CO2RR by learning from the natural chlorophyll and heme. Specifically, the conductive covalent organic frameworks (COFs) linked by piperazine serve as versatile supports for single-atom catalysts (SACs), and the pendant groups modified on the COFs can be readily tailored to offer different push-pull electronic effects for tunable microenvironment. As a result, while all the COFs exhibit high chemical structure stability under harsh conditions and good conductivity, the addition of -CH2NH2 can greatly enhance the activity and selectivity of CO2RR. As proven by experimental characterization and theoretical simulation, the electron-donating group (-CH2NH2) not only reduces the surface work function of COF, but also improves the adsorption energy of the key intermediate *COOH, compared with the COFs with electron-withdrawing groups (-CN, -COOH) near the active sites. This work provides insights into the microenvironment modulation of CO2RR electrocatalysts at the molecular level.

Value of near-infrared spectroscopy in evaluating the risk of neonatal necrotizing enterocolitis: A systematic review and meta-analysis.

PURPOSE: Recently, near-infrared spectroscopy (NIRS) has been proposed for diagnosing patients with neonatal necrotizing enterocolitis (NEC). However, a consensus on the credibility of NIRS in evaluating NEC risk has not been reached. This meta-analysis aimed to evaluate the relationship between NEC and splanchnic regional tissue oxygen saturation (SrSO2) and cerebral regional tissue oxygen saturation (CrSO2) detected by NIRS to clarify the clinical value of NIRS in evaluating the risk of NEC. METHODS: Studies using NIRS to monitor regional tissue oxygen saturation (rSO2) in neonates with NEC published in PubMed, Web of Science, Embase, and the Cochrane Library were searched from their inception to 30 July 2023. Mean difference (MD), pooled sensitivity, and pooled specificity, along with their 95 % confidence intervals (CI), were calculated, and the random-effects model was used for analysis. This study was registered with PROSPERO (no. CRD42022326783). RESULTS: Fourteen studies including 938 neonates (172 NEC, 766 controls) were identified. SrSO2 was significantly decreased in patients with NEC (MD: -12.52, 95 % CI: -15.95, -9.08; P < 0.00001), and this decrease was observed even before the diagnosis of NEC (MD: -13.79, 95 % CI: -17.97, -9.62; P < 0.00001). The pooled sensitivity and specificity of SrSO2 were 0.80 (95 % CI: 0.69, 0.88) and 0.90 (95 % CI: 0.61, 0.98), respectively. However, no significant difference in CrSO2 was found (MD: -4.37, 95 % CI: -10.62, 1.88; P = 0.17). CONCLUSIONS: SrSO2, detected by NIRS, could be a valuable non-invasive method for differentiating NEC from non-NEC neonates. It could differentiate prior to NEC diagnosis.

LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Effect of blueberry intervention on endothelial function: a systematic review and meta-analysis.

Introduction: Endothelial dysfunction indicates blood vessel injury and is a risk factor for cardiovascular diseases. Blueberry has been approved for its benefits on human health, especially on cardiovascular function. However, its effect on endothelial function remains unclear. We conducted a systematic review and meta-analysis to explore the impact of blueberries on endothelial function in adults. Methods: We searched PubMed, Web of Science, Embase, and the Cochrane Library, 16 studies were included in the systematic review, and 11 were used for the meta-analysis. Data associated with endothelial function were extracted and pooled as mean differences (MD) with 95% confidence intervals (CI). Results: Blueberry consumption significantly improved flow-mediated dilation (FMD) by 1.50% (95% CI: 0.81, 2.20; I2 = 87%) and reactive hyperemia index (RHI) by 0.26 (95% CI: 0.09, 0.42; I2 = 72%). A significant decrease in diastolic blood pressure (DBP) was also observed (MD: -2.20 mm Hg; 95% CI: -4.13, -0.27; I2 = 11%). Subgroup analysis indicated a significant decrease in blood pressure (Systolic blood pressure [SBP]: -3.92 mmHg; 95% CI: -6.88, -0.97; I2 = 20% and DBP: -2.20 mmHg; 95% CI: -4.13, -0.27; I2 = 11%) in the smoking population. However, SBP levels (MD: -1.43 mm Hg; 95% CI: -3.11, 0.26; I2 = 20%) and lipid status (high-density lipoprotein cholesterol [HDL-C]: 0.06; 95% CI: -0.04, 0.16; I2 = 77%; low-density lipoprotein cholesterol [LDL-C]: 0.05; 95% CI: -0.14, 0.24; I2 = 0%) did not significantly improve. Conclusion: Blueberry intervention improved endothelial function and DBP. Subgroup analysis revealed a notable improvement in blood pressure among the smoking population. However, no significant effects were observed on SBP, HDL-C, and LDL-C levels. Future research should delve into the mechanisms of endothelial improvement and verify blood pressure reduction in specific subpopulations through large-scale trials. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/, Identifier CRD42023491277.

U-shaped association between fasting blood glucose and suicide attempts in Chinese patients with first-episode drug-naïve major depressive disorder.

BACKGROUND: Evidence regarding the relationship between fasting blood glucose (FBG) and suicide attempts (SA) in patients with major depressive disorder (MDD) was limited. Therefore, the objective of this research was to investigate whether FBG was independently related to SA in Chinese patients with first-episode drug-naïve (FEDN) MDD after adjusting for other covariates. METHODS: The present study was a cross-sectional study. A total of 1718 participants (average age: 34.9 ± 12.4 years, 65.8% females) with FEDN MDD were involved in a hospital in China from September 2016 to December 2018. Multiple logistic regression analysis and smooth curve fitting were used to estimate the association between FBG and the risk of SA. The threshold effect was examined by the two-piecewise linear regression model. Interaction and stratified analyses were conducted according to sex, education, marital status, comorbid anxiety, and psychotic symptoms. RESULTS: The prevalence of SA in patients with FEDN MDD was 20.1%. The result of fully adjusted binary logistic regression showed FBG was positively associated with the risk of SA (odds ratio (OR) = 1.62, 95% CI: 1.13-2.32). Smoothing plots also revealed a nonlinear relationship between FBG and SA, with the inflection point of FBG being 5.34 mmol/l. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 0.53 (0.32-0.88, P = 0.014) and 1.48 (1.04-2.10, P = 0.030), respectively. CONCLUSIONS: A U-shaped relationship between FBG and SA in FEDN MDD patients was found, with the lowest risk of SA at a FBG of 5.34 mmol/l, indicating that both the lower and higher FBG levels may lead to an increased risk of SA.

Introduction of ex vivo perfusion of extended-criteria donor hearts in a single center in Asia.

The shortage of organs for heart transplantation has created a need to explore the use of extended-criteria organs. We report the preliminary use of normothermic TransMedics Organ Care System-an ex vivo approach to preserve extended-criteria brain-dead donor hearts. This System maintains a normal temperature, provides continuous perfusion and oxygenation, reduces ischemic time, and enables additional viability assessment options. In a retrospective single-centre study conducted from April 2020 to March 2023, four extended criteria brain-dead donor hearts were perfused and monitored using the Organ Care System. Suitability for transplantation was assessed based on stable or decreasing lactate levels, along with appropriate perfusion parameters. The Organ Care for use of the Organ Care System were coronary artery disease, left ventricular hypertrophy, high-dose inotrope use in the donor, a downtime exceeding 20 min, and a left ventricular ejection fraction of 40-50%. Three out of the four donor hearts were transplanted, while one was discarded due to rising lactate concentration. The three recipients had a higher surgical risk profile for heart transplant. All showed normal cardiac function and no primary graft dysfunction postoperatively. At 2-3 years post-transplant, all recipients have a ventricular function of > 60%, with only one showing evidence of mild rejection. The Organ Care System enables the successful transplantation of marginal donor organs in high-risk recipients, showcasing the feasibility of recruiting donors with extended criteria. This technique is safe and promising, expanding the donor pool and addressing the organ shortage in heart transplantation in Hong Kong.

Distinct epigenetic modulation of differentially expressed genes in the adult mouse brain following prenatal exposure to low-dose bisphenol A.

Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult mouse brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with more significant differentially expressed genes was observed in adult cortex from male offspring. Moreover, the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly associated with energy metabolism pathways. More evidence supporting impaired mitochondrial function included a decreased ATP level and a reduced number of mitochondria in the cortical neuron of the BPA group. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.

Identification and Verification of Ferroptosis-Related Genes in Keratoconus Using Bioinformatics Analysis.

Objective: Keratoconus is a commonly progressive and blinding corneal disorder. Iron metabolism and oxidative stress play crucial roles in both keratoconus and ferroptosis. However, the association between keratoconus and ferroptosis is currently unclear. This study aimed to analyze and verify the role of ferroptosis-related genes (FRGs) in the pathogenesis of keratoconus through bioinformatics. Methods: We first obtained keratoconus-related datasets and FRGs. Then, the differentially expressed FRGs (DE-FRGs) associated with keratoconus were screened through analysis, followed by analysis of their biological functions. Subsequently, the LASSO and SVM-RFE algorithms were used to screen for diagnostic biomarkers. GSEA was performed to explore the potential functions of the marker genes. Finally, the associations between these biomarkers and immune cells were analyzed. qRT‒PCR was used to detect the expression of these biomarkers in corneal tissues. Results: A total of 39 DE-FRGs were screened, and functional enrichment analysis revealed that the DE-FRGs were closely related to apoptosis, oxidative stress, and the immune response. Then, using multiple algorithms, 6 diagnostic biomarkers were selected, and the ROC curve was used to verify their risk prediction ability. In addition, based on CIBERSORT analysis, alterations in the immune microenvironment of keratoconus patients might be associated with H19, GCH1, CHAC1, and CDKN1A. Finally, qRT‒PCR confirmed that the expression of H19 and CHAC1 was elevated in the keratoconus group. Conclusion: This study identified 6 DE-FRGs, 4 of which were associated with immune infiltrating cells, and established a diagnostic model with predictive value for keratoconus.

Circ_0001495 influences the development of endometriosis through the miRNA-34c-5p/E2F3 axis.

Endometriosis is a chronic gynecological condition characterized by the presence of endometrial glands and stroma outside the uterine cavity., accounting for 7% of all female malignant tumors and 20%- 30% of malignant tumors of the female reproductive system. Multiple studies have shown that circular RNA (circRNA) has the potential to become a targeted target and marker for EM. However, the roles of circ_0001495 in EM are still unclear. Our research aims to reveal the molecular mechanism of circ_0001495 in EM. In this study, RT-PCR or western blot were conducted to determine mRNA and protein expression. cell viability, proliferation, migration, invasion, and apoptosis were assessed by CCK-8, EdU, wound healing, transwell, and flow cytometry analyses, respectively. Additionally, the targeting relationship between miR-34c-5p and circ_0001495 or E2F3 was confirmed through dual-luciferase reporter gene assay. We found significant overexpression of circ_0001495 in EM tissues and cells. Knockdown of circ_0001495 inhibited the proliferation, migration and invasion of ectopic endometrial stromal cells (EESCs) and increased cell apoptosis. Moreover, we found that circ_0001495 regulated E2F3 levels by interacting with miR-34c-5p in EESC. Furthermore, in vitro, miR-34c-5p inhibition or E2F3 overexpression could attenuate the effect of circ_0001495 silencing on EM progression. In addition, the vivo experiment demonstrated that inhibition of circ_0001495 could repress the development of endometriosis by regulating the miR-34c-5p/E2F3 axis. In conclusion, our study suggested that circ_0001495 promoted EM progression in vitro and in vivo through the miR-34c-5p/E2F3 axis, which might be a potential therapeutic target for EM.

Ultrasound-activated piezo-hot carriers trigger tandem catalysis coordinating cuproptosis-like bacterial death against implant infections.

Implant-associated infections due to the formation of bacterial biofilms pose a serious threat in medical healthcare, which needs effective therapeutic methods. Here, we propose a multifunctional nanoreactor by spatiotemporal ultrasound-driven tandem catalysis to amplify the efficacy of sonodynamic and chemodynamic therapy. By combining piezoelectric barium titanate with polydopamine and copper, the ultrasound-activated piezo-hot carriers transfer easily to copper by polydopamine. It boosts reactive oxygen species production by piezoelectrics, and facilitates the interconversion between Cu2+ and Cu+ to promote hydroxyl radical generation via Cu+ -catalyzed chemodynamic reactions. Finally, the elevated reactive oxygen species cause bacterial membrane structure loosening and DNA damage. Transcriptomics and metabolomics analysis reveal that intracellular copper overload restricts the tricarboxylic acid cycle, promoting bacterial cuproptosis-like death. Therefore, the polyetherketoneketone scaffold engineered with the designed nanoreactor shows excellent antibacterial performance with ultrasound stimulation and promotes angiogenesis and osteogenesis on-demand in vivo.

Isofraxidin attenuates dextran sulfate sodium-induced ulcerative colitis through inhibiting pyroptosis by upregulating Nrf2 and reducing reactive oxidative species.

BACKGROUND: Ulcerative colitis (UC), a non-specific gastrointestinal disease, is commonly managed with aminosalicylic acids and immunosuppressive agents to control inflammation and relieve symptoms, despite frequent relapses. Isofraxidin is a coumarin compound extracted from traditional Chinese medicine, exhibiting anti-inflammatory and antioxidant properties; however, its alleviating effect on UC remains unclear. Therefore, we investigated the mechanism of isofraxidin in lipopolysaccharide (LPS)-induced cell inflammation in human intestinal epithelial cell (HIEC) and human colorectal adenocarcinoma cells (Caco-2), as well as in dextran sulfate sodium (DSS)-induced UC in mice. METHODS: We established colitis models in HIEC and Caco-2 cells and mice with LPS and DSS, respectively. Additionally, NLRP3 knockout mice and HIEC cells transfected with NLRP3 silencing gene and ML385 illustrated the role of isofraxidin in pyroptosis and oxidative stress. Data from cells and mice analyses were subjected to one-way analysis of variance or a paired t-test. RESULTS: Isofraxidin significantly alleviated LPS-induced cell inflammation and reduced lactic dehydrogenase release. Isofraxidin also reversed DSS- or LPS-induced pyroptosis in vivo and in vitro, increasing the expression of pyroptosis-related proteins. Moreover, isofraxidin alleviated oxidative stress induced by DSS or LPS, reducing reactive oxidative species (ROS), upregulation nuclear factor erythroid 2-related factor 2 (Nrf2), and promoting its entry into the nucleus. Mechanistically, ML385 reversed the inhibitory effect of isofraxidin on ROS and increased pyroptosis. CONCLUSION: Isofraxidin can inhibit pyroptosis through upregulating Nrf2, promoting its entry into the nucleus, and reducing ROS, thereby alleviating DSS-induced UC. Our results suggest isofraxidin as a promising therapeutic strategy for UC treatment.

Sequential haplo-identical conditioning transplant regimen for pediatric patients with relapsed or refractory hemophagocytic lymphohistiocytosis.

Allogeneic hematopoietic stem cell transplantation (HSCT) currently stands as the sole remedy for individuals afflicted with hemophagocytic lymphohistiocytosis (HLH). In this study, we retrospectively evaluated how pediatric patients with relapsed or refractory (R/R) HLH responded to our institution's cocktail conditioning regimen. The disease was diagnosed according to criteria applicable to patients with familial/genetic, relapsing, or severe/persistent HLH. All donors were HLA haplo-identical family donors. In our cohort, sixty-five patients (P-HLH), including 28 with familial/genetic HLH, 36 with secondary HLH, and 1 with an unknown cause, underwent haplo-identical family donor HSCT. The conditioning regimen consisted of intravenous administration of etoposide (VP-16), busulfan, fludarabine, rabbit anti-human thymocyte globulin (r-ATG), and cyclophosphamide (Cy). Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GvHD) prevention. We observed that the median time for neutrophil recovery was 11 days (range, 8-24), and for platelet counts to exceed 20 × 109/L, it was 14 days (range, 7-130). There were 5 patients (7.7%) who experienced grades III to IV acute GvHD, and 6 patients (9.2%) developed extensive chronic GvHD. The estimated 3- and 5-year overall survival rates were 78.1% (95% CI, 65.8-84.6%) and 74.9% (95% CI, 61.2-84.4%), respectively. The estimated 3- and 5-year event-free survival rates were 73.5% (95% CI, 60.8-82.6%) and 70.3% (95% CI, 56.4-80.5%), respectively. Our findings demonstrate that our innovative conditioning regimen is both effective and safe, offering valuable insights for healthcare professionals evaluating the merits of existing therapies.

Exosome co-delivery of a STING agonist augments immunogenicity elicited by CVB3 VP1 vaccine via promoting antigen cross-presentation of CD8 + DCs.

The induction of a robust CD8+ T cell response is critical for the success of an antiviral vaccine. In this study, we incorporated a STING agonist (SA) 2'3'-cGAMP into a previously developed exosome-based CVB3 viral myocarditis vaccine (Exo-VP1) to enhance its ability to induce CD8+ T cell responses and immunoprotection. Our results showed that compared to free SA adjuvant, exosome-mediated co-delivery (ExoSA-VP1) significantly enhanced SA uptake by dendritic cells (DCs) and more potently stimulated DC maturation. Immunization of mice showed that the ExoSA-VP1 vaccine-induced higher levels of CVB3-specific T cell proliferation and cytotoxicity, significantly increased the percentage of IFN-γ+CD8+ rather than CD4+ T cells, effectively reduced cardiac viral loads, attenuated myocarditis and improved survival in mice compared to the previous Exo-VP1 vaccine. Further investigation showed that ExoSA-VP1 significantly increased both the percentage and antigen cross-presentation capacity of splenic CD8+ DCs. Depletion of these CD8+ DCs by cytochrome C administration nearly abolished the advantage of ExoSA-VP1 in dominantly inducing IFN-γ+CD8+ cytotoxic T lymphocyte (CTL) production in immunized mice. Taken together, our results demonstrated the potential of ExoSA-VP1 as a promising candidate for anti-CVB3 vaccines and provide insights into immune-enhancing strategies aiming at augmenting antigen cross-presentation by DCs and enhancing potent CTL responses.

Establishment of a TaqMan probe-based qPCR assay for detecting microsporidia Enterospora epinepheli in grouper.

Enterospora epinepheli is an intranuclear microsporidian parasite causing serious emaciative disease in hatchery-bred juvenile groupers (Epinephelus spp.). Rapid and sensitive detection is urgently needed as its chronic infection tends to cause emaciation as well as white faeces syndrome and results in fry mortality. This study established a TaqMan probe-based real-time quantitative PCR assays targeting the small subunit rRNA (SSU) gene of E. epinepheli. The relationship between the standard curve of cycle threshold (Ct) and the logarithmic starting quantity (SQ) was determined as Ct = -3.177 lg (SQ) + 38.397. The correlation coefficient (R2 ) was 0.999, and the amplification efficiency was 106.4%. The detection limit of the TaqMan probe-based qPCR assay was 1.0 × 101 copies/µL and that is 100 times sensitive than the traditional PCR method. There is no cross-reaction with other aquatic microsporidia such as Ecytonucleospora hepatopenaei, Nucleospora hippocampi, Potaspora sp., Ameson portunus. The intra-assay and inter-assay showed great repeatability and reproducibility. In addition, the test of clinical samples showed that this assay effectively detected E. epinepheli in the grouper's intestine tissue. The established TaqMan qPCR assays will be a valuable diagnostic tool for the epidemiological investigation as well as prevention and control of E. epinepheli.

A carboxymethyl chitosan/oxidized hyaluronic acid composite hydrogel dressing loading with stem cell exosome for chronic inflammation wounds healing.

Stem cell exosomes (Exo) play an important role in the transformation of macrophages, but the rapid clearance of Exo in vivo limits their therapeutic effects for chronic inflammation wounds healing. Here, stem cell Exo was isolated and introduced to a composite hydrogel including carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA) through chemical cross-linking, which formed an Exo-loaded (CMCS/OHA/Exo) hydrogel. The CMCS/OHA/Exo hydrogel exhibited a function of Exo sustained release and an Exo protection within 6 days. This CMCS/OHA/Exo hydrogel was much better than CMCS/OHA hydrogel or Exo solution in macrophage cell phagocytosis, proliferation and migration in vitro, especially, played an obviously positive role in the transformation of macrophages compared with the reference groups. For the treatment of the chronic inflammation wounds in vivo, the CMCS/OHA/Exo hydrogel had the best results at wound heal rate and inhibiting the secretion of inflammatory factors, and it was far superior to reference groups in wound re-epithelization and collagen production. CMCS/OHA/Exo hydrogels can promote Exo release based on hydrogel degradation to regulate macrophages transformation and accelerate chronic wound healing. The study offers a method for preparing Exo-loaded hydrogels that effectively promote the transformation of macrophages and accelerate chronic inflammatory wound healing.