Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment.

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

Prospect of value and application of transcutaneous electrical acupoint stimulation to control blood pressure in proactive healthcare perspective. / 主动健康视域下经皮穴位电刺激调控血压的价值与应用展望.

Hypertension is a global problem threatening human health and life. Although there are many antihypertensive drugs, the low compliance of medication affects its efficacy, and the effect in regulating hypertension has become increasingly prominent. Focusing on the new trend of proactive healthcare management, in the present paper, we made a summary about the status and existing problems of transcutaneous electrical acupoint stimulation (TEAS) in the regulation of blood pressure, and put forward some suggestions, such as selecting acupoints based on classical acupuncture theory to highlight the advantages of TEAS to control blood pressure as a whole, optimizing and screening the parameters of TEAS in the regulation of blood pressure, expanding the research observation indexes etc. We also made a prospect about its future application, hoping to provide new ideas for the proactive regulation, whole-process regulation and integrated regulation of blood pressure.

Dynamics of nutrients, sensory quality and microbial communities and their interactions during co-fermentation of pineapple by-products and whey protein.

In this study, a new fermented food was developed using pineapple by-products and whey protein (2.6%) as raw materials through the co-fermentation of autochthonous lactic acid bacteria and yeast. To better understand the fermentation mechanism and the impact of microorganisms on the entire fermentation system, we tracked the changes in carbohydrate and amino acid profiles, organoleptic quality and microbial community during the fermentation process. Compared with unfermented samples, dietary fiber and free amino acids increased significantly as fermentation proceeded. The fermented samples were significantly lower in astringency and bitterness and significantly higher in sourness, umami and richness. The fermented products were richer in volatile compounds with floral, cheesy, fruity and other flavors. Relevant analyses showed that the core microbial community was highly correlated with the quality attributes of the fermented products. Microorganisms such as Lactococcus, Weissella, Hanseniaspora, Saccharomyces and Lachancea contributed significantly to the fermented products.

Association between long-term ozone exposure and readmission for chronic obstructive pulmonary disease exacerbation.

The relationship between long-term ozone (O3) exposure and readmission for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains elusive. In this study, we collected individual-level information on AECOPD hospitalizations from a standardized electronic database in Guangzhou from January 1, 2014, to December 31, 2015. We calculated the annual mean O3 concentration prior to the dates of the index hospitalization for AECOPD using patients' residential addresses. Employing Cox proportional hazards models, we assessed the association between long-term O3 concentration and the risk of AECOPD readmission across several time frames (30 days, 90 days, 180 days, and 365 days). We estimated the disease and economic burden of AECOPD readmissions attributable to O3 using a counterfactual approach. Of the 4574 patients included in the study, 1398 (30.6%) were readmitted during the study period, with 262 (5.7%) readmitted within 30 days. The annual mean O3 concentration was 90.3 µg/m3 (standard deviation [SD] = 8.2 µg/m3). A 10-µg/m3 increase in long-term O3 concentration resulted in a hazard ratio (HR) for AECOPD readmission within 30 days of 1.28 (95% confidence interval [CI], 1.09 to 1.49), with similar results for readmission within 90, 180, and 365 days. Older patients (aged 75 years or above) and males were more susceptible (HR, 1.33; 95% CI, 1.10-1.61 and HR, 1.29; 95% CI, 1.09-1.53, respectively). The population attributable fraction for 30-day readmission due to O3 exposure was 29.0% (95% CI, 28.4%-30.0%), and the attributable mean cost per participant was 362.3 USD (354.5-370.2). Long-term exposure to elevated O3 concentrations is associated with an increased risk of AECOPD readmission, contributing to a significant disease and economic burden.

Exploration of Novel Meso-C═N-BODIPY-Based AIE Fluorescent Rotors with Large Stokes Shifts for Organelle-Viscosity Imaging.

The research on fluorescent rotors for viscosity has attracted extensive interest to better comprehend the close relationships of microviscosity variations with related diseases. Although scientists have made great efforts, fluorescent probes for cellular viscosity with both aggregation-induced emissions (AIEs) and large Stokes shifts to improve sensing properties have rarely been reported. Herein, we first report four new meso-C═N-substituted BODIPY-based rotors with large Stokes shifts, investigate their viscosity/AIE characteristics, and perform cellular imaging of the viscosity in subcellular organelles. Interestingly, the meso-C═N-phenyl group-substituted probe 6 showed an obvious 594 nm fluorescence enhancement in glycerol and a moderate 650 nm red AIE emission in water. Further, on attaching CF3 to the phenyl group, a similar phenomenon was observed for 7 with red-shifted emissions, attributed to the introduction of a phenyl group, which plays a key role in the red AIE emissions and large Stokes shifts. Comparatively, for phenyl-group-free probes, both the meso-C═N-trifluoroethyl group and thiazole-substituted probes (8 and 9) exhibited good viscosity-responsive properties, while no AIE was observed due to the absence of phenyl groups. For cellular experiments, 6 and 9 showed good lysosomal and mitochondrial targeting properties, respectively, and were further successfully used for imaging viscosity through the preincubation of monensin and lipopolysaccharide (LPS), indicating that C═N polar groups potentially work as rotatable moieties and organelle-targeting groups, and the targeting difference might be ascribed to increased charges of thiazole. Therefore, in this study, we investigated the structural relationships of four meso-C═N BODIPY-based rotors with respect to their viscosity/AIE characteristics, subcellular-targeting ability, and cellular imaging for viscosity, potentially serving as AIE fluorescent probes with large Stokes shifts for subcellular viscosity imaging.

Separation, enrichment and cytoprotection of antioxidant peptides from Xuanwei ham using aqueous two-phase extraction.

An ethanol/(NH4)2SO4 biphasic (aqueous two-phase) system was designed to effectively separate antioxidant peptides from Xuanwei ham, and its potential to prevent ultraviolet A-induced damage to skin cells was explored. Optimization via single factor experiments and response surface methodology revealed that under 20 % ethanol aqueous solution (w/w), 25.5 % (NH4)2SO4 aqueous solution (w/w), and pH 8.80 conditions, the optimal extraction ratio was 59.0 ± 1.73 %. In vitro antioxidant activity and cellular assays showed that the peptide purified in the upper phase exhibited strong antioxidant activity, increasing the viability of HaCat cells damaged by UVA irradiation from 56.14 ± 1.05 % to 66.3 ± 1.76 %. We used an in silico peptide screening strategy and identified 10 with potential antioxidant activity, emphasizing the important role of amino acids Pro, Gly, and Ala in antioxidant activity.

Comparative analysis of single-cell transcriptome reveals heterogeneity and commonality in the immune microenvironment of colorectal cancer and inflammatory bowel disease.

Background: During aging, chronic inflammation can promote tumor development and metastasis. Patients with chronic inflammatory bowel diseases (IBD) are at an increased risk of developing colorectal cancer (CRC). However, the molecular mechanism underlying is still unclear. Methods: We conducted a large-scale single-cell sequencing analysis comprising 432,314 single cells from 92 CRC and 24 IBD patients. The analysis focused on the heterogeneity and commonality of CRC and IBD with respect to immune cell landscape, cellular communication, aging and inflammatory response, and Meta programs. Results: The CRC and IBD had significantly different propensities in terms of cell proportions, differential genes and their functions, and cellular communication. The progression of CRC was mainly associated with epithelial cells, fibroblasts, and monocyte-macrophages, which displayed pronounced metabolic functions. In particular, monocyte-macrophages were enriched for the aging and inflammation-associated NF-κB pathway. And IBD was enriched in immune-related functions with B cells and T cells. Cellular communication analysis in CRC samples displayed an increase in MIF signaling from epithelial cells to T cells, and an increase in the efferent signal of senescence-associated SPP1 signaling from monocyte-macrophages. Notably, we also found some commonalities between CRC and IBD. The efferent and afferent signals showed that the pro-inflammatory cytokine played an important role. And the activity of aging and inflammatory response with AUCell analysis also showed a high degree of commonality. Furthermore, using the Meta programs (MPs) with the NMF algorithm, we found that the CRC non-malignant cells shared a substantial proportion of the MP genes with CRC malignant cells (68% overlap) and IBD epithelial cells (52% overlap), respectively. And it was extensively involved in functions of cell cycle and immune response, revealing its dual properties of inflammation and cancer. In addition, CRC malignant and non-malignant cells were enriched for the senescence-related cell cycle G2M phase transition and the p53 signaling pathway. Conclusion: Our study highlights the characteristics of aging, inflammation and tumor in CRC and IBD at the single-cell level, and the dual property of inflammation-cancer in CRC non-malignant cells may provide a more up-to-date understanding of disease transformation.

MRI quantitative assessment of the effects of low-carbohydrate therapy on Hashimoto's thyroiditis.

Objective: Hashimoto's thyroiditis is an inflammatory disease, and research suggests that a low-carbohydrate diet may have potential anti-inflammatory effects. This study aims to utilize Dixon-T2-weighted imaging (WI) sequence for a semi-quantitative assessment of the impact of a low-carbohydrate diet on the degree of thyroid inflammation in patients with Hashimoto's thyroiditis. Methods: Forty patients with Hashimoto's thyroiditis were recruited for this study and randomly divided into two groups: one with a normal diet and the other with a low-carbohydrate diet. Antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) were measured for all participants. Additionally, thyroid water content was semi-quantitatively measured using Dixon-T2WI. The same tests and measurements were repeated for all participants after 6 months. Results: After 6 months of a low-carbohydrate diet, patients with Hashimoto's thyroiditis showed a significant reduction in thyroid water content (94.84 ± 1.57% vs 93.07 ± 2.05%, P < 0.05). Concurrently, a decrease was observed in levels of TPOAb and TgAb (TPOAb: 211.30 (92.63-614.62) vs 89.45 (15.9-215.67); TgAb: 17.05 (1.47-81.64) vs 4.1 (0.51-19.42), P < 0.05). In contrast, there were no significant differences in thyroid water content or TPOAb and TgAb levels for patients with Hashimoto's thyroiditis following a normal diet after 6 months (P < 0.05). Conclusion: Dixon-T2WI can quantitatively assess the degree of thyroid inflammation in patients with Hashimoto's thyroiditis. Following a low-carbohydrate diet intervention, there is a significant reduction in thyroid water content and a decrease in levels of TPOAb and TgAb. These results suggest that a low-carbohydrate diet may help alleviate inflammation in patients with Hashimoto's thyroiditis.

Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury.

SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19. Our research, along with others', has demonstrated that mast cells (MCs) play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2. In previous study, we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice. Additionally, we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells, leading to subsequent lung injury. The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation, and inflammation in these regions could promote viral spread. MCs are widely distributed throughout the respiratory tract. Thus, in this study, we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium. Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2. MC degranulation caused lesions in trachea, and the formation of papillary hyperplasia was observed. Through transcriptome analysis in bronchial epithelial cells, we found that MC degranulation significantly altered multiple cellular signaling, particularly, leading to upregulated immune responses and inflammation. The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice. Taken together, our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions. Furthermore, our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation, thereby preventing tissue damage caused by hyper-inflammation.

The use of belimumab on patients with both systemic lupus erythematosus and immune thrombocytopenia: A retrospective cohort study.

OBJECTIVE: The objective of this study is to provide a description of a group of retrospective cohort outcomes in patients with systemic lupus erythematosus (SLE) complicated with immune thrombocytopenia (ITP) receiving belimumab. METHODS: This study reports on the treatment of 10 female patients (mean age 34.3 ± 14.0 years, mean weight 58.7 ± 18.2 kg) with both SLE and ITP who received belimumab in addition to basic drug therapy. The belimumab treatment regimen consisted of a dosage of 10 mg/kg, with an initial infusion every 2 weeks for the first 3 doses, followed by an infusion every 4 weeks. RESULTS: Ten patients were included in the study. The overall response rate of thrombocytopenia was 90% after treatment. The parameters such as platelet count, lymphocyte count, erythrocyte count, hemoglobin, dsDNA, C3, and C4 were significantly improved (p < .05). The SLE Disease Activity Index (SLEDAI), British Islet lupus Assessment Group 2004 (BILAG-2004), and Physician Global assessment (PGA) scores were significantly decreased (p < .05). There were no significant differences in glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), and serum creatinine (Scr) before and after treatment (p > .05). CONCLUSION: Belimumab shows promising clinical outcomes in the treatment on patients with both SLE and ITP. Further studies are needed to validate these findings in larger patient populations and compare the efficacy of belimumab with other treatments for SLE complicated with ITP. Long-term response rates and adverse events associated with belimumab treatment also warrant further investigation.

Inflammatory myofibroblastic tumor of the heart in an older woman with paroxysmal atrial fibrillation: a case report and review of the literature.

Inflammatory myofibroblastic tumors (IMTs) of the heart are rarely observed in the eldly. We report a case involving an elderly woman with an IMT situated on the right atrial wall. The tumor was fully excised. The patient had a smooth recovery post-surgery and remained free of recurrence for three years.

Contributing factors for pregnancy outcomes in women with PCOS after their first FET treatment: a retrospective cohort study.

OBJECTIVE: We aim to explore the contributing factors of clinical pregnancy outcomes in PCOS patients undergoing their first FET treatment. METHODS: A retrospective analysis was conducted on 574 PCOS patients undergoing their first FET treatment at a private fertility center from January 2018 to December 2021. RESULTS: During the first FET cycle of PCOS patients, progesterone levels (aOR 0.109, 95% CI 0.018-0.670) and endometrial thickness (EMT) (aOR 1.126, 95% CI 1.043-1.419) on the hCG trigger day were associated with the clinical pregnancy rate. Similarly, progesterone levels (aOR 0.055, 95% CI 0.007-0.420) and EMT (aOR 1.179, 95% CI 1.011-1.376) on the hCG trigger day were associated with the live birth rate. In addition, AFC (aOR 1.179, 95% CI 1.011-1.376) was found to be a risk factor for preterm delivery. CONCLUSIONS: In women with PCOS undergoing their first FET, lower progesterone levels and higher EMT on hCG trigger day were associated with clinical pregnancy and live birth, and AFC was a risk factor for preterm delivery. During FET treatment, paying attention to the patient's endocrine indicators and follicle status may have a positive effect on predicting and improving the pregnancy outcome of PCOS patients.

Regulation of depressive-like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala.

BACKGROUND AND PURPOSE: Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe that A-kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive-like behaviours in mice via a palmitoylation-dependent mechanism. EXPERIMENTAL APPROACH: Depressive-like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl-biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2-mediated AKAP150 palmitoylation signalling pathway in depressive-like behaviours. Electrophysiological recording, western blotting and co-immunoprecipitation were performed to define the mechanistic pathway. KEY RESULTS: Chronic stress successfully induced depressive-like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150-PKA interaction with the peptide Ht-31 abolished the CRS-induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS-induced depressive-like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS-treated mice. CONCLUSION AND IMPLICATIONS: These results delineate that DHHC2 modulates chronic stress-induced depressive-like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.

Fractional extraction of lignin from coffee beans with low cytotoxicity, excellent anticancer and antioxidant activities.

Lignin, a biopolymer generated from renewable resources, is widely present in terrestrial plants and possesses notable biosafety characteristics. The objective of this work was to assess the edible safety, in vitro antioxidant, and anti-cancer properties of various lignin fractions isolated from commercially available coffee beans often used for coffee preparation. The findings suggest that the phenolic hydroxyl content increased from 3.26 mmol/g (ED70L) to 5.81 mmol/g (ED0L) with decreasing molecular weight, which resulted in more significant antioxidant properties of the low molecular weight lignin fraction. The findings of the study indicate that the viability of RAW 264.7 and HaCaT cells decreased as the quantity of lignin fractions increased. It was observed that concentrations below 200 µg/mL did not exhibit any harmful effects on normal cells. The results of the study demonstrated a significant reduction of cancer cell growth (specifically A375 cells) at a concentration of 800 µg/mL for all lignin fractions, with an observed inhibition rate of 95 %. The results of this study indicate that the lignin extracts derived from coffee beans exhibit significant potential in mitigating diseases resulting from excessive radical production. Furthermore, these extracts show promise as natural antioxidants and anti-cancer agents.

Waste to Wealth: Dynamics and metabolic profiles of the conversion of jackfruit flake into value-added products by different fermentation methods.

Thus far, little is known about whether jackfruit flake, a byproduct of jackfruit, can be used as a fermentation substrate to obtain value-added products through microbial fermentation. Here, jackfruit flake puree was fermented by three different ways: spontaneous fermentation (JF), inoculated with LAB (JFL), inoculated co-fermentation with LAB and yeast (JFC). In contrast to JF, the total polyphenol and flavonoid content and syndrome-associated enzyme inhibition are significantly increased in JFC at the end of fermentation. Electronic tongue analysis revealed that the JFC was significantly lower in astringency and higher in bitterness. 41 volatile compounds were identified during fermentation by HS-SPME-GC-MS, and JFC was richer in honey, rose, and fruity flavors. A total of 290 compounds were screened for discriminative pre- and post-fermentation differential metabolites by non-target metabolomics analysis. These results provide a potential reference for the conversion of jackfruit waste into functional products using fermentation.

Effects of an explain-simulate-practice-communicate-support intervention on quality of life for patients with chronic heart failure: A randomized control trial.

Background: Patients with New York Heart Association (NYHA) grade III chronic heart failure (CHF) present with low capacity for daily activities, severe self-perceived burden, and poor quality of life. Effective nursing interventions may reduce patients' self-perceived burden and improve their quality of life. Objectives: To explore the effects of an explain-simulate-practice-communicate-support intervention on the self-perceived burden, cardiac function, and activities of daily living (ADL) ability in patients with New York Heart Association grade III chronic heart failure. Methods: Of the 100 patients with New York Heart Association grade III chronic heart failure who were electronically randomized and equally divided into control and intervention groups, data from 88 patients who completed our study were analyzed. The primary outcome was quality of life; secondary outcomes were self-perceived burden, 6-min walking test distances, serum N-terminal pro-brain natriuretic peptide levels, New York Heart Association cardiac function classification, and ability to perform activities of daily living. Results: After 12 weeks' intervention, the intervention group had significantly lower self-perceived burden, Minnesota Living with Heart Failure Questionnaire scores, N-terminal pro-brain natriuretic peptide levels, and New York Heart Association grades compared with the control group, while 6-min walking test distances, left ventricular ejection fraction, and modified Barthel Index scale scores were significantly higher than those in the control group (P > 0.05). Conclusions: The explain-simulate-practice-communicate-support intervention improved patients' quality of life through reducing the level of self-perceived burden, and improving cardiac function and activities of daily living ability. This intervention was found to be effective for patients with New York Heart Association grade III chronic heart failure.

Curvularin derivatives from the marine mangrove derived fungus Penicillium sumatrense MA-325.

Sumalarins D-G (1-4), four previously undescribed curvularin derivatives, along with two known related metabolites, curvularin (5) and dehydrocurvularin (6), were isolated and identified from the mangrove-derived fungus Penicillium sumatrense MA-325. Among them, sumalarin D (1) represents a unique example of curvularin derivative featuring a 5-methylfuran-2-yl-methyl group. Their structures were elucidated based on analysis of NMR and MS data as well as comparison of ECD spectra and quantum chemical calculations of NMR, and compound 1 was confirmed by X-ray crystallographic analysis. Compounds 1, 2, 5, and 6 are active against aquatic pathogenic bacteria Vibrio alginolyticus and V. harveyi with MIC values ranging from 4 to 64 µg/mL, while compound 6 is cytotoxic against tumor cell lines 5673, HCT 116, 786-O, and Hela with IC50 values of 3.5, 10.6, 10.9, and 14.9 µM, respectively.

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy.

PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.